WO2018219478A1 - Heteroaryl-carboxamides as histone demethylase inhibitors - Google Patents

Heteroaryl-carboxamides as histone demethylase inhibitors Download PDF

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Publication number
WO2018219478A1
WO2018219478A1 PCT/EP2017/063573 EP2017063573W WO2018219478A1 WO 2018219478 A1 WO2018219478 A1 WO 2018219478A1 EP 2017063573 W EP2017063573 W EP 2017063573W WO 2018219478 A1 WO2018219478 A1 WO 2018219478A1
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compound
carboxamide
bipyridine
alkyl
hydrogen
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PCT/EP2017/063573
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French (fr)
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Elena CARCELLER GONZÁLEZ
Alberto ORTEGA MUÑOZ
Jorge Salas Solana
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Oryzon Genomics, S.A.
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Priority to PCT/EP2017/063573 priority Critical patent/WO2018219478A1/en
Publication of WO2018219478A1 publication Critical patent/WO2018219478A1/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
    • C07D213/81—Amides; Imides
    • 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-carboxamides as described herein, useful as inhibitors of histone demethylases, such as KDMS.
  • 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 methyitransferases
  • KDMs histone lysine demethylases
  • RDMs arginine 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 KDMS 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 substituent (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 J JD2 and JARID1 families based on disubstituted pyridine compounds bearing at the 4-position a carboxy group (or a bioisoster thereof) 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 5 and N, and Z 4 and Z 5 are each independently selected from CR 3 and N, with the proviso that only one of Z 1 , Z 2 , Z 3 , Z 4 and Z s can be N;
  • R 1 and R 2 are each independently selected from hydrogen, C1.5 alkyl, &-s haloalkyl, -(C1-5 alkylene)-OR 6 , -(Cn alkylene)-NR 7 R 8 , -CN, -L 3 -carbocyclyl, -L 3 -aryl, -L 3 -heterocyclyi and -L 3 -heteroaryl, wherein the carbocyclyl in - L 3 -carbocyclyl, the aryl in -L 3 -aryl, the heterocyclyl in -L 3 -heterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R 9 ,
  • R 1 and R ? 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, C1-6 alkyl, C1-6 alkoxy, -OH, -NH2, -NH(Ci-s alkyl), and -N(Ci-s alkyl)?;
  • each R 3 is independently selected from hydrogen, halo, C-,.6 alkyl, C%6 haloalkyl, Ci s alkoxy, C1-6 hydroxyalkyl, -OH and -NH 2 ;
  • each R 5 is independently selected from hydrogen and halo
  • L 1 is C1-4 alkylene, C2-4 alkenylene or C2 alkynylene, wherein said C alkylene, said C2-4 alkenylene and said C2-4 alkynylene are optionally interrupted by 0, S or NR 11 , and wherein said C1-4 alkylene, said C2-4 alkenylene and said C2-4 alkynylene are optionally substituted with one or more R 13 ;
  • L 2 is C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene, wherein said Ci-e alkylene, said C2-6 alkenylene and said C2-6 alkynylene are optionally interrupted by 0, S or NR 11 , and wherein said d-6 alkylene, said C2-6 alkenylene and said d s alkynylene are optionally substituted with one or more R 13 ;
  • n and n are each independently selected from O and 1 ;
  • R 4 is -NR 1 R 15 or R 16 ;
  • R 7 and R 8 are each independently selected from hydrogen and Cn alkyl, or R 7 and R 8 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, d-e alkyl, -OH, -NH 2 , -NH(C, e alkyl), and -N(Ci, 3 alkyl) ? ;
  • each L 3 is independently selected from a bond and C1.4 alkylene
  • R 10 and R 11 are each independently selected from hydrogen, C1-6 alkyl and Ci s haloalkyl;
  • -R 12 - 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 12 - is linked to -(L 1 ) m - and -(L 2 ) n - R 4 in a 1 ,3-disposition;
  • each R 13 is independently selected from -e alkyl, halo, d-s haloalkyl, -L 3 -carbocyclyl, -L -aryl, -L 3 -heterocyclyl and -L 3 -heteroaryl, wherein the carbocyclyi in -L 3 -carbocyclyl, the aryl in -L 3 -aryl, the heterocyclyl in -L 3 - heterocyclyl and the heteroaryl in -IAheteroaryl are each optionally substituted with one or more R 17 , and wherein two groups R 13 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 Cu cycloalkyl and
  • R 14 and R 15 are each independently selected from hydrogen, C1 6 alkyl, d s haloalkyl, -(d- ⁇ a!kyiene)-OR 18 , -L 3 - carbocyclyi, -L 3 -aryi , -L 3 -hete rocyciy I and -LAheteroaryl, wherein the carbocyclyi in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyl in -LAheterocyciyl and the heteroaryl in -LAheteroaryl are optionally substituted with one or more R 19 ;
  • R 16 is a 3- to 18-membered saturated, partially saturated or aromatic heterocyclic group which contains one N atom and optionally contains one or more further heteroatoms selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 20 ;
  • each 9 , each R 17 , each R 19 and each R 24 is independently selected from Ci. 6 alkyl, Ci-e haloalkyl, halo, Ci e alkoxy, C,.
  • each R 21 is independently selected from d-e alkyl
  • each R 6 , each R 18 , each R 22 and each R 23 is independently selected from hydrogen and Ci s alkyl.
  • the compounds of Formula (I) as described herein are inhibitors of JmjC-KD s, particularly KD 5. These compounds, and pharmaceutical compositions comprising these compounds, are useful for the treatment of diseases associated with JmjC-KDMs, such as KDM5, including cancer or viral infections.
  • 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 in the treatment of a disease associated with KDM5.
  • 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 as a KDM5 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-KD .
  • 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 for treating a disease associated with KDM5, 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 of inhibiting KDM5 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 KDM5 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: wherein
  • Z 1 , Z 2 , and Z 3 are each independently selected from CR 5 and N, and Z 4 and Z 5 are each independently selected from CR 3 and N, with the proviso that only one of Z ⁇ Z 2 , Z 3 , Z 4 and Z 5 can be N;
  • R 1 and R 2 are each independently selected from hydrogen, Cw alkyl, Cu haloalkyl, - ⁇ C1 5 alkylene)-OR 6 , -(0-_ alkylene)-NR 7 R 8 , -CN, -L 3 -carbocyclyl, -L 3 -aryl, -L 3 -heterocyclyl and -L 3 -heteroaryl, wherein the carbocyclyl in - L 3 -carbocyc!yl, the aryl in -L 3 -aryl, the heterocyclyi in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R 9 ,
  • R 1 and R 2 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, C1.6 alkyl, C1-6 alkoxy, -OH, -NH2, -NH(Ci 6 alky!), and -N(Ci-6 alkyl)?;
  • each R 3 is independently selected from hydrogen, halo, Ci ⁇ alkyl, C1.5 haloalkyl, C -6 alkoxy, Ci e hydroxyalkyl, -OH and -NH 2 ;
  • each R 5 is independently selected from hydrogen and halo
  • L 1 is C1-4 alkylene, C24 alkenylene or C2-4 alkynylene, wherein said C alkylene, said C2.4 a!kenylene and said C2-4 alkynylene are optionally interrupted by 0, S or NR 11 , and wherein said C1.4 alkylene, said C2-4 alkenylene and said C 2 -4 alkynylene are optionally substituted with one or more R 13 ;
  • L 2 is C1-6 alkylene, CK. alkenylene or C26 alkynylene, wherein said C .6 alkylene, said C? 6 alkenylene and said C2-6 alkynylene are optionally interrupted by 0, S or NR 11 , and wherein said Ci-s alkylene, said C2-6 alkenylene and said C? 6 alkynylene are optionally substituted with one or more R 13 ;
  • n and n are each independently selected from 0 and 1 ;
  • R 4 is -NR 1 R 15 or R 16 ;
  • R 7 and R 8 are each independently selected from hydrogen and Ci-e alkyl, or R 7 and R 8 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, C1.5 alkyl, -OH, -NH 2 , -NH(Cu alkyl), and -N(&. 6 alkyl)?;
  • each L 3 is independently selected from a bond and C alkylene
  • R 10 and R 11 are each independently selected from hydrogen, C1-6 alkyl and C1 6 haloalkyi;
  • -R 12 - 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 12 - is linked to -(L - and -(L z ) n - R 4 in a 1 ,3-disposition;
  • each R 13 is independently selected from C1-6 alkyl, halo, d-e haloalkyi, -LAcarbocyclyl, -L 3 -ar l, -L 3 -heterocyclyl and -L 3 -heieroaryl, wherein the carbocyciyl in -LAcarbocyclyl, the aryl in -L 3 -aryl, the heterocyclyl in -L 3 - heterocyclyl and the heteroaryl in -L 3 -heteroaryl are each optionally substituted with one or more R 17 , and wherein two groups R 13 attached to a same C atom of the alkylene group are optionally linked together to form with said C atom a C 3 e 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
  • R 14 and R 15 are each independently selected from hydrogen, Ci-e alkyl, Ci-e haloalkyi, -(C1.6 alkylene)-OR 13 , -LA carbocyciyl, - LAary! -LAheterocyclyl and -L 3 -heteroaryl, wherein the carbocyciyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are optionally substituted with one or more R 19 ;
  • R 16 is a 3- to 18-membered saturated, partially saturated or aromatic heterocyclic group which contains one N atom and optionally contains one or more further heteroatoms selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 20 ;
  • each R 21 is independently selected from C1.5 alkyl
  • each R 6 , each R 18 , each R 22 and each R 23 is independently selected from hydrogen and Cu alkyl.
  • Compounds of this invention include those described above, and are further illustrated by the classes, subclasses, and species disclosed herein.
  • 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 5 and N
  • Z 4 and Z 5 are each independently selected from CR 3 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 5 in the case of Z 1 , 7?
  • a compound of formula (I) includes compounds of Formula (la), (lb), (Ic), (Id), (le) and (If):
  • 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 (Ic) as previously defined.
  • the present invention relates to a compound of any of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (il) 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 (Ib), or a salt thereof.
  • the compound of Formula (II) is a compound of Formula (ic), or a salt thereof. Accordingly, while various embodiments described herein below relate to a compound of Formula (I),
  • the compound specified in each one of these embodiments is a compound of Formula (II), i.e. a compound of formula (la), (Ib) or (Ic), or a salt thereof.
  • R 1 and R 2 are each independently selected from hydrogen, Cw alkyl, d-e haloalkyl, -(Ci-s alkylene)-OR 6 , -(Ci-e alkylene)-NR 7 R s , - L -carbocyclyl, -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 R 9 .
  • R 1 and R 2 are each independently selected from hydrogen, Ci.e alkyl and Ci-e haloalkyl.
  • R 1 is hydrogen
  • R 1 is hydrogen and R 2 is selected from hydrogen, CM alkyl and C-, s haloalkyl.
  • R 1 and R 2 are both hydrogen.
  • each R 3 is independently selected from hydrogen, halo, Ci 3 alkyl, Ci 3 haloalkyl and C1.3 hydroxyalkyl.
  • one of the groups R 3 is selected from hydrogen, halo, Ci 3 alkyl, Ci 3 haloalkyl and C1.3 hydroxyalkyl, and the remaining groups R 3 are hydrogen.
  • one of the groups R 3 is selected from hydrogen, fluoro, methyl, trifluoromethyl and -CH?OH, and the remaining groups R 3 are hydrogen.
  • each R 3 is hydrogen.
  • R 1 is hydrogen
  • R 2 is selected from hydrogen, Ci s alkyl and Ci-e haloalkyl, and preferably is hydrogen;
  • each R 3 is hydrogen.
  • one of the groups R 5 is selected from hydrogen and fluoro, and the remaining groups R 5 are hydrogen.
  • each R 5 is hydrogen. More preferably, in a compound of Formula (I), (ia), (lb), (lc), (Id), (le), (If) or (II), each R 3 and each R 5 is hydrogen.
  • L 1 is C1.4 alkylene, wherein said Cu alkylene is optionally interrupted by 0, S or NR 1 , and wherein said C alkylene is optionally substituted with one or more R 13 .
  • L 1 is (CH2 4, wherein said (CH 2 )u is optionally substituted with one or more (preferably one or two) R 13 .
  • L 1 is (CH 2 )u.
  • L 1 is (CH 2 )i.?.
  • L 1 is CH 2 .
  • L 2 is Cu; alkylene, wherein said C1.5 alkylene is optionally interrupted by 0, S or NR 11 , and wherein said C1-6 alkylene is optionally substituted with one or more R 13 .
  • L 2 is (CH?)i e, wherein said (CH?)i.s is optionally substituted with one or more (preferably one or two) R 13 .
  • L 2 is (CH 2 ) 2 -6, wherein said (Ch ⁇ -s is optionally substituted with one or more (preferably one or two) R 13
  • L 2 is (Ch ju, wherein said (CH2 4 is optionally substituted with one or more (preferably one or two) R 13 .
  • L 2 is (CH 2 ) 2 -4, wherein said (CH?) 2 -4 is optionally substituted with one or more (preferably one or two) R 13 .
  • L ? is (CH 2 )u, still more preferably (CH2) 2 -4, and even more preferably (Ch1 ⁇ 2)2-3.
  • m is selected from 0 and 1 , and n is 1.
  • m is selected from 0 and 1 , and preferably is 0; L 1 is (CH 2 )i ?, preferably CH 2 ; n is 1 ; and L 2 is (Ch1 ⁇ 2)i-4 wherein said (CH 2 )i-4 is optionally substituted with one or more (preferably one or two) R 13 , and preferably L 2 is (CH2)i- .
  • n 1 and L 2 is C2-6 alkylene (preferably wherein said C2-5 alkylene (or said (CH?)? 5) is optionally interrupted by 0, S or NR 11 , and wherein said C2-6 alkylene (or said (CH 2 )2-6 is optionally substituted with one or more R 13 .
  • n 1 and L 2 is (CH 2 ) 2 -6, wherein said (CH ? ) 2 .
  • S is optionally substituted with one or more R 13 .
  • the Cu alkylene, C2-4 alkenylene and C2-4 alkynylene in L 1 and the C alkylene, C2-6 alkenylene and C2-5 alkynylene in L 2 can be optionally substituted with one or more R 13 .
  • each R 13 is independently selected from C1.5 alkyl, halo, Ci- 6 haloalkyl, -LAcarbocyclyl, -L 3 -aryl, -L 3 -heierocyclyl and -LAheteroaryl, wherein the carbocyclyl in -LA carbocyclyl, the aryl in -L 3 -aryl, the heterocyciyl in -U-heterocyclyl and the heteroaryi in -L 3 -heteroaryl are each optionally substituted with one or more R 17 .
  • two groups R 13 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 C3-6 cycloalkyi and 4- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from halo and Ci s alkyl.
  • Examples of said Ca-6 cycloalkyi or 4- to 6-membered heterocyclic ring formed by said two R 13 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 Cj-s alkyl.
  • each R 13 is independently selected from d-c alkyl and -LAaryi, wherein the aryl in -lAaryl is optionally substituted with one or more R 17 .
  • said aryl is phenyl optionally substituted with one or more R".
  • -R 12 - 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 12 - is linked to the -(L 1 ) m - and -(L 2 ) n -R 4 group in a 1 ,3-disposition. Examples of such -R 12 - 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' 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 12 - is a group selected from Table 1. In some embodiments, -R 12 - is
  • Y is -NR 11 -.
  • Y is -0-.
  • Y is -CH 2 -.
  • Y is selected from -NR 11 -, - 0- and -CHr.
  • R 10 is hydrogen.
  • R 11 is hydrogen
  • Y is
  • Y is selected from -
  • m is selected from 0 and 1 ;
  • n is 1 ;
  • L 1 is (CHj)i ?; and L 2 is (CH2)i-s, wherein said (CH2)i-6 is optionally substituted with one or more (preferably one or two) R 13 ; with the proviso that when Y is -NR 11 - or -0- and R 4 is -NR 14 R 15 or N-!inked-R 15 , then V is (CH 2 ) 2 . 6 , wherein said (CH 2 ) 2 6 is optionally substituted with one or more (preferably one or two) R 13 .
  • n is 1 ;
  • Y is selected from -NR 11 -, -0- and -CH 2 -; m is selected from 0 and 1 , and preferably is 0; n is 1 ; L 1 is (CH?)i ?; and L 2 is (CH?)i 6, wherein said (CH 2 )i_6 is optionally substituted with one or more (preferably one or two) R' 3 , with the proviso that when Y is -NR 11 - or -0- and R 4 is -NR 14 R 15 or N-linked-R 15 , then L 2 is (CH 2 )M, wherein said (CH 2 ) 2 . 6 is optionally substituted with one or more (preferably one or two) R 13 .
  • Y is selected from -NR 11 -, -0- and -CH 2 -; m is selected from O and 1 , and preferably is 0; n is 1 ; V is CH3 ⁇ 4 and L 2 is (CH 2 )i-4, wherein said (CH?)i., is optionally substituted with one or more (preferably one or two) R 13 , with the proviso that when Y is -NR 11 - or -0- and R 4 is -NR 14 R « or N-linked-R 15 , then L 2 is (CH 2 ) 2 -4, wherein said (CH 2 ) 2 -4 is optionally substituted with one or more (preferably one or two) R 13 . While Y is selected from -NR 11 -, -0- and -CH 2 - and m is selected from 0 and 1 , it is preferred that when Y is selected from -NR 11 -, -0- and -CH 2 - and m is selected from 0 and 1 , it is preferred that when
  • Y is -
  • Y is -NR 11 -; m is selected from 0 and 1, and preferably is O; n is 1 ; L 1 is CH 2 ; and L 2 is (CH 2 )i./ court wherein said (CH?)u is optionally substituted with one or more (preferably one or two) R 13 , with the proviso that when R 4 is -NR 14 R 15 or N-linked- R 16 , then L 2 is (CH 2 ) 2j4 , wherein said (CH 2 ) 2 . 4 is optionally substituted with one or more (preferably one or two) R 1
  • Y is -
  • Y is -0-; m is selected from 0 and 1 ; n is 1 ; L 1 is CH 2 ; and L 2 is (CH 2 )i-4, wherein said (CH 2 )u is optionally substituted with one or more (preferably one or two) R 13 , with the proviso that when R 4 is -NR 1 R 15 or N-linked-R 16 , then L 2 is (CH 2 )2-4, wherein said (CH 2 ) 2 .4 is optionally substituted with one or more (preferably one or two) R 13 .
  • Y is -CH2-; m is 0; n is 1 ; and L 2 is (CH2)i-6, wherein said (CH2H6 is optionally substituted with one or more (preferably one or two) R 13 .
  • Y is -CH2-; m is 0; n is 1 ; and L 2 is (CH2)?- , wherein said (CH 2 )2-4 is optionally substituted with one or more (preferably one or two) R 13 .
  • any aikylene in the above groups can be optionally substituted with one or more (preferably one or two) R 13 as defined above.
  • Examples of groups in table 2 wherein such aikylene groups are substituted with one or more R 13 are provided in Table 3 below: able 3:
  • -(L 1 ) m -Y-(L 2 ) n - is selected from the groups listed in Table 2 or Table 3.
  • a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), -(U)m-Y-(L 2 )n- is selected from the groups listed in Table 4, below:
  • R 10 is hydrogen and R 11 is hydrogen.
  • -(L 1 ) m -Y-(L 2 ) n - is selected from the following list:
  • -(L 1 ) m -Y-(L 2 ) n - is selected from the following list:
  • R 4 is -NR 14 R 15 .
  • R 14 and R 15 are each independently selected from hydrogen, O-e alkyl, Ci s haloalkyl (preferably Cu fluoroalkyl), -(C alkylene)- OR 18 , -L 3 -carbocyclyl, -(CH2)i-4-aryl, and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocycly!, the aryl in - (CH2)i-4-aryl, and the heteroaryi in -LAheteroaryl are optionally substituted with one or more R 19 .
  • said aryl in -(CH?) -aryl is phenyl optionally substituted with one or more R 19 .
  • said carbocyclyl in - LAcarbocyclyl is C3-7 cycloalkyi optionally substituted with one or more R 19 .
  • R 14 and R 15 are each independently selected from hydrogen, Ci-e alkyl, C1 5 haloalkyl (preferably u fluoroalkyl), -(Ci-s alkylene)- OR 18 , -L 3 -Cj 7 cycloalkyi, -(CH?)i 4-phenyi and -L 3 -heteroaryl, wherein the C3.7 cycloalkyi in the -LAC3.7 cycloalkyi is optionally substituted with one or more groups independently selected from Ci e alkyl and halo, and the phenyl in -(CH2)i.4-phenyl and the heteroaryl in -L 3 -heteroaryl are each optionally substituted with one or more R 19 .
  • R 14 and R 15 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl (preferably Ci e fluoroalkyl), -IAC3-7 cycloalkyi, and -(CH2)i-4-phenyl, wherein the C3.7 cycloalkyi in the -LAC37 cycloalkyi is optionally substituted with one or more groups independently selected from Ci.$ alkyl and halo, and the phenyl in - ⁇ Chkju-phenyl is optionally substituted with one or more R 19 .
  • R 14 and R 15 are each independently selected from d.s alkyl and -(CH 2 )i-4-phenyl, wherein the phenyl in -(CH ⁇ )i-4-phenyi is optionally substituted with one or more R 19 .
  • said phenyl in said in -(CH?)i , -phenyl groups is unsubstituted.
  • R 14 and R 15 are each independently selected from hydrogen, methyl, ethyl, 2,2,2-trifiuoroethyl, C3-7 cycloalkyi, -CH2-C3-7 cycloalkyi, and -(CHjJi 2-phenyl, wherein the C3.7 cycloalkyi and the C3-7 cycloalkyi in the -CH2-C3-7 cycloalkyi are optionally substituted with one or more groups independently selected from Ci e alkyl and halo, and the phenyl in -(CH 2 )i-2-phenyl is optionally substituted with one or more R 19 .
  • R 4 is R 16 .
  • R 15 is a 3- to 18-membered saturated, partially saturated or aromatic heterocyclic group which contains one N atom and optionally contains one or more, preferably from 1 to 4, further heteroatoms selected from N, 0 and S.
  • Said heterocyclic group can be monocyclic or muiticyciic (e.g. fused, bridged or spiro rings, or a combination thereof).
  • R 16 can be attached to the rest of the molecule through any C or N atom that results in a stable structure; as used in the present specification, "C- linked-R 16 " means that a R 16 group that is linked to the remainder of the molecule through a C atom and "N- linked-R 16 " means a R 16 group that is linked to the remainder of the molecule through a N atom.
  • Any R 1S is optionally substituted with one or more R 20 , which can be the same or different and can be placed at any available position.
  • R 4 is -NR 14 R ⁇ or R 16 , wherein R 16 is a saturated 3- to 18-membered heterocyclic group which contains one N atom and optionally contains one or more, preferably one or two, further heteroatoms selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 20 .
  • said R 16 is N-linked-R 16 .
  • R 4 is R ,6 and R 16 is a saturated 3- to 18-membered heterocyclic group which contains one N atom and optionally contains one or more, preferably one or two, further heteroatoms selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 20 .
  • said R 16 is N-linked-R 16 .
  • R 4 is R 16 and R 16 is a saturated 4- to 7-membered heterocyclic group which contains one N atom and optionally contains one further heteroatom selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 20 .
  • each R 20 is independently selected from fr.s alkyl, C haloalkyl and halo.
  • said R 16 is N- linked-R 16 .
  • R 4 is R 16 and R 15 is selected from piperidinyl, pyrrol id inyl and morpholinyl, wherein R 15 is optionally substituted with one or more R 20 .
  • each R 20 is independently selected from CM alkyl, Cv 6 haloalkyl and halo.
  • R 4 is R 16 and R 16 is selected from 1 -piperidinyl, 1-pyrrolidinyi and 1 -morpholinyl, wherein R 16 is optionally substituted with one or more R 20 .
  • each R 20 is independently selected from C1.5 alkyl, C1.5 haloalkyl and halo.
  • R 4 is 1 -morpholinyl.
  • R 4 is 1-piperidiny optionally substituted with one or more groups independently selected from Ci-s alkyl, 0.6 haloalkyl and halo. It is particularly preferred that R 4 is 1 -piperidinyl substituted with one or more (preferably one or two) fluoro, and more preferably R 4 is 4,4-difluoro- 1 -piperidinyl.
  • the invention provides a compound of Formula (I), (la), (lb), (Ic), (Id), (le),
  • R 1 and R 2 are each independently selected from hydrogen, Ci. s alkyl and O r. haloalkyl, preferably R 1 is hydrogen and R 2 is selected from hydrogen, Ci. 6 alkyl and O e haloalkyl, and more preferably R 1 and R 2 are both hydrogen;
  • each R 3 is hydrogen
  • each R 5 is independently selected from hydrogen and halo (preferably fluoro), and preferably each R 5 is hydrogen;
  • U is (CH2)i-2, wherein said (CH 2 )i-2 is optionally substituted with one or more (preferably one or two) R 13 , and preferably L 1 is (CH?)y?; and
  • L 2 is (CH?)i 6, wherein said (CH?)i s is optionally substituted with one or more (preferably one or two) R 13 .
  • the invention provides a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably of Formula (II), or a salt thereof, wherein:
  • R 1 and R 2 are both hydrogen; each R 3 and each R 5 is hydrogen;
  • L 1 is (CH2)i-2, wherein said (Chfe) ⁇ is optionally substituted with one or more (preferably one or two) R 13 , preferably L 1 is (CH?)i ? and more preferably L 1 is CH2; and
  • L 2 is (CH2)i , wherein said (CH 2 )i-4 is optionally substituted with one or more (preferably one or two) R 13 ; with the proviso that when Y is -NR 11 - or -0- and R 4 is -NR 14 R 15 or N-linked-R 16 , then n is 1 and L 2 is (CH?)? 4, wherein said (CH 2 ) 2 -4 is optionally substituted with one or more (preferably one or two) R 13 .
  • the invention provides a compound of Formula (I), (la), (lb), (Ic), (Id),
  • R 1 and R 2 are both hydrogen
  • each R 3 and each R 5 is hydrogen
  • 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 13 , preferably L 1 is (CH2 2 and more preferably L 1 is CH2 and
  • L 2 is (CH 2 )i-4, wherein said (Chbjw is optionally substituted with one or more (preferably one or two) R 13 ; with the proviso that when Y is -NR 11 - or -0- and R 4 is -NR 14 R 15 or N-linked-R 1 ' 3 , then L 2 is (CH ? ) ? . , wherein said
  • (CH 2 )2 is optionally substituted with one or more (preferably one or two) R 13 .
  • the invention provides a compound of Formula (I), (la), (lb), (Ic), (Id),
  • R 1 and R 2 are both hydrogen
  • each R 3 and each R 6 is hydrogen
  • any aikylene depicted in the above groups is optionally substituted with one or more, preferably one or two, R 13 , and preferably -(L 1 ) m -Y-(L 2 )n- is selected from
  • -(L 1 ) m -Y-(L 2 ) n - is selected from:
  • R 4 is -NR 14 R 15 or N-linked-R 16 .
  • the invention provides a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably of Formula (II), or a salt thereof, wherein:
  • R 1 and R 2 are both hydrogen
  • each R 3 and each R 5 is hydrogen
  • L 2 is (CH2)i , wherein said (CH?)u is optionally substituted with one or more (preferably one or two) R 13 ; with the proviso that when Y is -NR 11 - or -0- and R 4 is -NR 14 R 15 or N-linked-R 1 * then n is 1 and L 2 is (CH 2 ) 2 -4, wherein said (CH? ⁇ is optionally substituted with one or more (preferably one or two) R 13 ; and
  • R 4 is -NR 14 R 15 or R 16 , wherein R 16 is a saturated 3- to 18-membered heterocyclic group which contains one N atom and optionally contains one or more, preferably one or two, further heteroatoms selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 20 ,
  • said R 16 is a saturated 4- to 7- membered heterocyclic group which contains one N atom and optionally contains one further heteroatom selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 20 ; more preferably said R 16 is selected from 1-piperidinyl, 1-pyrro!idinyl and 1-morpholinyl, wherein R 16 is optionally substituted with one or more R 20 , wherein preferably each R 20 is independently selected from Ci-e alkyi, Ci-e haloalkyl and halo. It is particularly preferred that R 13 is 1-piperidinyl substituted with one or more (preferably one or two) fluoro
  • the invention provides a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably of Formula (II), or a salt thereof, wherein:
  • R 1 and R 2 are both hydrogen
  • each R 3 and each R 5 is hydrogen
  • any alkylene depicted in the above groups is optionally substituted with one or more, preferably one or two, R 13 , and preferably -(L 1 ) m -Y-(L 2 ) n - is selected from
  • R 4 is -NR 1 R 15 or R 15 , wherein R 15 is a saturated 3- to 18-membered heterocyclic group which contains one N atom and optionally contains one or more, preferably one or two, further heteroatoms selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 20 .
  • said R 16 is N-linked-R 16 .
  • R 16 is a saturated 4- to 7-membered heterocyclic group which contains one N atom and optionally contains one further heteroatom selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 20 , and more preferably said R 16 is selected from 1-piperidinyi, 1-pyrrolidinyl and 1-morpholinyl, wherein R 16 is optionally substituted with one or more R 20 , wherein preferably each R 20 is independently selected from Cw alkyl, Ci.& haloalkyl and halo. It is particularly preferred that R 16 is 1-piperidinyi substituted with one or more (preferably one or two) fluoro, and more preferably R 16 is 4,4-difluoro-1-piperidinyl.
  • the invention provides a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably of Formula (II), or a salt thereof, wherein:
  • R 1 and R 2 are both hydrogen
  • each R 3 and each R 5 is hydrogen
  • n 0;
  • n is selected from 0 or 1 ,
  • L 2 is (Cti?)ii, wherein said (CH 2 )i- 4 is optionally substituted with one or more (preferably one or two) R 13 ;
  • R j S -N 1 R15 or Rio wherein R 16 is a saturated 3- to 18-membered heterocyclic group which contains one N atom and optionally contains one or more, preferably one or two, further heteroatoms selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 20 , In some embodiments, said R 16 is C-iinked-R 16 . In some embodiments, R 16 is 3-piperidinyl, 4-piperidinyl or 3-pyrrolidinyl, wherein R 16 is optionally substituted with one or more R 20 .
  • a preferred group of compounds of the invention corresponds to those compounds of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably of Formula (II), or a salt thereof, wherein:
  • R 1 and R 2 are each independently selected from hydrogen, Ci e alkyl and Ci-s haloalkyi, preferably R 1 is hydrogen and R 2 is selected from hydrogen, Ci e alkyl and C1-3 haloalkyi, and more preferably R 1 and R 2 are both hydrogen;
  • each R 3 and each R 5 is hydrogen
  • Y is selected from -NR 11 -, -0- and -CH 2 -,
  • n is selected from 0 and 1 , with the proviso that when m is 1 then Y is -0-, and preferably m is 0;
  • n 1 ;
  • Y is CH 2 ;
  • L 2 is (CH?)i , preferably (CH 2 ) 2 - 3 ;
  • R" is -NR 14 R 15 or R 16 ;
  • R 14 and R 15 are each independently selected from hydrogen, 0-s alkyl, Ci-e haloalkyi (preferably Ci-s fiuoroalkyl), -LAC3-7 cycloalkyl, and -(CH 2 )i 4 -phenyl, wherein the C3.7 cycloaikyl in the -L 3 -Ca.7 cycloalkyl is optionally substituted with one or more groups independently selected from Ci-s alkyl and halo, and the phenyl in -(CH 2 )i 4-phenyl is optionally substituted with one or more R ,s ; and
  • R 16 is a saturated 4- to 7-membered heterocyclic group which contains one N atom and optionally contains one further heteroatom selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 20 , wherein preferably each R 20 is independently selected from C1.5 alkyl, C1..3 haloalkyi and halo, and wherein said
  • R 16 is N-linked-R 16 . It is preferred that R 4 is 1-piperidinyl substituted with one or more (preferably one or two) fluoro, and more preferably R 4 is 4,4-difiuoro-1-piperidinyl.
  • Another preferred group of compounds of the invention corresponds to a compound of Formula (I), (la), (lb). (Ic), (Id), (le), (If) or (II), preferably of Formula (II), or a salt thereof, wherein:
  • R 1 and R 2 are each independently selected from hydrogen, Ci s alkyl and C1.6 haloalkyi, preferably R 1 is hydrogen and R 2 is selected from hydrogen, Crg alkyl and C1-6 haloalkyi, and more preferably R 1 and R 2 are both hydrogen;
  • each R 3 is hydrogen
  • each R 5 is independently selected from hydrogen and halo (preferably fluoro), and preferably each R 5 is hydrogen;
  • L 1 is (CH 2 )i-2, wherein said (CH 2 )i- 2 is optionally substituted with one or more (preferably one or two) R 13 , and preferably L 1 is (CH 2 )i. 2 ;
  • L 2 is (CH2)i-6, wherein said (CH2)i-6 is optionally substituted with one or more (preferably one or two) R 13 , preferably L 2 is (CH?)i.-i, and more preferably (CH?)? 3 ;
  • R 4 is 1-piperidinyl substituted with one or more (preferably one or two) fluoro, and preferably R 4 is 4,4-difluoro-
  • a particularly preferred group of compounds of the invention corresponds to those compounds of
  • R 1 and R 2 are each independently selected from hydroge Ci-e alkyl and Ci e haloalkyl, preferably R 1 is hydrogen and R 2 is selected from hydrogen, Cve alkyl and C 6 haloalkyl, and more preferably R 1 and R 2 are both hydrogen;
  • each R 3 and each R 5 is hydrogen
  • Y is selected from -NR 1 -, -0- and -CH 2 -;
  • n is selected from 0 and 1 , with the proviso that when m is 1 then Y is -0-, and preferably m is 0;
  • n 1 ;
  • L 1 is CH 2 :
  • L 2 is (CH 2 )i-4, preferably (CH 2 ) 2 . 3 and
  • R 4 is 1-piperidinyl substituted with one or more (preferably one or two) fluoro, and preferably R 4 is 4,4-difluoro- 1-piperidinyl.
  • the invention provides a compound of Formula (I) or a salt thereof, selected from:
  • the invention provides a compound of Formula (I) selected from the compounds listed in Table 5, or a salt thereof:
  • the invention provides a compound of Formula (I) selected from the compounds listed in Table 6, or a salt thereof:
  • aryl, heteroaryl, carbocyclyl and heterocyclyl groups are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency.
  • pyridyl (or pyridinyl) may refer to a pyridin-2- yl, pyridin-3-yl or pyridin-4-yl ring
  • piperidinyl may refer to a piperidin-1-yl, piperidin-2-yl, piperidin-3-yl or piperidin-4-yl ring.
  • n-membered where n is an integer describes the number of ring-forming atoms in a ring system where the number of ring-forming atoms is n.
  • phenyl is an example of a 6-membered aryl
  • cyclopropyl is an example of a 3-membered carbocyclyl
  • pyrazolyl is an example of a 5-membered heteroaryl
  • quinolinyl is an example of a 10-membered heteroaryl
  • piperidinyl is an example of a 6-membered heterocyclyl
  • decahydroquinolinyl is an example of a 10-membered heterocyclyl.
  • C y . z where y and z are integers, used in combination with a chemical group, designates a range of the number of carbon atoms in the chemical group, with y and z being the endpoints, which are included. Examples include C1-4, 0-6, Cn, C3-7 and the like.
  • C y 7 alkyl refers to a saturated straight or branched acyclic hydrocarbon group having y to z carbon atoms.
  • a 0 * alkyl is an alkyl having from one to six carbon atoms.
  • Examples of C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, or sec-hexyl.
  • a 0-3 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 y . z alkoxy" refers to an C y . z alkyl group (as defined above) covalently linked to an oxygen atom, i.e. a group of formula -O-alkyl where the alkyl group has y to z carbon atoms.
  • the term Cvs alkoxy thus refers to an alkoxy group wherein the alkyl moiety has from 1 to 6 carbon atoms.
  • C1-6 alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert- butoxy, n-pentoxy or n-hexyloxy.
  • C1.3 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 C1-6 alkylene is an alkylene having from one to six carbon atoms
  • a C/ 6 alkylene is an alkylene having from two to six carbon atoms
  • a Cu alkylene is an alkylene having from one to four carbon atoms.
  • said akylene groups are polymethylene groups, i.e. (Chbjx, 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 . 2 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 C2 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 alkynylene is an alkynylene having from two to six carbon atoms
  • a C? .i 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 multicyclic (e.g. fused, bridged or spiro rings), wherein at least one of the rings in the ring system is aromatic.
  • Aryl as used herein thus covers fully aromatic hydrocarbon ring systems, i.e. where all the ring(s) in the system are aromatic, like phenyl, naphthyl or anthracyl, as well as ring systems in which an aromatic hydrocarbon ring (e.g.
  • phenyl is fused to one or more non-aromatic hydrocarbon rings, like indanyl, indenyl, 1-oxo-2,3-dihydro-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 cycioalkyi 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycbpentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, bicycto[2.2.1]heptanyl, bi cyclo [2.2.2]octany I , 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 cycioalkyi refers to a monocyclic cycioalkyi having from y to z ring-forming carbon atoms.
  • a C3.7 cycioalkyi has 3 to 7 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a C3-6 cycioalkyi has from 3 to 6 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycioalkyi 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 haloaikyl refers to an aikyl 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 haloaikyl is a C1-6 alkyl which is substituted one or more times with one or more halo, and a CM haloaikyl is a C1-3 alkyl which is substituted one or more times with one or more halo.
  • Haloaikyl groups include perhaloalkyl groups, i.e. alkyl groups where all hydrogen atoms are replaced by halo.
  • haloaikyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1-fluoro- 2-fluoroethyl, pentafiuoroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, chloromethyl, dichloromethyl, trichloromethyi difluorochloromethyi, dichlorofluoromethyl, 1 ,2-dichloroethyl, 3,3-dichloropropyl and the like.
  • the haloaikyl is a fluoroalkyl, i.e. an alkyl group which is substituted one or more times with one or more fluoro.
  • C - Z haloalkoxy refers to an haloaikyl group having y to z carbon atoms as defined herein covalently linked to an oxygen atom, i.e. a group of formula -0-C y - z haloaikyl.
  • a Ci-s haloalkoxy group thus refers to a haloalkoxy group wherein the haloaikyl moiety has from 1 to 6 C atoms.
  • 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 imidazotyl, 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-tetrahydroquinoiine, 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.
  • the heteroaryl group is fully aromatic.
  • Nonlimiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl, pyrrolyl, imidazoly!, pyrazolyl, oxazolyl, thiazolyi, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazine, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, phthalazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazoly
  • 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 sp ' iro rings) which comprises, in addition to C atoms, from 1 to 6 heteroatoms independently selected from N, 0 and S.
  • Heterocyclyl as used herein also includes groups in which a partially or fully saturated heterocyclic ring is fused to one or more phenyl rings, as in 1 ,2,3,4- tetrahydroquinolinyl, benzodioxolyl, carbazolyl or phthaiimidyi.
  • the heterocycyl 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, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahyd rof u ra n I , tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, homopiperidinyl, oxepanyl, thiepanyl, 2H-pyranyl, 4H-pyranyi, dioxanyl, 1 ,3-dioxolanyl, dithian l, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrrolinyl, pyrazolinyl, pyrazolid
  • 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 Cn hydroxyalkyl is a Ci-e alkyl which is substituted one or more times with one or more hydroxy and a C1-3 hydroxyalkyl is a C1.3 alkyl which is substituted one or more times with one or more hydroxy
  • hydroxyl or "hydroxy” refers to -OH.
  • optionally interrupted means that the respective alkylene, alkenylene, alkynylene or ((3 ⁇ 4)* group is uninterrupted or is interrupted between adjacent carbon atoms by a heteroatom selected from 0 and S or a heterogroup NR 11 , i.e. an 0, S or NR 11 is placed between two adjacent carbon atoms in the alkylene, aikenylene, alkynylene or ⁇ C ?) X group.
  • Optionally interrupted as used herein also includes alkylene, alkenylene, alkynylene or (Chfejx groups where the heteroatom or heterogroup (i.e.
  • an optionally interrupted C alkylene group includes groups such as - CH 2 OCH 2 CH2CHr, -OCH2CH2CH2CH2- and -NR 11 CH2CH 2 CH 2 CH2-.
  • 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 unsaturation, but is not intended to include aryl or heteroaryl groups, as herein defined.
  • 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-enol 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 isotopscafly labeled forms thereof.
  • Isotopically labeled forms of the compounds are compounds that differ only in the replacement of one or more atoms by a corresponding isotopically enriched atom.
  • isotopes that can be incorporated into compounds of the invention include for example isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F, 36 CI, and 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, hydrobromkJes, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, nitrates, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1 ,4 dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxy
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine and the like.
  • the pharmaceutically acceptable salts of the present invention can be prepared from the parent compound which contains a basic or acidic moiety by conventional chemical methods. For example, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in a suitable solvent.
  • compounds of the present invention may exist in hyd rated or unhyd rated (anhydrous) form or as solvates with other solvent molecules.
  • “Solvate” as used herein means solvent addition forms that contain either stoichometric or non-stoichometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate.
  • Non-limiting examples of solvates include hydrates and solvates with alcohols (also named alcoholates) such as ethanol (ethanolates).
  • solvates thereof are intended to be included in the scope of the present invention, particularly pharmaceutically acceptable solvates.
  • a "pharmaceutically acceptable solvate” is a solvate formed with a pharmaceutically acceptable solvent.
  • Pharmaceutically acceptable solvents are well known in the art and include solvents such as water and ethanol.
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , R 1 , R 2 , R 3 , R 4 L 1 , L 2 , Y, m and n have the same meaning described for compound of Formula (I),
  • A is COORa or CN
  • Ra is Cn alkyl or aryl-Cu alkyi, preferably methyl, ethyl or benzyl
  • M and X have the meaning defined below.
  • the first step involves a cross-coupling reaction of a heteroaryl organometallic species with a heteroaryl halide.
  • Organometallic intermediates can be generated either on the heteroaryl bearing the COOR a or CN substituent (i.e. a compound of Formula (Ilia) or (lllb) ), or in the heteroaryl bearing the -(L 1 ) m -Y-(L 2 ) R 4 substituent (i.e. a compound of Formula (VII) ).
  • the ester or cyano group in a compound of Formula (Va) and (Vb), respectively is transformed into an amido group -CONRW to give a compound of Formula (I),
  • cross-coupling reactions can be used for the first step in Scheme 1 , including: a Suzuki cross coupling where M is a boronic acid or boron derivative and X is CI, Br or I; a Stille reaction where M is tnalkylstannanyi group and X is Ci, Br or I; a Negishi coupling where M is a zinc halide and X is triflate, CI, Br or I; and a Hiyama coupling where M is a trialkylsily! 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(PPh 3 )4, in the presence of a suitable Cu salt such as Cu(OAc)2 or Cul, in a suitable solvent such as tetrahydrofuran or dimethylformamide, using a suitable base such as potassium carbonate.
  • a suitable Pd/ligand combination such as XPhos and Pd2(dba)3 or Pd(PPh 3 )4
  • a suitable Cu salt such as Cu(OAc)2 or Cul
  • a suitable solvent such as tetrahydrofuran or dimethylformamide
  • 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 1 h to 48h.
  • boronic derivatives include diethyl, dimethyl, N-methyliminodiacetic acid (MIDA) derivative and 2,2'-(phenylazanedi
  • the reaction can be performed using a suitable Pd/ligand combination such as Pd(PPh 3 ) 4 , Pd(PPh 3 )CI 2 or Pd(dppb)CI 2 in the presence of a suitable Cu salt such as Cul or CuO, in the presence or absence of CsF, in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • a suitable Cu salt such as Cul or CuO
  • CsF tetrahydrofuran, dioxane or dimethylformamide
  • the temperature of the reaction can go from room temperature to 120°C and the time of reaction from 1 h to 48h.
  • the organotin employed can be trimethy!stanny! derivative.
  • An intermolecular Stille Kelly reaction can also be used, in which both reagents are haloheteroaryls and are treated with (Bu 3 Sn) 2 , EUNI, and a Pd/ligand combination.
  • the reaction can be performed using a suitable Pd/ligand combination such as PPh 3 and Pd 2 (dba) 3 , XPhos and Pd 2 (dba) 3 , RuPhos and Pd 2 (dba) 3 or Pd(PPh 3 ) 4 , in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • a suitable Pd/ligand combination such as PPh 3 and Pd 2 (dba) 3 , XPhos and Pd 2 (dba) 3 , RuPhos and Pd 2 (dba) 3 or Pd(PPh 3 ) 4
  • a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • the reaction can be performed using a suitable Pd/ligand combination such as PdCI 2 (PPh 3 ) 2 and PPh 3 or Pd(OAc)? and di(1-adamantyl)-n-butylphosphine in the presence of a suitable Cu salt such as Cul or CuBr, in the presence or absence of tetrabutylammonium fluoride in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • a suitable Pd/ligand combination such as PdCI 2 (PPh 3 ) 2 and PPh 3 or Pd(OAc)?
  • di(1-adamantyl)-n-butylphosphine in the presence of a suitable Cu salt such as Cul or CuBr
  • tetrabutylammonium fluoride in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • the temperature of the reaction can go from
  • 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 three steps through a direct arylation of a compound of Formula (Villa) or (VI I lb) with halo derivative of Formula (IV) followed by reduction of the resulting N -oxide of Formula (IXa) or (IXb) and subsequent transformation of the ester or cyano derivative (IXa) or (IXb) into compounds of Formula (I), as outlined in Scheme 2.
  • Reaction of (Villa) or (Vlllb) with (IV) can be performed using a suitable Pd/ligand combination such as PBu3 and Pd(OAc)? or PBU3-HBF4 and Pd(OAc)2, in the presence of a suitable base as potassium carbonate, in a suitable solvent such as toluene.
  • 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 1 h to 48h.
  • the resulting N -oxide (IXa) and (IXb) can easily be reduced to compound (Va) and (Vb) with hydrogen or sodium borohydnde using palladium on charcoal as a catalyst or also using phosphorous trichoride.
  • compounds of Formula (Vb) can be treated with a base such as KOH in a suitable solvent such as tert-butanol, at a temperature going from room temperature to reflux for a reaction time from 1h to 3 days to give a compound of Formula (i)
  • 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.
  • compounds of Formula (IVa) can be obtained by reaction of (X) with (XI) by means of activating agents.
  • 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-(1Hbenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluor
  • 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, A/,/V'-dimethylformamide, tetrahydrofuran, dichloromethane or dioxane.
  • a base such as, disopropylethylamine, pyridine, thriethylamine, or N-methylmorpholine
  • a solvent such as dimethoxyethane, A/,/V'-dimethylformamide, tetrahydrofuran, dichloromethane or dioxane.
  • carboxylic acids in (XI) are activated as mixed anhydrides or acid chlorides and then coupled with (X) 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 (X) with (XII) by means of reductive amination in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a suitable solvent such as dioxane, THF, dichloromethane or diethyl ether.
  • a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride
  • a suitable solvent such as dioxane, THF, dichloromethane or diethyl ether.
  • compounds of Formula (IVb) can be obtained by means of amine aikylation of compounds of Formula (X) in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate or the like.
  • a base such as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate or the like.
  • Other preferred solvents include dioxane, tetrahydorfurane and
  • compounds of Formula (IVc) can be obtained by ether synthesis by reaction of (XIII) with (XIV) in presence of a base such us sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide.
  • a base such us sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide.
  • compounds of Formula (IVd) can be obtained in one step by reaction of compounds of Formula (XV) with the corresponding isothiocyanate 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 THF, dioxane or DMF at a temperature from 0°C to 80°C for a time from 1 h to 24h.
  • a coupling agent such as 1-ethyl-3-(3'- dimethylamino)carbodiimide (EDC)
  • EDC 1-ethyl-3-(3'- dimethylamino)carbodiimide
  • compounds of Formula (IVe) can be obtained by reaction of compounds of Formula (IVe).
  • 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 adition of N-methyliminodiacetic acid; trimethyltin heterocycles can be prepared by reaction;of haloheterocycles with hexamethylditin and Pd (PPh 3 )4 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 trimetilsilyl heterocycles can be prepared by reaction of haoheterocycles with nBuLi in the presence of
  • 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 (VII), a corresponding intermediate carrying a partially elaborated (L 1 ) m -Y-(L 2 ) n -R 4 group is used and after cross coupling step, the complete structure of (L 1 ) m -Y-(L 2 ) complicat-R 4 is built by the methodologies described above in Scheme 3.
  • Said transformations include, for example: the substitution of a primary or secondary amine by treatment with an alkylating agent under standard conditions, or by reductive amination, i.e. by treatment with an aldehyde or a ketone in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride; the conversion of an amine into a sulfonamide by reaction with a sulfonyl halide, such as sulfonyl chloride, optionally in the presence of a base such as 4-dimethylaminopyridine, in a suitable solvent such as dioxane, chloroform, dichloromethane or pyridine, optionally in the presence of a base such as triethylamine or pyridine; the conversion of an amine into an amide or urea under standard conditions; the alkylation of an amide by treatment with an alkylating agent under basic conditions; the conversion of an alcohol into an ether under standard conditions;
  • any of the aromatic rings of the compounds of the present invention can undergo electrophilic aromatic substitution reactions or nucleophilic aromatic substitution reactions, widely described in the literature.
  • the salts of a compound of Formula (I) can be obtained during the final isolation and purification of the compounds of the invention or can be prepared by treating a compound of Formula (I) with a sufficient amount of the desired acid (or base) to give the salt in a conventional manner.
  • individual stereoisomers of a compound of Formula (I) can be obtained for example by resolution, starting from a compound of formula I obtained as a mixture of stereoisomers, using well known methods such as formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallization and regeneration of the free base, or by chiral preparative chromatography.
  • optically pure or enantiomerically enriched synthetic intermediates which can then be used as such in subsequent steps, at various stages of the synthetic procedures described above, using any known method for chiral resolution.
  • the compounds of the invention inhibit the activity of a histone demethylase comprising a JmjC domain (JmjC-KDM).
  • JmjC-KDM histone demethylase comprising a JmjC domain
  • the compounds of the invention have been found to be potent inhibitors of a JmjC-KDM of the KDM5 subfamily.
  • Certain compounds of the invention can be selective for KDM5 over other JmjC-KDMs.
  • KD 5" refers to the KDM5 subfamily of JmjC-KDMs.
  • Selective means that the compound has a greater effect on KDM5 than on other JmjC-KDMs (e.g. KDM2, KDM3, KDM4, KDM6, KDM7).
  • a selective compound may have at least a 10-fold greater effect on KDM5 than on other JmjC- KDMs, more preferably at least 20-fold greater effect, or at least 50-fold greater effect or at least 100-fold greater effect.
  • the compound of the invention is selective for KDM5.
  • the activity of the compounds of the invention as KD 5 inhibitors can be determined using for example the in vitro assay described in the Examples section.
  • Example 16 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 16.
  • compounds of the invention show in general selectivity for KDMS over KDM4 and/or KD 6.
  • Compounds of the invention have also been shown to inhibit JmjC-KDM activity in cells, as shown by the results described in Example 17. 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.
  • 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-methyiated H3K4, using FAD as a cofactor.
  • KDM1A lysine specific demethylase-1
  • JmjC-KDMs JmjC-domain containing histone demethylases
  • Fe(ll)-dependent 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 KD 2 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. e a/. 2005, Mol Cell 18(6):623-35) and induction of senescence (Chicas A. ef al. 2012, PNAS 109(23):8971-6).
  • the oncogenic role of KD 5A is highlighted by knock out studies showing that KDM5A inactivation reduces tumor formation in Rb+/- and Men-/- mice (Lin W. et 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. et al. 2014, Mol Cancer Res 12(4):571-82), temozolomide-resistant glioblastomas (Bannelli B. ef al.
  • KDM5A was found highly expressed in neuroendocrine tumors and it was described to promote a neoplastic phenotype in this tumor subtype (Maggi E.C. ef al. 2016, Oncogenesis 5(8):e257). Translocations involving the human KDM5A and NUP98 gene have also been described in pediatric acute megakaryobiastic leukemias (de Rooij J.D. ef al. 2013, Leukemia 27(12):2280-8).
  • KDM5B-mediated histone demethylation is required for inhibiting the expression of E2F target genes during induction of senescence in murine and human embryonal fibroblasts (Chicas A. ef al. 2012, PNAS 109(23):8971-6).
  • KDM5B represses CDKN1A expression, effectively promoting oncogenic transformation (Wong P.P. et al. 2012, Mol Cell Biol 32(9):1633-44).
  • Genetic inhibition of KDM5B is able to reduce proliferation, epithelial-mesenchymal transition (EMT), migration and invasion in models of hepatocellular carcinoma (Wang D. ef al. 2016, J Exp Clin Cancer Res 35:37).
  • 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 Cell 25(6):762-77).
  • KDM5B inhibition is also relevant in basal-like (Bamodu OA et al. 2016, BMC Cancer 16(1):160) and advanced- stage breast cancers (Yamane K.
  • KDM5B KDM5B Depletion of KDM5B was also shown to inhibit cell proliferation of hepatocellular carcinoma (Wang D. et al. 2016, J Exp Clin Cancer Res. 35:37). In addition, high expression of KDM5B is associated to EMT of Non-Small-Cell Lung Cancer cells (Haley J .A. et al. 2014, Front Oncol 4:344) and reduced response to therapy and/or poorer prognosis in ovarian (Wang L. ef al.
  • High KDM5B expression has been observed within a small subset of melanoma cells, characterized by increased clonogenic potential and resistance to several anticancer drugs. KDM5B inhibition sensitizes melanoma cells to chemotherapy (Roesch A. ef al. 2013, Cancer Cell 23(6):811-25) and reduces tumorigenicity. High KDM5B expression was detected also in uveal melanoma (Radberger P. ef al.
  • KDM5B inhibitors As a possible strategy to boost the efficacy of dendritic cells-based vaccines (Ptaschinski C. et 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. et al. 2005, Am J Hum Genet 76(2):227-36) and affects memory in men and mice (Simensen R.J. et 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. et al. 2013, PNAS 110 ⁇ 3027- ⁇ 3036).
  • KDM5C 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. et 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).
  • the compounds of the invention are thus expected to be useful for treating diseases associated with activity of a JmjC-KDM, particularly a KDM5 protein.
  • a JmjC-KDM particularly a KDM5 protein.
  • any of the compounds of the invention including any of the embodiments thereof, may be used.
  • the invention further provides a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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), or pharmaceutically acceptable salt thereof, for use in treating a disease associated with a JmjC-KDM, particularly a KDM5.
  • the present invention further provides the use of a compound of Formula (I), (la), (lb), (lc), (Id), (ie),
  • 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), or pharmaceutically acceptable salt thereof, for treating a disease associated with a JmjC-KDM, particularly a KDM5.
  • the present invention further provides a method for treating a disease associated with a JmjC-KDM, particularly a KDM5, comprising administering a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • the present invention further provides a method of inhibiting a KDM5 activity, comprising administering to a patient in need of said treatment an amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), or pharmaceutically acceptable salt thereof, sufficient to inhibit a KDM5 activity.
  • the present invention further provides a method of inhibiting a KDM5 activity in a biological sample, comprising contacting said biological sample with a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), or pharmaceutically acceptable salt thereof.
  • the present invention further provides the use of a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), or a pharmaceutically acceptable salt thereof, as a JmjC-KDM inhibitor in research, particularly as a research tool compound for inhibiting a JmjC-KDM, particularly KDM5 .
  • the invention relates to the in vitro use of a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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), the method comprising applying a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), or a pharmaceutically acceptable salt thereof, to a sample.
  • a JmjC-KDM such as 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.
  • the present invention further provides a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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 squamous carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, neuroendocrine tumors, melanoma, glioblastoma, neuroblastoma, multiple myeloma, and leukemia.
  • the cancer is selected from breast cancer, bladder cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, liver cancer, lung cancer, melanoma, glioblastoma, neuroblastoma, ovarian cancer, prostate cancer and leukemia.
  • the present invention further provides the use of a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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 squamous carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, neuroendocrine tumors, melanoma, glioblastoma, neuroblastoma, multiple myeloma, and leukemia.
  • the cancer is selected from breast cancer, bladder cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, liver cancer, lung cancer, melanoma, glioblastoma, neuroblastoma, ovarian cancer, prostate cancer and leukemia.
  • the present invention further provides the use of a compound of Formula (I), (la), (lb), (ic), (Id), (le),
  • the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, neuroendocrine tumors, melanoma, glioblastoma, neuroblastoma, multiple myeloma, and leukemia.
  • the cancer is selected from breast cancer, bladder cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, liver cancer, lung cancer, melanoma, glioblastoma, neuroblastoma, ovarian cancer, prostate cancer 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), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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 squamous carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, neuroendocrine tumors, melanoma, glioblastoma, neuroblastoma, multiple myeloma, and leukemia.
  • the cancer is selected from breast cancer, bladder cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, liver cancer, lung cancer, melanoma, glioblastoma, neuroblastoma, ovarian cancer, prostate cancer and leukemia.
  • the present invention further provides a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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), (!e), (If) or (II), preferably a compound of Formula (II), 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), 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” and the like refer to any disease or condition in which a JmjC-KDM, such as a KDM5, 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 diseases or conditions the course of which can be influenced by modulating the methylation status of histones or other proteins, wherein said methylafjon status is mediated at least in part by the activity of a JmjC-KDM, such as a KDM5. 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 include, without limitation, the diseases and conditions as described herein.
  • said disease is a cancer, such as breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, iiver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, neuroendocrine tumors, melanoma, glioblastoma, neuroblastoma, multiple myeloma, and leukemia.
  • said cancer is breast cancer, bladder cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, Iiver cancer, lung cancer, melanoma, glioblastoma, neuroblastoma, ovarian cancer, prostate cancer or 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, s wince, cattle, sheep, horses, or primates, and most preferably humans.
  • biological sample includes, without limitation, a cell, cell cultures or extracts thereof; biopsied material obtained from an animal, e.g. a human, or extracts thereof; and blood, saliva, urine, feces, or any other body fluids or extracts thereof.
  • a therapeutically effective amounf 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 ceil 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.
  • 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.
  • lubricating agents such as talc, magnesium stearate and mineral oil
  • wetting agents such as talc, magnesium stearate and mineral oil
  • emusifying and suspending agents preserving agents such as methyl- and propylhydroxybenzoates: sweetening agents; flavouring agents; and colouring agents.
  • Suitable oral dosage forms include, for examples, tablets, pills, sachets or capsules of hard or soft gelatin or any other suitable material.
  • the active compound can be incorporated into a formulation that includes pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating agents (e.g., alginate, Primogel, corn starch), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). They can then be compressed into tablets or enclosed in capsules using conventional techniques.
  • pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating
  • the capsules and tablets can also be coated with various coatings known in the art to modify the flavors, tastes, colors, and shapes of the capsules and tablets.
  • liquid carriers such as fatty oil can also be included in capsules.
  • Oral formulations can also be in the form of suspensions, solutions, syrups and the like. If desired, conventional agents for modifying flavors, tastes, color and the like can be added.
  • compositions suitable for parenteral administration include sterile aqueous solutions or suspensions, or can be alternatively prepared in lyophilized form for extemporaneous preparation of a solution or suspension using a sterile aqueous carrier prior to use.
  • diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used.
  • Other conventional solvents, pH buffers, stabilizers, anti-bacterial agents, surfactants, and antioxidants can all be included.
  • useful components include sodium chloride, acetates, citrates or phosphates buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like.
  • the parenteral formulations can be stored in any conventional containers such as vials and ampoules.
  • compositions for administration by inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositons may include suitable pharmaceutically acceptable excipients as described above.
  • Such compositions maye be administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions can be nebulized by use of a suitable gas. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask or the breathing chamber. Solutions, suspensions and powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Topical formulations can contain one or more conventional carriers.
  • ointments can contain water and one or more hydrophobic carriers selected from liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline and the like.
  • Carrier compositions of creams can be based on water in combination with glycerol and one or more other components such as cetylstearyl alcohol, glycerin monostearate and the like.
  • Gels can be formulated using isopropyl alcohol and water, suitably in combination with other excipients such as glycerol, hydroxyethyl cellulose and the like.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for administration to subjects, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with one or more suitable pharmaceutical carriers.
  • compositions are be administered in a manner appropriate to the disease to be treated, as determined by a person skilled in the medical arts.
  • An appropriate dose and suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the disease, the particular form of the active ingredient, the method of administration, among others.
  • an appropriate dose and administration regimen provides the pharmaceutical composition in an amount sufficient to provide therapeutic benefit, for example an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or lessening of symptoms severity, or any other objectively identifiable improvement as noted by the clinicial.
  • Effective doses may generally be assessed or extrapolated using experimental models like dose- response curves derived from in vitro or animal model test systems.
  • compositions of the invention can be included in a container, pack or dispenser together with instructions for administration.
  • the compounds of the invention can be administered in monotherapy (e.g., without concomitantly administering any further therapeutic agents, or without concomitantly administering any further therapeutic agents against the same disease that is to be treated with the compound of the invention).
  • they can be used in the monotherapeutic treatment of cancer (i.e., without administering any other antineoplastic agent until the treatment with the compound of the invention is terminated).
  • the invention also provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier, for use in the monotherapeutic treatment of cancer.
  • the compounds of the invention can also be administered in combination with another active agent as long as the other active agent does not interfere with or adversely affect the effects of the active compounds of this invention.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each additional active agent in its own separate pharmaceutical dosage formulation. If administered separately, the administration can be simultaneous, sequential or separate, and the compound of the invention and the additional therapeutic agent(s) can be administered via the same administration route or using different administration routes, for example one compound can be administered orally and the other intravenously.
  • any antineoplastic agent that has activity versus a cancer being treated or prevented with a compound of the invention may be used.
  • anti-plastic agent refers broadly to any agent used in the therapy of cancer, including chemotherapy and/or radiotherapy.
  • antineoplastic agents examples include, in general, and as appropriate, alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.
  • alkylating agents include, in general, and as appropriate, alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.
  • alkylating agents examples include, in general, and as appropriate, alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazines,
  • Particularly useful members of those classes include, for example, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5- fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo- phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like.
  • antineoplastic agents include estramustine, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11 , topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindoie derivatives, interferons and interieukins.
  • 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 hexamethy!melamine (altretamine), triethylenemelamine, ThioTEPA ( ⁇ , ⁇ ' ⁇ '-triethylenethiophosphoramide), carboquone, or triaziquone), a hydrazine (such as procarba
  • a platinum coordination complex which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, or triplatin tetranitrate.
  • a cytotoxic drug which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, an antimetabolite, including folic acid analog antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analog antimetabolites (such as cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6- ttiioguanine), and pyrimidine analog antimetabolites (such as cytarabine, decitabine, azacytidine, 5-fluorouracil (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 docetaxel, larotaxel, ortataxei, paclitaxe!/taxol, or tesetaxel), a Vinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine, vinzolidine, or vinorelbine), an epothilone (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F) or an epothilone B analog (such as ixabepilone/azaepothilone B).
  • a taxane such as docetaxel, larotaxel, ortataxei, paclitaxe!/taxol, or tesetaxel
  • a Vinca alkaloid such as
  • An anti-tumor antibiotic which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, an anthracycline (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin), an anthracenedione (such as mitoxantrone, or pixantrone) or an anti-tumor antibiotic isolated from Streptomyces (such as actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin).
  • an anthracycline such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin
  • An inhibitor of MAPK/ERK pathway (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 EK inhibitor like cobetinib, binimetinib, selumetinib or trametinib.
  • a B-Raf inhibitor like vemurafenib (PLX4032), encorafenib or dabrafenib
  • EK 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, eriotinib, 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, rubitecan, or lamellarin D) or a topoisomerase II inhibitor (such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin).
  • a topoisomerase I inhibitor such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D
  • a topoisomerase II inhibitor such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin.
  • antineoplastic agents may be used in combination with a compound of the present invention.
  • the antineoplastic agents may include biological or chemical molecules, such as TNF-related apoptosis- inducing ligand (TRAIL), tamoxifen, toremifene, fluoxymesterol, raloxifene, diethylstibestrol, bicalutamide, nilutamide, flutamide, aminoglutethimide, anastrozole, tetrazole, luteinizing hormone release hormone (LHRH) analogues, ketoconazole, goserelin acetate, leuprolide, megestrol acetate, prednisone, mifepristone, amsacrine, bexarotene, estramustine, irofulven, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, alvocidib
  • 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-ketoretino) (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 !
  • histone deacetylase inhibitors include, without limitation, MS-275 (SNDX-275; Entinostat), FK228 (FR901228; depsipeptide; Romidepsin), CI-994 (Acetyldinaline; Tacedinaline), Apicidin (cyclo[(2S)-2- amino-8-oxodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-(2R)-2-piperidinexcarbonyl]), A-161906 (7-[4-(4- cyanophenyl)phenoxy]-heptanohydroxamic acid), Scriptaid (6-(1 ,3-Dioxo-1 H,3H-benzo[de]isoquinolin-2-yl)- hexanoic acid hydroxyamide), PXD-101 (Belinostat), Panobinostat, CHAP (cyclic hydroxamic acid-containing peptide), LAQ-824
  • biological drugs like antibodies, antibody fragments, antibody constructs (for example, single-chain constructs), and/or modified antibodies (like CDR-grafted antibodies, humanized antibodies, "full humanized” antibodies, etc.) directed against cancer or tumor markers/factors/cytokines involved in cancer can be employed in cotherapeutic approaches with the compounds of the invention.
  • Such biological molecules are alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, eiiizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizuma
  • 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), carcinoe
  • 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), or a pharmaceutically acceptable salt thereof, and an antineoplastic agent
  • the respective amounts of the compound of the invention and the antineoplastic agent are effective to increase the period of cancer sensitivity and/or delay the development of cancer cell resistance to the antineoplastic agent.
  • the respective amounts of the compound of the invention and the antineoplastic agent are effective to increase efficacy of a cancer treatment comprising the antineoplastic agent.
  • the respective amounts of the compound of the invention and the antineoplastic agent are effective to increase response compared to a cancer treatment comprising administering the antineoplastic agent without the compound of the invention.
  • the invention further provides a method for increasing efficacy of a cancer therapy comprising an antineoplastic agent in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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), 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), 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), 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), 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, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, liver cancer, lung cancer, melanoma, glioblastoma, neuroblastoma, ovarian cancer, prostate cancer and leukemia.
  • a cancer selected from breast cancer, bladder cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, liver cancer, lung cancer, melanoma, glioblastoma, neuroblastoma, ovarian cancer, prostate cancer and leukemia.
  • the present invention in particular relates to the following:
  • Z 1 , Z 2 , and Z 3 are each independently selected from CR 5 and N, and Z 4 and Z 5 are each independently selected from CR 3 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 and R 2 are each independently selected from hydrogen, 0-6 alkyl, 0-6 ha!oalkyl, -(Ci-s alkylene)-OR s , -(0-6 alkylene)-NR 7 R 8 , -CN, -lAcarbocyclyl, -L 3 -aryl, -LAheterocyclyl and -L 3 -heteroaryl, wherein the carbocyclyi in - L 3 -carbocyclyl, the aryl in -LAaryl, the heterocyclyl in -lAheterocyclyl and the heteroaryl in -L -heteroaryl are each optionally substituted with one or more R s ,
  • R 1 and R 2 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, e alkyl, -s alkoxy, -OH, -NH 2 , - ⁇ (0- ⁇ alkyl), and -N(C, 6 alkyl) 2 ;
  • each R 3 is independently selected from hydrogen, halo, O- ⁇ alkyl, Cu haloalkyi, Ci s alkoxy, ⁇ ⁇ hydroxyalkyl, -OH and -NH 2 ;
  • each R 5 is independently selected from hydrogen and halo
  • U is Ci-4 alkylene, C 2 -4 alkenylene or C? . alkynylene, wherein said C1.4 alkylene, said C 2 -4 alkenylene and said C2-4 alkynylene are optionally interrupted by 0, S or NR", and wherein said C1.4 alkylene, said C2.4 alkenylene and said C2-4 alkynylene are optionally substituted with one or more R 13 ;
  • L 2 is Ci-6 alkylene, Cu a!kenylene or C2-8 alkynylene, wherein said Cvs alkylene, said C2-6 alkenylene and said C2-6 alkynylene are optionally interrupted by 0, S or NR 11 , and wherein said C1-5 alkylene, said C2-3 alkenylene and said C? e alkynylene are optionally substituted with one or more R 13 ;
  • n and n are each independently selected from 0 and 1 ;
  • R 4 is -NR 14 R 15 or R 16 ;
  • R 7 and R 8 are each independently selected from hydrogen and C1.5 alkyl, or R 7 and R s 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, CM alkyl, -OH, -NH?, -NH(Ci 6 alkyl), and -N(Ci. 6 alkyl) 2 ;
  • each L 3 is independently selected from a bond and C1-4 alkylene
  • R 10 and R 11 are each independently selected from hydrogen, Ci-e alkyl and Cn haloalkyl;
  • -R 12 - 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 12 - is linked to -(L 1 ) m - and -(L 2 ) n - R 4 in a 1 ,3-disposition;
  • each R 13 is independently selected from G1-6 alkyl, halo, C $ haloalkyl, -L 3 -carbocyclyl, -L 3 -aryl, -L 3 -heterocyclyl and -L 3 -heteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -lAary!, 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 1 attached to a same C atom of the alkylene group are 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 C3-6 cycloalkyi and 4- to 6-membered heterocyclic ring are each optionally substituted with
  • R 14 and R 15 are each independently selected from hydrogen, Ci-s alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-OR' 8 , -L 3 - carbocyclyl, -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 R 13 ;
  • R 16 is a 3- to 18-membered saturated, partially saturated or aromatic heterocyclic group which contains one N atom and optionally contains one or more further heteroatoms selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 20 ;
  • each R 2Q is independently selected from C alkyl, C%s haloalkyl, halo, C1-3 alkoxy, C1 6 haloalkoxy, -OH, -NH3 ⁇ 4 -NH(Ci-6 alkyl), -N(C,.
  • each R 21 is independently selected from C « alkyl
  • each R 6 , each R 18 , each R 22 and each R 23 is independently selected from hydrogen and O e alkyl.
  • any alkylene is optionally substituted with one or more R 13 .
  • R* is -NR 14 R 15 or R 16 , wherein R 16 is a saturated 3- to 18-membered heterocyclic group which contains one N atom and optionally contains one or more further heteroatoms selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 20 .
  • R 14 and R 15 are each independently selected from hydrogen, Ci. 6 alkyl, Ci « haloalkyl, -IAC3-7 cycloalkyi, and -(CH 2 )i-4-pnenyl, wherein the C3-7 cycloalkyi in the - LAC3.7 cycloalkyi is optionally substituted with one or more groups independently selected from CM alkyl and halo, and the phenyl in -(CH 2 )i-rphenyl is optionally substituted with one or more R 19 .
  • a pharmaceutical composition which comprises a compound of any one of items 1 to 12 or a
  • DCM Dichloromethane
  • DIEA A/,A/-diisopropylethylamine
  • DIPEA N,W-Diisopropylethylamine
  • Pd(PPfi3)4 tetrakis(thphenylphosphine) palladium (0)
  • Pd(PPh3)2C Bis(triphenylphosphine)palladium chloride
  • Pet ether petroleum ether, RT: room temperature
  • T3P Propylphosphonic Anhydride
  • Method 2 Column: KINETEX-1.7u XB-C18 100A (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, 0.3/97,3.2/2,4.8/2,5/97,5.10/97 Column Temp: 35°C; Flow Rate: 0.6 rrt/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 Acetate 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 2.1 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 7 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, 0.4/97, 2.0/2, 5/2, 5.5/97, 6/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min.
  • Method 8 Column: Xbridge C18 (75mm x 4.6mm, 3.5 ⁇ ); 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 9 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 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, 4.2/97, 4.5/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min.
  • Method 10 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/% 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 11 Column: L-Column2 (150mm x 4.6mm, 5pm); 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 12 Column: Clarity 5pm Oligo (250mm x 4.6mm); Mobile Phase: A: Acetonitrile, B: 10 mM Ammonium Bicarbonate in Aq; Gradient: Time/% A: 0/5, 5/5, 15/80, 20/90, 20.1/5; Flow Rate: 1.0 mL/min; Diluent: Acetonitri!e:Water (1 :1).
  • Method 13 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/% A: 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 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: 0/5, 1/5, 3/15, 7/55, 10/98, 13/98, 13.1/5, 15/5; Flow Rate: 1.0 mL/min; Diluent: Acetonitrile:DMSO (1 :1).
  • Method 16 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, 3/15, 7/55, 10/98, 13/98, 13.1/5, 15/5; Flow Rate: 1.0 mL/min; Diluent: Acetonitrile: H 2 0 (1 :1).
  • Method 17 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 18 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ,um); 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 19 Column: Eclipse XDB-C18 (150mmX4.6mm, 5 ⁇ ); Mobile Phase: A: 0.01 Ammonium Bicarbonate in Aq, B: 100% Acetonitrile; Gradient: Time/% B: 0/5, 1.5/5, 3/15, 7/55, 10/95, 14/95, 17/5. 20/5; Column Temp: RT; Flow Rate: 1 mL min; Diluent: Acetonitrile: H?0: eOH (1 :2:2).
  • Method 20 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ,um); 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, 3.04/97, Column Temp: 35°C; Flow Rate: 0.6 mL/min;
  • Method 21 Column: Gemini Phenomenex C18 (150mm x 4.6mm, 5 ⁇ ); Mobile Phase: A: 0.01 M Ammonium Bicarbonate (aq), B: Acetonitrile; Gradient: Time/% B: 0/10, 1/10, 7/80, 10/98, 15/98, 15.01/10; Flow Rate: 1.0 mL/min; Diluent: AcetonitrikhbO.
  • Method 22 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, 8.01/5; Flow Rate: 1.0 mL/min.
  • Method 23 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 Cm); Mobile Phase: A: 0.1% Formic Acid in Water B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A of: 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 24 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 Dm); Mobile Phase: A: 0.1% Formic Acid in Water B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A of: 0/90,1/10,2.2/10,2.3/90,2.6/90; Column Temp: 50 °C; Flow Rate: 0.8 mL/min.
  • Method 25 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 Gm); Mobile Phase: B: 0.1% Formic Acid in Water A: 0.1 % Formic Acid in Acetonitrile; Gradient: Time/% B of: 0/97,0.3/97,2.2/2,3/2,3.01/97; Column Temp: 35 °C; Flow Rate: 0.6 mL min.
  • Method 26 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 3m); Mobile Phase: B: ACN, A: Ammonium Bicarbonate; Gradient: Time/% B of: 0/3, 1/3, 7/100, 7.5/100,9/3,10/3; Column Temp: 35 °C; Flow Rate: 0.500 mL/min
  • Method 27 Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 Dm); Mobile Phase: A: 0.1% Formic Acid in Water B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B of: 0/10, 1.8/100, 3.8/100, 4.0/10,5/10; Column Temp: 50 °C; Flow Rate: 0.7 mL/min.
  • Method 28 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 Dm); Mobile Phase: A: 0.1% Formic Acid in Water B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B of: 0/5,0.3/5, 2/95, 3.7/95, 4.2/5,5.7/5; Column Temp: 40 °C; Flow Rate: 0.5 mL/min.
  • the reaction mixture was diluted with DCM (100 mL), washed with water (50 mL) and aq.NaHCC solution (50 mL). The organic layer was dried over anhydrous NasSO*, 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 under 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 Na2S0 . 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 mo!) and Boc 2 0 (16 mL, 0.071 mol) in methanol (30 mL) was added NiCI 2 .6H 2 0 (1.6 g, 0.007 mol) and followed by aBH (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 NajSO,, 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.
  • step c To a stirred solution of the compound obtained in the previous section, step c, (2.4 g, 0.008 mo! in 1 ,4-dioxane (15 mL) was added 4M HC! 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- (feri-butoxycarbonyi)piperidine-3-carboxylic acid (2.7 g, 0.012 mol) in DCM (10 mL) was added TEA (7.0 mL, 0.05 mol) and followed by T 3 P (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 I ⁇ SC , 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 b Tert-butyl (5-bromopyrazin-2-yl)(3-(diethylamino)propyl)carbamate
  • step a To a stirred solution of 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 2 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 Na?SO,, 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 solid.
  • Step b W-(6"Bromopyridin-3-yl)-3-(phenethyiamino)propanamide
  • step b To a stirred solution of the compound obtained in the previous section, step b, (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 Na2SOa, 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 2 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 a2S0 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 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 to a suspension of Raney-Nickel (1 g, wet) in methanol (15 mL) and followed by added 25% NH4OH solution (5 mL). 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 d 7erf-butyl (3-(1 H-pyrazol-1 -yl)propyl)(5-bromopyrazin-2-yl)carbamate
  • step c To a stirred solution of the compound obtained in the previous section, step c, (1.5 g, 5.319 mmol) in ACN (15 mL) was added TEA (2.2 mL, 15.95 mmol), Boc 2 0 (1.73 g, 7.97 mmol) and DMAP (0.12 g, 1.06 mmol) 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 Na?S0 , 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 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 NaHCCb 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-bronropyridin-3-yl)(methyl)amino)-3-oxopropyl)carbarnate
  • 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 E3 ⁇ 4N (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 NajSC 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 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 NaHCOa (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 Na?S04 and concentrated to obtain the title compound (1.7 g, crude) as a liquid compound.
  • the crude compound was used as such 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 Na2SO, 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?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 a2SO ⁇ and concentrated to obtain the title compound (1.2 g, 84%) as a colorless liquid.
  • Step e fert-butyl (3-((6-bromopyridin-3-yl)amino)-3-oxo-1-phenylpropyl)(ethyl)carbamate
  • 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) was added and TEA (0.93 g, 9.21 mmol) 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 Na2S04, filtered and 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 a /T-(5-Bromopyrazin-2-yl)-W 2 ,W 2 -diet ylethane-1,2"dsamine
  • Step b Tert-butyl (5-bromopyrazin-2-yl)(2-(diethylamino)ethyl)carbamate
  • Step b Tert-butyl (6-bromopyrldin-3-yl) ⁇ 3-(diethylamino)propyl)carbamate
  • Step b A/,W-Diethyl-2-(1H-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 c 2- ⁇ 1 - ⁇ 6-Bromopyridin-3-yl)-1 H-pyrazol-4-yl)-W,W-diethylethan-1 -amine
  • 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 K 2 C0 3 (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 Na?SO», filtered and concentrated.
  • 2-bromo-5-fluoropyridine 6.286 g, 35.92 mmol
  • K 2 C0 3 7.435 g, 53.88 mmol
  • step a (2.0 g, 5.763 mmol, HCI salt) in MeOH (30 mL) was added acetaldehyde (2.5 g, 57.636 mmol), 4A 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-Pyrazol-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 NaCNBH3.(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 NaHCOa 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 a2S0 , filtered and concentrated under reduced pressure to afford 700 mg of the title compound (89.5 % yield).
  • step a 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 eOH (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 4-(6-methoxypyridin-3-yl)butan-1 -ol , as a light brown gummy liquid.
  • Step d 4-(6-bromopyridin-3-yl)-W,W-diethylbutan-1 -amine
  • step d (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 (LCMS purity 32 % ), Purified by column chromatography using, 230-400 silica with 8% MeOH/DCM to afford 1.7 g (87.3 % yield) of 4-(6-bromopyridin-3-yl)-W,W- diethylbutan-1 -amine.
  • step a To a solution of the compound obtained in the previous section, step a, (3.0 g, 9.009 mmol) in formic acid (40 mL), paraformaldehyde (2.705 g, 90.09 mmol) was added and heated at 100°C for 16h.
  • the reaction mixture was concentrated under reduced pressure: The crude residue was dissolved in water and basified to pH ⁇ 8 using saturated NaHC(3 ⁇ 4 solution and extracted with EtOAc (3x 50 mL). The separated organic layers were dried over anhydrous NajSC , filtered and concentrated under reduced pressure
  • the crude compound was purified by silica gel column chromatography and eluted at 20% EtOAc in pet ether to afford the title compound (2.5 g, 79%) as an off-white solid.
  • step a (3.50 g, 15.08 mmol) in DCM (50 mL), TPP (11.0 g, 30.17 mmol) and CBr. (9.98 g, 30.17 mmol) were added at 0 °C.
  • the resulting mixture was stirred at room temperature for 6 h.
  • the solvent was removed under reduced pressure and the crude residue was purified by silica gel column using with 10% ethyl acetate in pet ether as an eluent to afford the title compound (2.50 g, 56%) as color less liquid.
  • Step c 3-((6-bromopyridin-3-yl)oxy)-W-phenethylpropan-1 -amine
  • step b (2.50 g, 8.47 mmol) andd 2- phenylethanamine (1.54 g, 12.71 mmol) in ACN (50 mL), Nal (1.27 g, 8.47 mmol) and K 2 C0 3 (3.50 g, 25.42 mmol) were added.
  • the resulting mixture was heated at 60°C for 16h.
  • the reaction mixture was tempered, filtered and filtrate was concentrated under reduced pressure, obtained crude 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 (1.50 g, 53%) as color less liquid.
  • Step d 3-((6-bromopyrldin-3-yl)oxy)-N-ethyl-N-phenethylpropan-1-amine
  • step c (1.50 g, 4.47 mmol) in DMF (20 mL) was added K2CO3 (1.85 g, 13.43 mmol) followed by ethyl iodide 7 (1.04 g, 6.71 mmol) and stirred at room temperature for 16h.
  • Reaction mixture was poured into ice water, extracted with ethyl acetate (2X60 mL).
  • step a (2 g, 7.98 mmol) in acetonitrile was added 4,4-difluoropiperidine.HCI (1.88 g, 11.97 mmol), K2CO3 (3.3 g, 23.95 mmol), Nal (1.19 g, 7.98 mmol) at RT t RT and heated to 70°C for 24 h.
  • reaction was allowed to RT and poured into ice water (30 mL) and extracted with EtOAc (2 x 80 mL) and the separated organic layer was dried over anhydrous Na2SC ⁇ 4, filtered and concentrated under reduced pressure to get crude, was washed with n-pentane and dried to afford 1.5 g (56 %) of the title compound as a gummy liquid.
  • Step b 2-(4,4-difluoropiperidin-1-yl)ethan-1-ol
  • 4,4-Difluoropiperidine hydrochloride 3.0 g, 19 mmol
  • acetonitri!e 30 mL
  • triethyiamine 9.6 g, 13.7 mL, 95 mmol
  • 2- Bromoethanol 1.9 g, 15 mmol
  • step b (1 g, 6.1 mmol), NaH (0.72 g, 30.0 mmol) in THF at 0°C the compound obtained in the previous section, step a (1.67 g, 6.7 mmol) was added lowly at same temperature and allowed to stir for 4 h from 0°C to RT. Reaction was monitored by TLC & LCMS.
  • the reaction mixture was diluted with 40 mL ice cold water and extracted with 2 X 50 mL EtOAC, washed with brine, dried over anhydrous Na2S04, evaporated to get crude 2-bromo-5-((2-(4,4- difluoropiperidin-1-yl)ethoxy)methyl)pyridine (3) as pale yellow liquid.
  • the crude was purified flash column chromatography by 40% EtOAC/Hexane in 100-200 silica to get 1.3 g (64%) of of the title compound as pale yellow liquid.
  • step a To a solution of the compound obtained in reference example 26, step a, (1 ,1g,3.303mmol) in DCM(15ml) was added TEA (2.3ml,13.21mmol) and butyryl chloride (0.65ml,6.606mmol) at 0°C and allowed to stir at RT for 16h and the progress of the reaction was monitored by LCMS.
  • the reaction mixture was diluted with DCM and washed with water, 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 15% EtOAc in pet ether to afford of the title compound (1.00g,81.8%) as a yellow gummy ;
  • Step b 6-bromo-W-butyl-W-(3-(4,4-difiuoropiperidin-1 -yl)propyl)pyridin-3-amine
  • step a (0.990g,2.23mmol) in THF(15ml) was added BH3.DMS (3.34ml,6.69mmol) at 0°C and heated to 75°C for 16h.
  • the progress of the reaction was monitored by LCMS and TLC.
  • LCMS shows of desired mass, the reaction mixture was concentrated under reduced pressure.
  • MeOH was added to the reaction mixture and stirred at 65°C for 2h and concentrated under reduced pressure.
  • the crude compound was purified by silica gel column chromatography and eluted at 10% EtOAc in pet ether to afford the title compound (590mg,61.7%) as a green gummy ;
  • Step a Methyl 5'-(1-(fert-butoxycarbonyl)piperidine-4-carboxamido)-[2,2 ! -bipyridine]-4-carboxyIate
  • DCM DCM
  • T3P 1,3-bis(ferf- butoxycarbonyl)piperidine-4-carboxylic acid
  • TEA TEA
  • the reaction mixture was diluted with aq.NaHCOs solution and extracted with DCM (3 X 10 mL). The organic layer was dried over anhydrous Na?S0.4, 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 titie compound.
  • Step b Tert-butyi 4-((4'-carbamoyl-[2,2'-bipyridin]-5-yl)carbamoyl)piperidine-1-carboxyiate
  • step a In a pressure tube, to a stirred solution of the compound obtained in the previous section, step a, (200 mg, 0.4545 mmol) in MeOH (4 mL) was added saturated methanolic ammonia (10 mL). The pressure tube was sealed with Teflon screw cap and the reaction mixture was heated at 100°C for 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was triturated with Et?0 (2 X 2 mL) and dried in vacuum to afford the title compound (150 mg, 77.64%) as an off-white solid.
  • step b To a stirred solution of the compound obtained in the previous section, step b, (140 mg, 0.329 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, n-pentane and dried under reduced pressure. The crude compound was dissolved in DM water and lyophilized to afford the title compound (95 mg, 88%) as a pale brown solid.
  • Step a Methyl 5'-(3-((fert-butoxycarbonyl)amino)-3-phenylpropanamido)-[2,2'-bipyridine]-4-carboxylate
  • reference example 4 To a stirred solution of reference example 4 (780 mg, 1.857 mmol) in 1 ,4-dioxane (15 mL) was added reference example 1 (804 mg, 2.674 mmol), CsF (566 mg, 3.714 mmol) and followed by Cul (70 mg, 0.3714 mmol). The resulting solution was degassed with nitrogen gas. then added Pd(PPhs)- (214 mg, 0.1857 mmol), the mixture was again degassed and then heated to 110 °C for 16h. The reaction mixture was cooled to RT, the reaction mixture was filtered through the Celite pad, washed with EtOAc, the filtrate was dried over anhydrous Na?SO.t and concentrated to get crude compound. The crude compound was purified by flash column chromatography using siiicagel and eiuted with 50%EtOAc/pet ether to afford the title compound (450 mg, 50%) as a pale brown solid.
  • Step b Tert-butyl ⁇ 3-((4'-carbamoyl-[2,2'-bipyridin]-5-yl)amino)-3-oxo-1-phenylpropyl)carbamate
  • step a In a sealed tube, to a solution of the compound obtained in the previous section, step a, (280mg, 0.588 mmol) in methanol (5 mL) was added NH 3 in methanol (25 mL) at 0°C. The reaction mixture was allowed to stir at RT and then heated to 80°C for 16h. The reaction was continued further another 6h. The reaction mixture was cooled to RT and concentrated at reduced pressure. The crude compound was washed with aq.NaOH solution, diethyl ether and dried under reduced pressure to afford the title compound (180 mg, 66%) as an off-white solid.
  • Preparative HPLC Conditions Column: Inertsil ODS-3 (20 x 250 mm, 5.0 Mm);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 mL/min; Wavelength: 215 nm & 254 nm.
  • Step b Terf-butyl (3- ⁇ 1H-pyrazol-1-yl)propyl)(4'-carbamoyl-[2,2'-bipyridin]-5-yl)carbamate
  • Preparative HPLC Conditions Column: X-SELECT (20 x 150 mm, 5.0 pm); Mobile phase: A: 10 mm Ammonium bicarbonate in Aq; B: Acetonitrile; Gradient Method (A / B): 0/20, 2/20, 10/45, 15/98; Flow rate: 18.0 mL/min; Wavelength: 215 nm & 254 nm.
  • Step c. 5 -((3-(1 H-Pyrazol-1-yl)propyl)amino)-[2,2'-bipyridine]-4-carboxamide di-trifluoracetate
  • step b To a stirred solution of the compound obtained in the previous section, step b, (35mg, 0.082 mmol) in DCM (2 mL) was added TFA (0.6 mL) at 0°C. The resulting solution was stirred at RT for 3h. The reaction mixture was evaporated under reduced pressure, the residue was triturated with diethyl ether to obtain gummy solid compound. The compound was dissolved in demineralized H 2 0 and Iyophilized to afford 32 mg (81.7 %) of the title compound as a TFA salt.
  • Step b Methyl 5'-((3-(1-methyl-1H-pyrazol -yl)propyl)amino)-[2,2'-bipyridine3-4-carboxylaie
  • step a To a stirred solution of the compound obtained in the previous section, step a, (300 mg, 2.173 mmol) in methanol (10 mL) was added reference example 3a (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 NaCNBHs (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 NaHCOa solution and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO Implement filtered and concentrated under reduced pressure.
  • the crude compound was purified by silica gel flash column chromatography and eiuted at 100% EtOAc to afford the title compound (250 mg, 32%) as a pale yellow solid.
  • Step c 5'-(P-(1-lethyI-1H-pyrazoI -yl)propyI)amino)-[2,2' ⁇ ipyridine] -carboxamide
  • Step a Tert-butyl S- ⁇ '-cyano-p ⁇ '-bipyridinl-S-yllcarbamoy piperidine-l-carboxylate
  • reference example 4b 1.0 g, 2.61 mmol in 1 ,4-dioxane (10 mL) was added reference example 1a (0.76 g, 2.87 mmol), CsF (0.79 g, 5.22 mmol) and followed by Cul (0.1 g, 0.52 mmol).
  • the resulting reaction mixture was degassed using N 2 gas and then added Pd(PPhj)4 (0.3 g, 0.26 mmol).
  • the reaction mixture was again degassed and heated to 110 °C for 16h.
  • the reaction mixture was cooled to RT and diluted with water (70 mL) and extracted with EtOAc (2 X 70 mL). The combined organic layers were dried over anhydrous filtered and concentrated under reduced pressure.
  • the crude compound was purified by flash column chromatography and eluted with 50% EtOAc/ pet ether to afford the title compound (0.5 g, 47%) as an off white solid.
  • Step b Tert-butyl 3-((4'-carbamoyl-[2,2'-bipyridin]-5-yl)carbamoyl)piperidine-1"Carboxylate
  • step a To a stirred solution of the compound obtained in the previous section, step a, (0.2 g, 0.49 mmol) in MeOH (5 mL) was added NaOH (59 mg, 1.47 mmol) and 30% H2O2 (50 mg, 1.47 mmol) at RT. The reaction mixture was heated at 65 °C for 2h. The reaction mixture was cooled to RT and evaporated under reduced pressure. The crude compound was dissolved in EtOAc (70 mL) and washed with 10% NaOH solution (2 x 30 mL). The organic layer was dried over Na2SO ⁇ i and concentrated to obtain the title compound (95 mg, 48%) as an off white solid.
  • step b To a stirred solution of the compound obtained in the previous section, step b, (90 mg, 0.21 mmol) in 1 ,4- dioxane (3 mL) was added 4M HCI in dioxane (3 mL) at 0 °C. The reaction mixture was stirred at RT for 5h. The reaction mixture was evaporated under reduced pressure and the crude compound was triturated with pentane (10 mL) to obtain the title compound (50 mg, 62.6 %) as a HCI salt.
  • Step b N-I '-Cyano- ⁇ .Z-bipyridinJ-S-yl ⁇ diethylaminoJpropanamide
  • step a To a stirred solution of the compound obtained in the previous section, step a, (0.5 g, 1.75 mmol) in THF (5 mL) was added diethyi amine (1.28 g, 17.50 mmol) at RT. The resulting reaction mixture was heated to 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) and dried to obtain the title compound (0.5 g, 89%) as an off white solid.
  • step b To a stirred solution of the compound obtained in the previous section, step b, (0.2 g, 0.61 mmoi) in MeOH (5 mL) was added NaOH (74 mg, 1.85 mmol) and 30% H (0.2 g, 1.85 mmol) at RT. The resulting reaction mixture was heated to 60°C for 2h. The reaction mixture was cooled to RT and evaporated under reduced pressure. The residue was suspended with 20% MeOH in DCM (50 mL), the insoluble solid was separated and the organic layer was concentrated to obtain the crude compound. The crude compound was purified by preparative HPLC to obtain the title compound (50 mg, 24%) as a formate salt.
  • Step b Methyl S'-ffS-ltert-butoxycarbonyllaminoJpropylaminoJ-p ⁇ '-bipyridinel ⁇ -carboxylate
  • Step c Tert-butyl (3- ⁇ (4 , -carbamoyl-[2,2 , -bipyridin]-5-yl)amino)propyl)carbamate
  • step b To a stirred solution of the compound obtained in the previous section, step b, (200 mg, 0.51 mmol) in MeOH (2 mL) was added methanolic ammonia (20 mL) at RT and the reaction mixture was stirred at 100°C in a sealed tube for 16 h. The reaction mixture was concentrated under reduced pressure the obtained residue was dissolved in 10% Methanol in DCM (60 mL) and washed with saturated NaHC03 solution (2x25 mL) and dried over NazSO-i. The dried organic layer was concentrated under reduced pressure and the resultant crude compound was triturated with diethyl ether to afford the title compound (140 mg, 72%) as yellow solid.
  • step c To a stirred solution of the compound obtained in the previous section, step c, (135 mg, 0.36 mmol) in DCM: THF (10 mL:5 mL) was added 4M HCI in 1 ,4-dioxane (1.0 mL) at RT and stirred for 6 h. The mixture was concentrated under reduced pressure and the obtained crude compound was triturated with acetonitrile and diethyl ether to afford the title compound (85 mg, 77%) as yellow solid.
  • Step a Tert-butyl (3-oxo-3-((6-(trimethylstannyl)pyridin-3-yl)amino)propyl)carbamate
  • Pd(PPh3)2Cb 0.05205 g, 0.291 mmol
  • the reaction mixture was heated at 100°C for 16 h in a sealed tube and the reaction mixture was allowed to cool to RT, filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the resultant crude compound was purified by flash column chromatography on neutral alumina using 50% EtOAc in petroleum ether as eluent to afford the title compound (1.5 g, 60%).
  • Step b Tert-butyl (3- ⁇ (6-(4-cyanopyrimidin-2-yl)pyridin-3-yl)amino)-3-oxopropyl)carbamate
  • step a To a stirred solution of 2-chioropyrimidine-4-carbonitrile (0.25 g, 1.79 mmol) and the compound obtained in the previous section, step a, (0.925 g, 2.15 mmol).in toluene (10 mL) was added Pd(PPh 3 )4 (0.207 g, 0.18 mmol) at RT. The resulting solution was degassed with nitrogen for 10 min. The mixture was stirred at 120 °C for 16 h in a sealed tube.
  • reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure, the obtained crude was purified by Grace column chromatography (reverse phase) using 40% acetonitrile in 0.1%TFA (aqueous) as eluent to afford the title compound (80 mg, 12%).
  • Step c Tert- butyl (3- ⁇ (6-(4-carbamoylpyrimidin-2-yl)pyridin-3-yl)amino)-3-oxopropyl)
  • step b To a stirred solution of the compound obtained in the previous section, step b, (0.11 g, 0.29 mmol) in tert- butanol (10 mL) was added KOH (0.05 g, 0.89 mmol) at RT and the reaction mixture was stirred at 100°C for 45 min. The reaction mixture was concentrated under reduced pressure the obtained residue was dissolved in 20% Methanol in DCM (60 mL) and washed with saturated NaHCC solution and dried over anhydrous a 2 S04, filtered and the filtrate was concentrated under reduced pressure. The obtained crude compound was purified by Prep HPLC to afford the title compound (12 mg, 10%)
  • Step a Methyl 5'-(3-amino-3-pheny!propanamido)-[2,2'-bipyridine]-4-carboxylate hydrochloride salt 4 HCI in 1 ,4-dioxane (3 mL) was added to a stirred solution of the compound obtained in example 2 step a (640 mg) in methanol (3 mL) at 10°C, the reaction mixture was allowed to stir at RT for 4 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated; the residue was triturated with diethyl ether and dried under reduced pressure to afford the title compound as a hydrochloride salt.
  • Step b Methyl 5'-(3"(diethylamino)-3 » phenylpropanamido)-[2,2'-bipyridine]-4-carboxylate
  • step a To a stirred solution of the compound obtained in the previous section, step a, (460 mg) in methanol (4 mL) was added acetaldehyde (294 mg, 6.69 mmol), 4A molecular sieves, followed by AcOH (134 mg, 2.23 mmol) at 0°C. The mixture was stirred for 10 minutes, then added NaCNBH 3 (211 mg, 3.34 mmol) at 0°C. The resulting reaction mixture was allowed to stir at RT for 16h. The progress of the reaction was monitored by LCMS.
  • the reaction mixture was concentrated; the residue was diluted with DCM (50 mL), filtered through the Celite pad, the filtrate was washed with aq.NaHCOa solution (2 x 20 mL), water (20 mL). The organic layer was dried over anhydrous a2S04, filtered and the filtrate was concentrated.
  • the crude compound was purified by prep. HPLC to afford the titie compound (200 mg, 41%) as an off-white solid.
  • Preparative HPLC conditions Column: Inertsil ODS-3 (20 x 250 mm), 5.0 ⁇ ; Mobile phase: pump (A): 10 mM NH4HCO3 in water, pump (B): Acetonitrile; Isocratic method: % of B: 78% A: 22%; Flow: 18 mL/min; Max: 215 & 254 nm.
  • Step c 5'-(3-(Diet ylamino)-3-phenylpropanamido)-[2,2'-bipyridine]-4-carboxamide
  • step b To a stirred solution of the compound obtained in the previous section, step b, (80 mg, 0.185 mmol) in methanol (1 mL) was added methano!ic NH3 (5 mL) at 0°C, the reaction mixture was allowed to stir at RT for 48h. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated; the residue was washed with diethyl ether (5 mL) and dried under reduced pressure to get 65 mg of crude. The crude compound was purified by prep.HPLC and lyophilized to afford the title compound (29 mg, 37%) as a white solid.
  • Preparative HPLC conditions Column: Inertsil ODS-3 (20 x 250 mm), 5.0pm; Mobile phase: (A): 10 mM NH4HCO3 in water, (B): Acetonitrile; Isocratic method: T% of B; 2/50, 10/5, 15/50; Flow: 18 mL/min; Max: 215 nm.
  • Step b A/-(6-Bromopyridin-3- l)-3-(pyrrolidin-1-yi)propanamide
  • 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 a2S04, filtered and concentrated under reduced pressure.
  • the crude compound was purified by silica gel flash column chromatography and eluted at 4%MeOH/DC to afford 3.0 g (quantitative yield) of the title compound
  • Step c 3- ⁇ Pyrro!idin-1 -yl)-W-(6-(trimethylstannyl)pyridin-3-yl)propanamide
  • step b To a stirred solution of 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 then Pd (PPhs ⁇ (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/DC to afford the title compound (1.0 g, 77%) as a gummy.
  • Prep.HPLC condition Column: Kinetex C18 (150 x 21 mm), 5.0 ⁇ ; Pump (A): 10 mM ammonium bicarbonate in aqueous, Pump (B): Acetonitrile; Gradient: time/% of B: 0/10,1/10,10730,15/98. Flow: 17.0 ml/min;
  • Step a Methyl 5 , -(3-((tert-butoxycarbonylKcycIopentyl)amino)propanamido)-[2,2'-bipyridine]-4- carboxyiate

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Abstract

The invention relates to heteroaryl-carboxamides as described herein, useful as histone demethyiase 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-CARBOXAMIDES AS HISTONE DEMETHYLASE INHIBITORS
TECHNICAL FIELD
The invention relates to compounds, particularly heteroaryl-carboxamides as described herein, useful as inhibitors of histone demethylases, such as KDMS. The invention also relates to pharmaceutical compositions comprising these compounds and to their use in therapy, including e.g., in the treatment of cancer.
BACKGROUND
Histones are highly conserved proteins that play a dynamic role in modulating chromatin structure.
The covalent modification of histones is closely associated with regulation of gene transcription. Chromatin modifications have been suggested to represent an epigenetic code that is dynamically 'written' and 'erased' by specialized proteins, and 'read', or interpreted, by proteins that translate the code into gene expression changes. Histone methylation is among the most relevant modifications. Methyiation of histone lysines or arginines by histone methyitransferases (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 KDMS 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 substituent (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 J JD2 and JARID1 families based on disubstituted pyridine compounds bearing at the 4-position a carboxy group (or a bioisoster thereof) 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 such as KDM5. 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
wherein
Z Z2, and Z3are each independently selected from CR5 and N, and Z4 and Z5 are each independently selected from CR3 and N, with the proviso that only one of Z1, Z2, Z3, Z4 and Zs can be N;
R1 and R2 are each independently selected from hydrogen, C1.5 alkyl, &-s haloalkyl, -(C1-5 alkylene)-OR6, -(Cn alkylene)-NR7R8, -CN, -L3-carbocyclyl, -L3-aryl, -L3-heterocyclyi and -L3-heteroaryl, wherein the carbocyclyl in - L3-carbocyclyl, the aryl in -L3-aryl, the heterocyclyl in -L3-heterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R9,
or R1 and R? 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, C1-6 alkyl, C1-6 alkoxy, -OH, -NH2, -NH(Ci-s alkyl), and -N(Ci-s alkyl)?;
each R3 is independently selected from hydrogen, halo, C-,.6 alkyl, C%6 haloalkyl, Ci s alkoxy, C1-6 hydroxyalkyl, -OH and -NH2;
each R5 is independently selected from hydrogen and halo;
Y is selected from -NR10C(=O)-, -NR 1-, -0-, -R12- and -CH2-, wherein said -NR,0C(=O)- is linked to -(!_ - via the NR10 group and to -(L2)n-R4 via the C(=0) group;
L1 is C1-4 alkylene, C2-4 alkenylene or C2 alkynylene, wherein said C alkylene, said C2-4 alkenylene and said C2-4 alkynylene are optionally interrupted by 0, S or NR11, and wherein said C1-4 alkylene, said C2-4 alkenylene and said C2-4 alkynylene are optionally substituted with one or more R13; L2 is C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene, wherein said Ci-e alkylene, said C2-6 alkenylene and said C2-6 alkynylene are optionally interrupted by 0, S or NR11, and wherein said d-6 alkylene, said C2-6 alkenylene and said d s alkynylene are optionally substituted with one or more R13;
m and n are each independently selected from O and 1 ;
R4 is -NR1 R15 or R16;
R7 and R8 are each independently selected from hydrogen and Cn alkyl, or R7 and R8 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, d-e alkyl, -OH, -NH2, -NH(C, e alkyl), and -N(Ci,3 alkyl)?;
each L3 is independently selected from a bond and C1.4 alkylene;
R10 and R11 are each independently selected from hydrogen, C1-6 alkyl and Ci s haloalkyl;
-R12- 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 -R12- is linked to -(L1)m- and -(L2)n- R4 in a 1 ,3-disposition;
each R13 is independently selected from -e alkyl, halo, d-s haloalkyl, -L3-carbocyclyl, -L -aryl, -L3-heterocyclyl and -L3-heteroaryl, wherein the carbocyclyi in -L3-carbocyclyl, the aryl in -L3-aryl, the heterocyclyl in -L3- heterocyclyl and the heteroaryl in -IAheteroaryl are each optionally substituted with one or more R17, and wherein two groups R13 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 Cu cycloalkyl and 4- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from halo and -6 alkyl;
R14 and R15 are each independently selected from hydrogen, C1 6 alkyl, d s haloalkyl, -(d-β a!kyiene)-OR18, -L3- carbocyclyi, -L3-aryi , -L3-hete rocyciy I and -LAheteroaryl, wherein the carbocyclyi in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyl in -LAheterocyciyl and the heteroaryl in -LAheteroaryl are optionally substituted with one or more R19;
R16 is a 3- to 18-membered saturated, partially saturated or aromatic heterocyclic group which contains one N atom and optionally contains one or more further heteroatoms selected from N, 0 and S, wherein R16 is optionally substituted with one or more R20;
each R20 is independently selected from d-s alkyl, C e haloalkyl, halo, C-.6 alkoxy, d-e haloalkoxy, -OH, -NH2, -NH(Ci-6 alkyl), -N(Ci.6 alkyl)?, -CN, -C(=0)R2', -C(=0)NR22R23, -NR22C(=0)R21, -NR22C(=0)NR22R23, -NR 2S02R21, -SO?NR22R23, -S02R21, -L3-carbocyclyl, -L3-aryl, -L -heterocyclyl and -LAheteroaryl, wherein the carbocyclyi in -L3-carbocyclyl, the aryl in -L3-aryl, the heterocyclyl in -L3-heterocyclyl and the heteroaryl in -L3- heteroaryl are optionally substituted with one or more R24; each 9, each R17, each R19 and each R24 is independently selected from Ci.6 alkyl, Ci-e haloalkyl, halo, Ci e alkoxy, C,.6 haloalkoxy, -OH, -NH2, -NH(Ci.6 alkyl), -N(Ci-6 alkyl)? ,-CN, -C(=0)R21, ~C(=0)NR22R23, -NR22C(=0)R21, -NR22C(=0)NR22R23, -NR22SO?R21, -S02NR22R23 and -S02R21;
each R21 is independently selected from d-e alkyl; and
each R6, each R18, each R22 and each R23 is independently selected from hydrogen and Ci s alkyl.
The compounds of Formula (I) as described herein are inhibitors of JmjC-KD s, particularly KD 5. These compounds, and pharmaceutical compositions comprising these compounds, are useful for the treatment of diseases associated with JmjC-KDMs, such as KDM5, including cancer or viral infections.
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 in the treatment of a disease associated with KDM5.
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 as a KDM5 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-KD .
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 for treating a disease associated with KDM5, 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 of inhibiting KDM5 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 KDM5 activity.
The present invention further provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
The present invention further provides a method for treating a viral infection, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a compound of Formula (I) or a salt thereof:
Figure imgf000007_0001
wherein
Z1, Z2, and Z3 are each independently selected from CR5 and N, and Z4 and Z5 are each independently selected from CR3 and N, with the proviso that only one of Z\ Z2, Z3, Z4 and Z5 can be N;
R1 and R2 are each independently selected from hydrogen, Cw alkyl, Cu haloalkyl, -{C1 5 alkylene)-OR6, -(0-_ alkylene)-NR7R8, -CN, -L3-carbocyclyl, -L3-aryl, -L3-heterocyclyl and -L3-heteroaryl, wherein the carbocyclyl in - L3-carbocyc!yl, the aryl in -L3-aryl, the heterocyclyi in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R9,
or R1 and R2 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, C1.6 alkyl, C1-6 alkoxy, -OH, -NH2, -NH(Ci 6 alky!), and -N(Ci-6 alkyl)?;
each R3 is independently selected from hydrogen, halo, Ci β alkyl, C1.5 haloalkyl, C -6 alkoxy, Ci e hydroxyalkyl, -OH and -NH2;
each R5 is independently selected from hydrogen and halo;
Y is selected from -NRi0C(=O)-, -NR11-, -0-, -R12- and -CH2-, wherein said -NR10C(=O)- is linked to -(L - via the NR10 group and to -(L2)r,-R4 via the C(=0) group;
L1 is C1-4 alkylene, C24 alkenylene or C2-4 alkynylene, wherein said C alkylene, said C2.4 a!kenylene and said C2-4 alkynylene are optionally interrupted by 0, S or NR11, and wherein said C1.4 alkylene, said C2-4 alkenylene and said C2-4 alkynylene are optionally substituted with one or more R13;
L2 is C1-6 alkylene, CK. alkenylene or C26 alkynylene, wherein said C .6 alkylene, said C? 6 alkenylene and said C2-6 alkynylene are optionally interrupted by 0, S or NR11, and wherein said Ci-s alkylene, said C2-6 alkenylene and said C? 6 alkynylene are optionally substituted with one or more R13;
m and n are each independently selected from 0 and 1 ;
R4 is -NR1 R15 or R16; R7 and R8 are each independently selected from hydrogen and Ci-e alkyl, or R7 and R8 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, C1.5 alkyl, -OH, -NH2, -NH(Cu alkyl), and -N(&.6 alkyl)?;
each L3 is independently selected from a bond and C alkylene;
R10 and R11 are each independently selected from hydrogen, C1-6 alkyl and C1 6 haloalkyi;
-R12- 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 -R12- is linked to -(L - and -(Lz)n- R4 in a 1 ,3-disposition;
each R13 is independently selected from C1-6 alkyl, halo, d-e haloalkyi, -LAcarbocyclyl, -L3-ar l, -L3-heterocyclyl and -L3-heieroaryl, wherein the carbocyciyl in -LAcarbocyclyl, the aryl in -L3-aryl, the heterocyclyl in -L3- heterocyclyl and the heteroaryl in -L3-heteroaryl are each optionally substituted with one or more R17, and wherein two groups R13 attached to a same C atom of the alkylene group are optionally linked together to form with said C atom a C3 e 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 C1-6 alkyl;
R14 and R15 are each independently selected from hydrogen, Ci-e alkyl, Ci-e haloalkyi, -(C1.6 alkylene)-OR13, -LA carbocyciyl, - LAary! -LAheterocyclyl and -L3-heteroaryl, wherein the carbocyciyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are optionally substituted with one or more R19;
R16 is a 3- to 18-membered saturated, partially saturated or aromatic heterocyclic group which contains one N atom and optionally contains one or more further heteroatoms selected from N, 0 and S, wherein R16 is optionally substituted with one or more R20;
each R20 is independently selected from C e alkyl, Ci-s haloalkyi, halo, C a!koxy, C1-6 haloalkoxy, -OH, -NH2, -NH(Ci 6 alkyl), -N(Gi-s alkyl)2, -CN, -C(=0)R21, -C(=0)NR22R23, -NR22C(=0)R21, -NR22C(=0)NR22R23, -NR 2S02R21, -S02NR22R23, -S02R21, -LAcarbocyclyl, -L3-aryl, -LAheterocyclyl and -L3-heteroaryl, wherein the carbocyciyl in -LAcarbocyclyl, the aryl in -L3-aryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -L3- heteroaryl are optionally substituted with one or more R24;
each R3, each R1'", each R19 and each R24 is independently selected from alkyl, Ci-B haloalkyi, halo, Ci e alkoxy, C, 6 haloalkoxy, -OH, -NH2, -NH(C! 6 alkyl), -N(C,.6 alkyl)2 ,-CN, -C(=0)R21, -C(=0)NR22R23, -NR22C(=0)R21, -NR22C(=0)NR22R23, -NR 2S02R21, -S02NR 2R23 and -S02R21;
each R21 is independently selected from C1.5 alkyl; and
each R6, each R18, each R22 and each R23 is independently selected from hydrogen and Cu 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 CR5 and N, and Z4 and Z5 are each independently selected from CR3 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 (CR5 in the case of Z1, 7? and Z3, and CR3 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 (CR5 in the case of Z\ Z2 and Z3, and CR3 in the case of Z4 and Z5). Accordingly, a compound of formula (I) includes compounds of Formula (la), (lb), (Ic), (Id), (le) and (If):
Figure imgf000009_0001
(la) (lb)
Figure imgf000010_0001
One subset of the compounds of Formula (I) includes those of Formula (II):
Figure imgf000010_0002
A compound of Formula (II) corresponds to compounds of Formula (la), (lb) and (Ic) as previously defined.
The present invention relates to a compound of any of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (il) 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 (Ib), or a salt thereof.
In some embodiments, the compound of Formula (II) is a compound of Formula (ic), or a salt thereof. Accordingly, while various embodiments described herein below relate to a compound of Formula (I),
(la), (Ib), (Ic), (Id), (le), (If) or (II), it is particularly preferred that the compound specified in each one of these embodiments is a compound of Formula (II), i.e. a compound of formula (la), (Ib) or (Ic), or a salt thereof.
Preferably, in a compound of Formula (I), (la), (Ib), (ic), (Id), (le), (If) or (II), R1 and R2 are each independently selected from hydrogen, Cw alkyl, d-e haloalkyl, -(Ci-s alkylene)-OR6, -(Ci-e alkylene)-NR7Rs, - L -carbocyclyl, -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 R9.
More preferably, in a compound of Formula (I), (la), (Ib), (Ic), (Id), (le), (If) or (II), R1 and R2 are each independently selected from hydrogen, Ci.e alkyl and Ci-e haloalkyl.
In some embodiments, in a compound of Formula (I), (la), (Ib), (Ic), (Id), (le), (If) or (II), R1 is hydrogen.
More preferably, in a compound of Formula (I), (la), (Ib), (Ic), (Id), (le), (If) or (II), R1 is hydrogen and R2 is selected from hydrogen, CM alkyl and C-, s haloalkyl.
Still more preferably, in a compound of Formula (I), (la), (Ib), (Ic), (Id), (le), (If) or (II), R1 and R2 are both hydrogen.
In some embodiments, in a compound of Formula (I), (la), (Ib), (Ic), (Id), (le), (If) or (II), each R3 is independently selected from hydrogen, halo, Ci 3 alkyl, Ci 3 haloalkyl and C1.3 hydroxyalkyl.
In some embodiments, in a compound of Formula (I), (la), (Ib), (Ic), (Id), (le), (If) or (II), one of the groups R3 is selected from hydrogen, halo, Ci 3 alkyl, Ci 3 haloalkyl and C1.3 hydroxyalkyl, and the remaining groups R3 are hydrogen.
In some embodiments, in a compound of Formula (I), (la), (ib), (Ic), (Id), (le), (If) or (II), one of the groups R3 is selected from hydrogen, fluoro, methyl, trifluoromethyl and -CH?OH, and the remaining groups R3 are hydrogen.
Preferably, in a compound of Formula (I), (la), (Ib), (Ic), (Id), (le), (If) or (II), each R3 is hydrogen.
More preferably, in a compound of Formula (I), (la), (Ib), (Ic), (Id), (le), (If) or (II):
R1 is hydrogen;
R2 is selected from hydrogen, Ci s alkyl and Ci-e haloalkyl, and preferably is hydrogen; and
each R3 is hydrogen.
In some embodiments, in a compound of Formula (I), (la), (Ib), (ic), (Id), (le), (If) or (II), one of the groups R5 is selected from hydrogen and fluoro, and the remaining groups R5 are hydrogen.
Preferably, in a compound of Formula (I), (la), (Ib), (Ic), (Id), (le), (If) or (II), each R5 is hydrogen. More preferably, in a compound of Formula (I), (ia), (lb), (lc), (Id), (le), (If) or (II), each R3 and each R5 is hydrogen.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), L1 is C1.4 alkylene, wherein said Cu alkylene is optionally interrupted by 0, S or NR 1, and wherein said C alkylene is optionally substituted with one or more R13.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), L1 is (CH2 4, wherein said (CH2)u is optionally substituted with one or more (preferably one or two) R13.
Preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), L1 is (CH2)u.
More preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), L1 is (CH2)i.?.
Still more preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), L1 is CH2.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), L2 is Cu; alkylene, wherein said C1.5 alkylene is optionally interrupted by 0, S or NR11, and wherein said C1-6 alkylene is optionally substituted with one or more R13.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), L2 is (CH?)i e, wherein said (CH?)i.s is optionally substituted with one or more (preferably one or two) R13.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), L2 is (CH2)2-6, wherein said (Ch^-s is optionally substituted with one or more (preferably one or two) R13
Preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), L2 is (Ch ju, wherein said (CH2 4 is optionally substituted with one or more (preferably one or two) R13.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), L2 is (CH2)2-4, wherein said (CH?)2-4 is optionally substituted with one or more (preferably one or two) R13.
More preferably, L? is (CH2)u, still more preferably (CH2)2-4, and even more preferably (Ch½)2-3.
Preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), m is selected from 0 and 1 , and n is 1.
More preferably, in a compound of Formula (I), (Ia), (lb), (lc), (Id), (le), (If) or (II), m is 0, and n is 1.
In preferred embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), m is selected from 0 and 1 , and preferably is 0; L1 is (CH2)i ?, preferably CH2; n is 1 ; and L2 is (Ch½)i-4 wherein said (CH2)i-4 is optionally substituted with one or more (preferably one or two) R13, and preferably L2 is (CH2)i- .
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), when Y is - NR11- or -0- and R4 is -NR14R15 or N-linked-R 6, n is 1 and L2 is C2-6 alkylene (preferably
Figure imgf000012_0001
wherein said C2-5 alkylene (or said (CH?)? 5) is optionally interrupted by 0, S or NR11, and wherein said C2-6 alkylene (or said (CH2)2-6 is optionally substituted with one or more R13.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), when Y is - NR11- or -0- and R4 is -NR14R15 or N-linked-R15, n is 1 and L2 is (CH2)2-6, wherein said (CH?)2.S is optionally substituted with one or more R13. In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is selected from -NR13C(=0)-, -NR11-, -0-, and -CH2-, wherein said -NR10C(=O)- is linked to -(L1)m- via the NR10 group and to -(L2)„-R4 via the C(=0) group.
In a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), the Cu alkylene, C2-4 alkenylene and C2-4 alkynylene in L1 and the C alkylene, C2-6 alkenylene and C2-5 alkynylene in L2 can be optionally substituted with one or more R13. As defined above, each R13 is independently selected from C1.5 alkyl, halo, Ci- 6 haloalkyl, -LAcarbocyclyl, -L3-aryl, -L3-heierocyclyl and -LAheteroaryl, wherein the carbocyclyl in -LA carbocyclyl, the aryl in -L3-aryl, the heterocyciyl in -U-heterocyclyl and the heteroaryi in -L3-heteroaryl are each optionally substituted with one or more R17. Moreover, two groups R13 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 C3-6 cycloalkyi and 4- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from halo and Ci s alkyl. Examples of said Ca-6 cycloalkyi or 4- to 6-membered heterocyclic ring formed by said two R13 groups attached to a same C atom together with said C atom are shown below:
Figure imgf000013_0001
wherein each ring depicted above can be optionally substituted with one or more substituents independently selected from halo and Cj-s alkyl.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), each R13 is independently selected from d-c alkyl and -LAaryi, wherein the aryl in -lAaryl is optionally substituted with one or more R17. Preferably, said aryl is phenyl optionally substituted with one or more R".
In a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), -R12- 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 -R12- is linked to the -(L1)m- and -(L2)n-R4 group in a 1 ,3-disposition. Examples of such -R12- groups are shown in Table 1 , below.
Figure imgf000014_0001
wherein unless specified otherwise, these groups can be read in each of the two possible orientations, i.e. they can be linked to L' 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), -R12- is a group selected from Table 1. In some embodiments, -R12- is
Figure imgf000014_0002
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (li), Y is -NR11-.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (if) or (II), Y is -0-.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is -CH2-.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is -NR10C(=O)-, wherein said -NR!0C(=O)- is linked to -(L - via the NR10 group and to -(L2)„-R4 via the C(=0) group.
Preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is selected from -NR11-, - 0- and -CHr. In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), R10 is hydrogen.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), R11 is hydrogen.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is selected from -NR10C(=O)-, -NR 1-, -0-, -R12- and -CHr, wherein said -NR10C(=O)- is linked to -([_ - via the NR10 group and to -(L2)n-R4 via the C(=0) group; m and n are each independently selected from 0 and 1 : L1 is (CH∑)i-2; and L2 is (CH2)i-6, wherein said (CH?)i e is optionally substituted with one or more (preferably one or two) R13; with the proviso that when Y is -NR11- or -0- and R4 is -NR14R15 or N-linked-R 6, then n is 1 and L2 is (CH2)2-6, wherein said (CH?)? 6 is optionally substituted with one or more (preferably one or two) R13.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is selected from -NR13C(=0)-, -NR11-, -0-, -R12- and -CHr, wherein said -NR1CC(=0)- is linked to -(L - via the NR10 group and to -(L2)n-R4 via the C(=0) group; m and n are each independently selected from 0 and 1 : L1 is CH?; and L2 is (CH2)i-4, wherein said (CH2>i-4 is optionally substituted with one or more (preferably one or two) R13; with the proviso that when Y is -NR11- or -0- and R4 is -NR1 R15 or N-linked-R16, then n is 1 and L2 is (CH?)2.4, wherein said (CH2)2 is optionally substituted with one or more (preferably one or two) R13.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (if) or (II), Y is -NR10C(=O)-, wherein said -NR19C(=0)- is linked to -(L - via the NR10 group and to -(L2)„-R4 via the C(=0) group; m and n are each independently selected from 0 and 1 ; L1 is (CH2)i-4, wherein said (CH?)i , is optionally substituted with one or more (preferably one or two) R13; and L2 is (Ch ji-e, wherein said (CH∑)ts is optionally substituted with one or more (preferably one or two) R13.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is -NR^C^O)-, wherein said -NR10C(=O)- is linked to -(L1)m- via the NR10 group and to -(L )„-R4 via the C(=0) group; m and n are each independently selected from 0 and 1; U is (Chb)^; and L2 is (CH2) , wherein said (CH2)i-4 is optionally substituted with one or more (preferably one or two) R13.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is -NR 0C(=O)-, wherein said -NR10C(=O)- is linked to -(L - via the NR10 group and to -(L2)„-R4 via the C(=0) group; m is 0; n is 0 or 1 ; and L2 is (CH2)v4, wherein said (CH?)u is optionally substituted with one or more (preferably one or two) R13.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is
-NR10C(=O)-, wherein said -NR10C(=O)- is linked to via the NR10 group and to -(L2)n-R4 via the C(=0) group; m is 0; n is 0; and R4 is C-linked-R16.
Preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is selected from -
NR13C(=0)-, -NR1'-, -0-, -R12- and -CH , wherein said -NR15C(=0)- is linked to -{l_V via the NR10 group and to -(L2)„-R4 via the C(=0) group; m is selected from 0 and 1 ; n is 1 ; L1 is (CHj)i ?; and L2 is (CH2)i-s, wherein said (CH2)i-6 is optionally substituted with one or more (preferably one or two) R13; with the proviso that when Y is -NR11- or -0- and R4 is -NR14R15 or N-!inked-R15, then V is (CH2)2.6, wherein said (CH2)2 6 is optionally substituted with one or more (preferably one or two) R13.
More preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), Y is selected from - NR10C(=O)-, -NR11-, -0-, -R12- and -CHr, wherein said -NR10C(=O)- is linked to -(L. - via the NR10 group and to -(L?)n-R* via the C(=0) group; m is selected from 0 and 1 ; n is 1 ; L1 is CH2; and L2 is (CH2)i-4, wherein said (CH2)i is optionally substituted with one or more (preferably one or two) R13; with the proviso that when Y is - NR11- or -0- and R4 is -NR14R15 or N-linked-R16, then L2 is (CH?)2 >, wherein said (CH2)2-4 is optionally substituted with one or more (preferably one or two) R13.
Still more preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), Y is selected from -NR11-, -0- and -CH2-; m is selected from 0 and 1 , and preferably is 0; n is 1 ; L1 is (CH?)i ?; and L2 is (CH?)i 6, wherein said (CH2)i_6 is optionally substituted with one or more (preferably one or two) R'3, with the proviso that when Y is -NR11- or -0- and R4 is -NR14R15 or N-linked-R15, then L2 is (CH2)M, wherein said (CH2)2.6 is optionally substituted with one or more (preferably one or two) R13.
Even more preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), Y is selected from -NR11-, -0- and -CH2-; m is selected from O and 1 , and preferably is 0; n is 1 ; V is CH¾ and L2 is (CH2)i-4, wherein said (CH?)i., is optionally substituted with one or more (preferably one or two) R13, with the proviso that when Y is -NR11- or -0- and R4 is -NR14R« or N-linked-R15, then L2 is (CH2)2-4, wherein said (CH2)2-4 is optionally substituted with one or more (preferably one or two) R13. While Y is selected from -NR11-, -0- and -CH2- and m is selected from 0 and 1 , it is preferred that when m is 1 then Y is -0-.
In some preferred embodiments, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (if) or (II), Y is -
NR11-; m is selected from 0 and 1 , and preferably is 0; n is 1 ; L1 is (CH2)i ?; and L2 is (CH?)^, wherein said (CH2)i-6 is optionally substituted with one or more (preferably one or two) R13, with the proviso that when R4 is - NR14R15 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) R13.
More preferably, in a compound of Formula (I), (la), (lb), (Ic), (id), (le), (If) or (II), Y is -NR11-; m is selected from 0 and 1, and preferably is O; n is 1 ; L1 is CH2; and L2 is (CH2)i./„ wherein said (CH?)u is optionally substituted with one or more (preferably one or two) R13, with the proviso that when R4 is -NR14R15 or N-linked- R16, then L2 is (CH2)2j4, wherein said (CH2)2.4 is optionally substituted with one or more (preferably one or two) R1
In some preferred embodiments, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), Y is -
0-; m is selected from 0 and 1 ; n is 1 ; L1 is (CH )i 2; and L2 is (CH2)i-6, wherein said (CH2)t.e is optionally substituted with one or more (preferably one or two) R13, with the proviso that when R4 is -NR1 R15 or N-linked- R15, then L2 is (CH2)? 6, wherein said (CH2)2.6 is optionally substituted with one or more (preferably one or two) R13.
More preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), Y is -0-; m is selected from 0 and 1 ; n is 1 ; L1 is CH2; and L2 is (CH2)i-4, wherein said (CH2)u is optionally substituted with one or more (preferably one or two) R13, with the proviso that when R4 is -NR1 R15 or N-linked-R16, then L2 is (CH2)2-4, wherein said (CH2)2.4 is optionally substituted with one or more (preferably one or two) R13.
In some preferred embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is -CH2-; m is 0; n is 1 ; and L2 is (CH2)i-6, wherein said (CH2H6 is optionally substituted with one or more (preferably one or two) R13.
More preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is -CH2-; m is 0; n is 1 ; and L2 is (CH2)?- , wherein said (CH2)2-4 is optionally substituted with one or more (preferably one or two) R13.
While each of U, 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 imgf000018_0001
wherein any aikylene in the above groups can be optionally substituted with one or more (preferably one or two) R13 as defined above. Examples of groups in table 2 wherein such aikylene groups are substituted with one or more R13 are provided in Table 3 below: able 3:
Figure imgf000019_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 preferred embodiments, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), -(U)m-Y-(L2)n- is selected from the groups listed in Table 4, below:
Table 4:
Figure imgf000020_0001
wherein any a!kylene in the above groups is optionally substituted with one or more, preferably one or two, R13.
In some embodiments, in the groups listed in Table 4, R10 is hydrogen and R11 is hydrogen.
More preferably, -(L1)m-Y-(L2)n- is selected from the following list:
Figure imgf000020_0002
even more preferably, -(L1)m-Y-(L2)n- is selected from the following list:
Figure imgf000020_0003
The specific divalent groups -(.. - Y-(L2)n- shown at various instances, including in tables 2, 3 and 4 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 R4.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), R4 is -NR14R15.
Preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), R14 and R15 are each independently selected from hydrogen, O-e alkyl, Ci s haloalkyl (preferably Cu fluoroalkyl), -(C alkylene)- OR18, -L3-carbocyclyl, -(CH2)i-4-aryl, and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocycly!, the aryl in - (CH2)i-4-aryl, and the heteroaryi in -LAheteroaryl are optionally substituted with one or more R19. Preferably, said aryl in -(CH?) -aryl is phenyl optionally substituted with one or more R19. Preferably, said carbocyclyl in - LAcarbocyclyl is C3-7 cycloalkyi optionally substituted with one or more R19.
More preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), R14 and R15 are each independently selected from hydrogen, Ci-e alkyl, C1 5 haloalkyl (preferably u fluoroalkyl), -(Ci-s alkylene)- OR18, -L3-Cj 7 cycloalkyi, -(CH?)i 4-phenyi and -L3-heteroaryl, wherein the C3.7 cycloalkyi in the -LAC3.7 cycloalkyi is optionally substituted with one or more groups independently selected from Ci e alkyl and halo, and the phenyl in -(CH2)i.4-phenyl and the heteroaryl in -L3-heteroaryl are each optionally substituted with one or more R19.
Still more preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), R14 and R15 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl (preferably Ci e fluoroalkyl), -IAC3-7 cycloalkyi, and -(CH2)i-4-phenyl, wherein the C3.7 cycloalkyi in the -LAC37 cycloalkyi is optionally substituted with one or more groups independently selected from Ci.$ alkyl and halo, and the phenyl in -{Chkju-phenyl is optionally substituted with one or more R19. In some preferred embodiments, R14 and R15 are each independently selected from d.s alkyl and -(CH2)i-4-phenyl, wherein the phenyl in -(CH∑)i-4-phenyi is optionally substituted with one or more R19. In some embodiments, said phenyl in said in -(CH?)i , -phenyl groups is unsubstituted. In some embodiments, R14 and R15 are each independently selected from hydrogen, methyl, ethyl, 2,2,2-trifiuoroethyl, C3-7 cycloalkyi, -CH2-C3-7 cycloalkyi, and -(CHjJi 2-phenyl, wherein the C3.7 cycloalkyi and the C3-7 cycloalkyi in the -CH2-C3-7 cycloalkyi are optionally substituted with one or more groups independently selected from Ci e alkyl and halo, and the phenyl in -(CH2)i-2-phenyl is optionally substituted with one or more R19.
In some embodiments, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), R4 is R16. In a compound of Formula (I), (la), (lb), (Ic), (id), (le), (If) or (II), R15 is a 3- to 18-membered saturated, partially saturated or aromatic heterocyclic group which contains one N atom and optionally contains one or more, preferably from 1 to 4, further heteroatoms selected from N, 0 and S. Said heterocyclic group can be monocyclic or muiticyciic (e.g. fused, bridged or spiro rings, or a combination thereof). Nitrogen or sulfur atoms may be optionally oxidized (e.g., -N=0, -S(=0)-, or -S(=0)2-) and additionally one or more of the carbon atoms of the heterocyclyl may be optionally oxidized to give an oxo group, R16 can be attached to the rest of the molecule through any C or N atom that results in a stable structure; as used in the present specification, "C- linked-R16" means that a R16 group that is linked to the remainder of the molecule through a C atom and "N- linked-R16" means a R16 group that is linked to the remainder of the molecule through a N atom. Any R1S is optionally substituted with one or more R20, which can be the same or different and can be placed at any available position.
Preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), R4 is -NR14R^ or R16, wherein R16 is a saturated 3- to 18-membered heterocyclic group which contains one N atom and optionally contains one or more, preferably one or two, further heteroatoms selected from N, 0 and S, wherein R16 is optionally substituted with one or more R20. Preferably, said R16 is N-linked-R16. More preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), R4 is R,6 and R16 is a saturated 3- to 18-membered heterocyclic group which contains one N atom and optionally contains one or more, preferably one or two, further heteroatoms selected from N, 0 and S, wherein R16 is optionally substituted with one or more R20. Preferably, said R16 is N-linked-R16.
Yet more preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), R4 is R16 and R16 is a saturated 4- to 7-membered heterocyclic group which contains one N atom and optionally contains one further heteroatom selected from N, 0 and S, wherein R16 is optionally substituted with one or more R20. Preferably, each R20 is independently selected from fr.s alkyl, C haloalkyl and halo. Preferably, said R16 is N- linked-R16.
Still more preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), R4 is R16 and R15 is selected from piperidinyl, pyrrol id inyl and morpholinyl, wherein R15 is optionally substituted with one or more R20. Preferably, each R20 is independently selected from CM alkyl, Cv6 haloalkyl and halo.
Even more preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), R4 is R16 and R16 is selected from 1 -piperidinyl, 1-pyrrolidinyi and 1 -morpholinyl, wherein R16 is optionally substituted with one or more R20. Preferably, each R20 is independently selected from C1.5 alkyl, C1.5 haloalkyl and halo. In some embodiments R4 is 1 -morpholinyl. In some embodiments R4 is 1-piperidiny optionally substituted with one or more groups independently selected from Ci-s alkyl, 0.6 haloalkyl and halo. It is particularly preferred that R4 is 1 -piperidinyl substituted with one or more (preferably one or two) fluoro, and more preferably R4 is 4,4-difluoro- 1 -piperidinyl.
In a preferred embodiment, the invention provides a compound of Formula (I), (la), (lb), (Ic), (Id), (le),
(If) or (II), preferably of Formula (II), or a salt thereof, wherein:
R1 and R2 are each independently selected from hydrogen, Ci.s alkyl and O r. haloalkyl, preferably R1 is hydrogen and R2 is selected from hydrogen, Ci.6 alkyl and O e haloalkyl, and more preferably R1 and R2 are both hydrogen;
each R3 is hydrogen;
each R5 is independently selected from hydrogen and halo (preferably fluoro), and preferably each R5 is hydrogen;
Y is selected from -NR,^(=0)-, -NR11-, -0-, -R12- and -CH2-, wherein said -NR1SC(=0)- is linked to -{L%- via the NR10 group and to -(L )n-R4 via the C(=0) group, and preferably Y is selected from -NR11-, -0- and -CH2-; m and n are each independently selected from 0 and 1 ;
U is (CH2)i-2, wherein said (CH2)i-2 is optionally substituted with one or more (preferably one or two) R13, and preferably L1 is (CH?)y?; and
L2 is (CH?)i 6, wherein said (CH?)i s is optionally substituted with one or more (preferably one or two) R13.
In further preferred embodiments, the invention provides a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably of Formula (II), or a salt thereof, wherein:
R1 and R2 are both hydrogen; each R3 and each R5 is hydrogen;
Y is selected from -NR10C(=O)-, -NR11-, -0-. -R12- and -CHr, wherein said -NR1»C(=0)- is linked to via the NR10 group and to -(L2)„-R4 via the C(=0) group, and preferably Y is selected from -NR11-, -0- and -CH2; m and n are each independently selected from 0 and 1 ;
L1 is (CH2)i-2, wherein said (Chfe)^ is optionally substituted with one or more (preferably one or two) R13, preferably L1 is (CH?)i ? and more preferably L1 is CH2; and
L2 is (CH2)i , wherein said (CH2)i-4 is optionally substituted with one or more (preferably one or two) R13; with the proviso that when Y is -NR11- or -0- and R4 is -NR14R15 or N-linked-R16, then n is 1 and L2 is (CH?)? 4, wherein said (CH2)2-4 is optionally substituted with one or more (preferably one or two) R13.
in further preferred embodiments, the invention provides a compound of Formula (I), (la), (lb), (Ic), (Id),
(le), (if) or (II), preferably of Formula (II), or a salt thereof, wherein:
R1 and R2 are both hydrogen;
each R3 and each R5 is hydrogen;
Y is selected from -NR10C(=O)-, -NR11-, -0-, -R12- and -CH?-, wherein said -NR1¾(=0)- is linked to -(L - via the NR10 group and to -(L2)n-R4 via the C(=0) group, and preferably Y is selected from -NR11-, -0- and -CH2; m is selected from O 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) R13, preferably L1 is (CH2 2 and more preferably L1 is CH2 and
L2 is (CH2)i-4, wherein said (Chbjw is optionally substituted with one or more (preferably one or two) R13; with the proviso that when Y is -NR11- or -0- and R4 is -NR14R15 or N-linked-R1'3, then L2 is (CH?)?. , wherein said
(CH2)2 is optionally substituted with one or more (preferably one or two) R13.
In further preferred embodiments, the invention provides a compound of Formula (I), (la), (lb), (Ic), (Id),
(le), (If) or (II), preferably of Formula (II), or a salt thereof, wherein:
R1 and R2 are both hydrogen;
each R3 and each R6 is hydrogen; and
-{L1)m-Y-(L2)n- is selected from the following list:
Figure imgf000024_0001
wherein any aikylene depicted in the above groups is optionally substituted with one or more, preferably one or two, R13, and preferably -(L1)m-Y-(L2)n- is selected from
Figure imgf000024_0002
more preferably, -(L1)m-Y-(L2)n- is selected from:
Figure imgf000024_0003
It is preferred that R4 is -NR14R15 or N-linked-R16.
More preferably, the invention provides a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably of Formula (II), or a salt thereof, wherein:
R1 and R2 are both hydrogen;
each R3 and each R5 is hydrogen;
Y is selected from -NR10C(=O)-, -NR1 -, -0-, -R12- and -CH2-, wherein said -NR10C(=O)- is linked to -(L - via the NR10 group and to -{L2)„-R4 via the C(=0) group, and preferably Y is selected from -NR1'-, -0- and -CH?; m and n are each independently selected from 0 and 1 , preferably m is selected from 0 and 1 and n is 1 , and more preferably m is 0 and n is 1 ; L1 is (CH?) , wherein said (CH2)i-2 is optionally substituted with one or more (preferably one or two) R13, preferably L1 is (CH2)i-2 and more preferably L1 is CH¾
L2 is (CH2)i , wherein said (CH?)u is optionally substituted with one or more (preferably one or two) R13; with the proviso that when Y is -NR11- or -0- and R4 is -NR14R15 or N-linked-R1* then n is 1 and L2 is (CH2)2-4, wherein said (CH?^ is optionally substituted with one or more (preferably one or two) R13; and
R4 is -NR14R15 or R16, wherein R16 is a saturated 3- to 18-membered heterocyclic group which contains one N atom and optionally contains one or more, preferably one or two, further heteroatoms selected from N, 0 and S, wherein R16 is optionally substituted with one or more R20, Preferably, said R16 is a saturated 4- to 7- membered heterocyclic group which contains one N atom and optionally contains one further heteroatom selected from N, 0 and S, wherein R16 is optionally substituted with one or more R20; more preferably said R16 is selected from 1-piperidinyl, 1-pyrro!idinyl and 1-morpholinyl, wherein R16 is optionally substituted with one or more R20 , wherein preferably each R20 is independently selected from Ci-e alkyi, Ci-e haloalkyl and halo. It is particularly preferred that R13 is 1-piperidinyl substituted with one or more (preferably one or two) fluoro, and more preferably R16 is 4,4-difluoro-1 -piperidinyl.
Still more preferably, the invention provides a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably of Formula (II), or a salt thereof, wherein:
R1 and R2 are both hydrogen;
each R3 and each R5 is hydrogen;
-(L1)m-Y-(L2)n- is selected from the following list:
Figure imgf000025_0001
wherein any alkylene depicted in the above groups is optionally substituted with one or more, preferably one or two, R13 , and preferably -(L1)m-Y-(L2)n- is selected from
Figure imgf000026_0001
and
R4 is -NR1 R15 or R15, wherein R15 is a saturated 3- to 18-membered heterocyclic group which contains one N atom and optionally contains one or more, preferably one or two, further heteroatoms selected from N, 0 and S, wherein R16 is optionally substituted with one or more R20. Preferably, said R16 is N-linked-R16. It is further preferred that said R16 is a saturated 4- to 7-membered heterocyclic group which contains one N atom and optionally contains one further heteroatom selected from N, 0 and S, wherein R16 is optionally substituted with one or more R20, and more preferably said R16 is selected from 1-piperidinyi, 1-pyrrolidinyl and 1-morpholinyl, wherein R16 is optionally substituted with one or more R20 , wherein preferably each R20 is independently selected from Cw alkyl, Ci.& haloalkyl and halo. It is particularly preferred that R16 is 1-piperidinyi substituted with one or more (preferably one or two) fluoro, and more preferably R16 is 4,4-difluoro-1-piperidinyl.
In some embodiments, the invention provides a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably of Formula (II), or a salt thereof, wherein:
R1 and R2 are both hydrogen;
each R3 and each R5 is hydrogen;
Y is -NR10C(=O)-, wherein said -NR10C(=O)- is linked to -(L - via the NR10 group and to -(L2)„-R4 via the C(=0) group;
m is 0;
n is selected from 0 or 1 ,
L2 is (Cti?)ii, wherein said (CH2)i-4 is optionally substituted with one or more (preferably one or two) R13;
R jS -N 1 R15 or Rio wherein R16 is a saturated 3- to 18-membered heterocyclic group which contains one N atom and optionally contains one or more, preferably one or two, further heteroatoms selected from N, 0 and S, wherein R16 is optionally substituted with one or more R20, In some embodiments, said R16 is C-iinked-R16. In some embodiments, R16 is 3-piperidinyl, 4-piperidinyl or 3-pyrrolidinyl, wherein R16 is optionally substituted with one or more R20.
A preferred group of compounds of the invention corresponds to those compounds of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably of Formula (II), or a salt thereof, wherein:
R1 and R2 are each independently selected from hydrogen, Ci e alkyl and Ci-s haloalkyi, preferably R1 is hydrogen and R2 is selected from hydrogen, Ci e alkyl and C1-3 haloalkyi, and more preferably R1 and R2 are both hydrogen;
each R3 and each R5 is hydrogen;
Y is selected from -NR11-, -0- and -CH2-,
m is selected from 0 and 1 , with the proviso that when m is 1 then Y is -0-, and preferably m is 0;
n is 1 ;
Y is CH2;
L2 is (CH?)i , preferably (CH2)2-3;
R" is -NR14R15 or R16;
R14 and R15 are each independently selected from hydrogen, 0-s alkyl, Ci-e haloalkyi (preferably Ci-s fiuoroalkyl), -LAC3-7 cycloalkyl, and -(CH2)i 4-phenyl, wherein the C3.7 cycloaikyl in the -L3-Ca.7 cycloalkyl is optionally substituted with one or more groups independently selected from Ci-s alkyl and halo, and the phenyl in -(CH2)i 4-phenyl is optionally substituted with one or more R,s; and
R16 is a saturated 4- to 7-membered heterocyclic group which contains one N atom and optionally contains one further heteroatom selected from N, 0 and S, wherein R16 is optionally substituted with one or more R20, wherein preferably each R20 is independently selected from C1.5 alkyl, C1..3 haloalkyi and halo, and wherein said
R16 is N-linked-R16. It is preferred that R4 is 1-piperidinyl substituted with one or more (preferably one or two) fluoro, and more preferably R4 is 4,4-difiuoro-1-piperidinyl.
Another preferred group of compounds of the invention corresponds to a compound of Formula (I), (la), (lb). (Ic), (Id), (le), (If) or (II), preferably of Formula (II), or a salt thereof, wherein:
R1 and R2 are each independently selected from hydrogen, Ci s alkyl and C1.6 haloalkyi, preferably R1 is hydrogen and R2 is selected from hydrogen, Crg alkyl and C1-6 haloalkyi, and more preferably R1 and R2 are both hydrogen;
each R3 is hydrogen;
each R5 is independently selected from hydrogen and halo (preferably fluoro), and preferably each R5 is hydrogen;
Y is selected from -NR10C(=O)-, -NR11-, -0-, -R12- and -CH?-, wherein said -NR1CC(=0)- is linked to -(l_V via the NR12 group and to -(L?)n-R4 via the C(=0) group, and preferably Y is selected from -NR11-, -0- and -CH?-; m and n are each independently selected from O and 1 , and preferably m is 0 and n is 1 ;
L1 is (CH2)i-2, wherein said (CH2)i-2 is optionally substituted with one or more (preferably one or two) R13, and preferably L1 is (CH2)i.2; L2 is (CH2)i-6, wherein said (CH2)i-6 is optionally substituted with one or more (preferably one or two) R13, preferably L2 is (CH?)i.-i, and more preferably (CH?)? 3 ; and
R4 is 1-piperidinyl substituted with one or more (preferably one or two) fluoro, and preferably R4 is 4,4-difluoro-
1-piperidinyl.
A particularly preferred group of compounds of the invention corresponds to those compounds of
Formula (I), (la), (lb), (Ic), (id), (le), (If) or (II), preferably of Formula (II), more preferably of formula (la), or a salt thereof, wherein:
R1 and R2 are each independently selected from hydroge Ci-e alkyl and Ci e haloalkyl, preferably R1 is hydrogen and R2 is selected from hydrogen, Cve alkyl and C 6 haloalkyl, and more preferably R1 and R2 are both hydrogen;
each R3 and each R5 is hydrogen;
Y is selected from -NR 1-, -0- and -CH2-;
m is selected from 0 and 1 , with the proviso that when m is 1 then Y is -0-, and preferably m is 0;
n is 1 ;
L1 is CH2:
L2 is (CH2)i-4, preferably (CH2)2.3 and
R4 is 1-piperidinyl substituted with one or more (preferably one or two) fluoro, and preferably R4 is 4,4-difluoro- 1-piperidinyl.
In another particularly preferred embodiment, the invention provides a compound of Formula (I) or a salt thereof, selected from:
5'-((3-(4,4-Difiuoropiperidin-1-yl)propyl)amino)-[2,2'-bipyridine]-4-carboxamide;
5'-(3-(4,4-Difluoropiperidin-1-yl)propoxy)-[2,2'-bipyridine]-4-carboxamide;
5'-(4-(4,4-Difluoropiperidin-1-yl)butyl)-[2,2'-bipyridine]-4-carboxamide;
5'"((3-Morpholinopropyl)amino)-[2,2'-bipyridine]-4-carboxamide;
2-(5-((3-(Diethyl amino)propyl)amino) pyrazin-2-yl) isonicotinamide;
5'-((3-(4,4-Difluoropiperidin-1-yl)propyl)(methyl)amino)-[2,2'-bipyridine]4-carboxamide;
5'-(3-(Ethyl(phenethyl)amino)propoxy)-[2,2'-bipyridine]-4-carboxamide;
or a salt thereof.
In some embodiments, the invention provides a compound of Formula (I) selected from the compounds listed in Table 5, or a salt thereof:
Table 5:
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
In some embodiments, the invention provides a compound of Formula (I) selected from the compounds listed in Table 6, or a salt thereof:
Table 6:
Figure imgf000031_0002
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000034_0002
Figure imgf000034_0003
Figure imgf000035_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, heteroaryl, carbocyclyl and heterocyclyl groups are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term "pyridyl" (or pyridinyl) may refer to a pyridin-2- yl, pyridin-3-yl or pyridin-4-yl ring, and the term "piperidinyl" may refer to a piperidin-1-yl, piperidin-2-yl, piperidin-3-yl or piperidin-4-yl ring.
The term "n-membered" where n is an integer describes the number of ring-forming atoms in a ring system where the number of ring-forming atoms is n. For example, phenyl is an example of a 6-membered aryl, cyclopropyl is an example of a 3-membered carbocyclyl, pyrazolyl is an example of a 5-membered heteroaryl, quinolinyl is an example of a 10-membered heteroaryl, piperidinyl is an example of a 6-membered heterocyclyl, and decahydroquinolinyl is an example of a 10-membered heterocyclyl.
The term "Cy.z", where y and z are integers, used in combination with a chemical group, designates a range of the number of carbon atoms in the chemical group, with y and z being the endpoints, which are included. Examples include C1-4, 0-6, Cn, C3-7 and the like.
The term "Cy 7 alkyl" refers to a saturated straight or branched acyclic hydrocarbon group having y to z carbon atoms. Thus, a 0 * alkyl is an alkyl having from one to six carbon atoms. Examples of C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, or sec-hexyl. A 0-3 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 " Cy.z alkoxy" refers to an Cy.z alkyl group (as defined above) covalently linked to an oxygen atom, i.e. a group of formula -O-alkyl where the alkyl group has y to z carbon atoms. The term Cvs 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 C1.3 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 C1-6 alkylene is an alkylene having from one to six carbon atoms, a C/ 6 alkylene is an alkylene having from two to six carbon atoms, and a Cu alkylene is an alkylene having from one to four carbon atoms. Preferably, said akylene groups are polymethylene groups, i.e. (Chbjx, 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.2 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 C2 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 alkynylene is an alkynylene having from two to six carbon atoms, and a C? .i 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 multicyclic (e.g. fused, bridged or spiro rings), wherein at least one of the rings in the ring system is aromatic. Aryl as used herein thus covers fully aromatic hydrocarbon ring systems, i.e. where all the ring(s) in the system are aromatic, like phenyl, naphthyl or anthracyl, as well as ring systems in which an aromatic hydrocarbon ring (e.g. phenyl) is fused to one or more non-aromatic hydrocarbon rings, like indanyl, indenyl, 1-oxo-2,3-dihydro-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 cycioalkyi 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 "cycioalkyi". Examples of carbocyclyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycbpentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, bicycto[2.2.1]heptanyl, bi cyclo [2.2.2]octany I , 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 cycioalkyi" refers to a monocyclic cycioalkyi having from y to z ring-forming carbon atoms. A C3.7 cycioalkyi has 3 to 7 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A C3-6 cycioalkyi has from 3 to 6 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycioalkyi 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 haloaikyl" refers to an aikyl 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 haloaikyl is a C1-6 alkyl which is substituted one or more times with one or more halo, and a CM haloaikyl is a C1-3 alkyl which is substituted one or more times with one or more halo. Haloaikyl groups include perhaloalkyl groups, i.e. alkyl groups where all hydrogen atoms are replaced by halo. Examples of haloaikyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1-fluoro- 2-fluoroethyl, pentafiuoroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, chloromethyl, dichloromethyl, trichloromethyi difluorochloromethyi, dichlorofluoromethyl, 1 ,2-dichloroethyl, 3,3-dichloropropyl and the like. Preferably, the haloaikyl is a fluoroalkyl, i.e. an alkyl group which is substituted one or more times with one or more fluoro.
The term "C -Z haloalkoxy" refers to an haloaikyl group having y to z carbon atoms as defined herein covalently linked to an oxygen atom, i.e. a group of formula -0-Cy-z haloaikyl. A Ci-s haloalkoxy group thus refers to a haloalkoxy group wherein the haloaikyl 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 imidazotyl, 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-tetrahydroquinoiine, 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, imidazoly!, pyrazolyl, oxazolyl, thiazolyi, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazine, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, phthalazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, cinnolinyl, indazolyl, indolizinyl, isoindolyl, pteridinyl, purinyi, furopyridinyi, acridinyl, phenazinyl, 5,6,7,8-tetrahydroquinoiine, 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 sp'iro 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, carbazolyl or phthaiimidyi. The heterocycyl 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, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahyd rof u ra n I , tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, homopiperidinyl, oxepanyl, thiepanyl, 2H-pyranyl, 4H-pyranyi, dioxanyl, 1 ,3-dioxolanyl, dithian l, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, indolinyl, 1-oxoisoindolinyl, decahydroquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 6-azabicyclo[3.3.1 ]heptany 1 , 8-azabicyclo[3.2.1 joctanyl , 3-azaspiro[5.5]undecanyl, 7- azaspiro[3.5]nonanyl, carbazolyl, phthaiimidyi, tetrahydrothiopyranyl 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 Cn hydroxyalkyl is a Ci-e alkyl which is substituted one or more times with one or more hydroxy and a C1-3 hydroxyalkyl is a C1.3 alkyl which is substituted one or more times with one or more hydroxy
As used herein, the term "hydroxyl" or "hydroxy" refers to -OH.
The term "optionally interrupted" means that the respective alkylene, alkenylene, alkynylene or ((¾)* group is uninterrupted or is interrupted between adjacent carbon atoms by a heteroatom selected from 0 and S or a heterogroup NR11, i.e. an 0, S or NR11 is placed between two adjacent carbon atoms in the alkylene, aikenylene, alkynylene or {C ?)X group. Optionally interrupted as used herein also includes alkylene, alkenylene, alkynylene or (Chfejx groups where the heteroatom or heterogroup (i.e. 0, S or NR11) is placed at either end of the alkylene, alkenylene, alkynylene or (CH?)X group instead of between two adjacent carbon atoms in said group. For example, an optionally interrupted C alkylene group includes groups such as - CH2OCH2CH2CHr, -OCH2CH2CH2CH2- and -NR11CH2CH2CH2CH2-.
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 -R12- means that the two points of attachment of the heteroaryl ring R12 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 unsaturation, but is not intended to include aryl or heteroaryl groups, as herein defined.
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-enol 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 isotopscafly labeled forms thereof. Isotopically labeled forms of the compounds are compounds that differ only in the replacement of one or more atoms by a corresponding isotopically enriched atom. Examples of isotopes that can be incorporated into compounds of the invention include for example isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 15N, 180, 170, 35S, 18F, 36CI, and 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, hydrobromkJes, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, nitrates, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1 ,4 dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, ethane-sulfonates, propanesulfonates, benzenesulfonates, toluenesulfonates, trifluoromethansulfonates, naphthalene-1 -sulfonates, naphthalene-2-sulfonates, mandelates, pyruvates, stearates, ascorbates, or salicylates. When the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine and the like. The pharmaceutically acceptable salts of the present invention can be prepared from the parent compound which contains a basic or acidic moiety by conventional chemical methods. For example, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in a suitable solvent.
Additionally, compounds of the present invention, or salts thereof, may exist in hyd rated or unhyd rated (anhydrous) form or as solvates with other solvent molecules. "Solvate" as used herein means solvent addition forms that contain either stoichometric or non-stoichometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate. Non-limiting examples of solvates include hydrates and solvates with alcohols (also named alcoholates) such as ethanol (ethanolates). When compounds of the invention (or salts thereof) exist as solvates, all solvates thereof are intended to be included in the scope of the present invention, particularly pharmaceutically acceptable solvates. As used herein a "pharmaceutically acceptable solvate" is a solvate formed with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents are well known in the art and include solvents such as water and ethanol.
Compounds of the invention, including salts thereof, can be prepared using a number of synthetic routes, including the general synthetic routes described below, starting from commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures. Standard synthetic methods and procedures for the preparation of organic compounds and functional group transformations and manipulations are known in the art and can be found in standard textbooks such as Smith .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", 4th edition, Wiley, 2006) The reaction schemes described below are only meant as illustrative of methods to obtain the compounds of the invention. Other routes known by the ordinary skilled artisan, as well as other reactants and intermediates, can also be used to arrive at the compounds of Formula (I).
In some of the processes described below it may be necessary or advisable to protect reactive or labile groups with conventional protecting groups. Both the nature of these protecting groups and the procedures for their introduction and removal are well known in the art (see for example Greene TW and Wuts PGM, cited supra). Whenever a protecting group is present, a subsequent deprotection step will be required, which can be performed under standard conditions well known in the art, such as those described in the above reference.
Unless otherwise stated, in the methods described below the meanings of the different substituents in each synthetic intermediate and in each compound of Formula (!) 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 Z1, Z2, Z3, Z4, Z5, R1, R2, R3, R4 L1, L2, Y, m and n have the same meaning described for compound of Formula (I), A is COORa or CN, Ra is Cn alkyl or aryl-Cu alkyi, preferably methyl, ethyl or benzyl, and M and X have the meaning defined below.
The first step involves a cross-coupling reaction of a heteroaryl organometallic species with a heteroaryl halide. Organometallic intermediates can be generated either on the heteroaryl bearing the COORa or CN substituent (i.e. a compound of Formula (Ilia) or (lllb) ), or in the heteroaryl bearing the -(L1)m-Y-(L2) R4 substituent (i.e. a compound of Formula (VII) ). In the second step, the ester or cyano group in a compound of Formula (Va) and (Vb), respectively, is transformed into an amido group -CONRW to give a compound of Formula (I),
Several cross-coupling reactions can be used for the first step in Scheme 1 , including: a Suzuki cross coupling where M is a boronic acid or boron derivative and X is CI, Br or I; a Stille reaction where M is tnalkylstannanyi group and X is Ci, Br or I; a Negishi coupling where M is a zinc halide and X is triflate, CI, Br or I; and a Hiyama coupling where M is a trialkylsily! 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(PPh3)4, in the presence of a suitable Cu salt such as Cu(OAc)2 or Cul, in a suitable solvent such as tetrahydrofuran or dimethylformamide, 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 1 h to 48h. Examples of boronic derivatives include diethyl, dimethyl, N-methyliminodiacetic acid (MIDA) derivative and 2,2'-(phenylazanediyl)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/ligand combination such as Pd(PPh3)4, Pd(PPh3)CI2 or Pd(dppb)CI2 in the presence of a suitable Cu salt such as Cul or CuO, in the presence or absence of CsF, in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide. The temperature of the reaction can go from room temperature to 120°C and the time of reaction from 1 h to 48h. The organotin employed can be trimethy!stanny! derivative. An intermolecular Stille Kelly reaction can also be used, in which both reagents are haloheteroaryls and are treated with (Bu3Sn)2, EUNI, and a Pd/ligand combination.
When compounds of Formula (I) are prepared through a Negishi cross coupling with the intermediates indicated in Scheme 1 , the reaction can be performed using a suitable Pd/ligand combination such as PPh3 and Pd2(dba)3 , XPhos and Pd2(dba)3 , RuPhos 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 1h to 48h.
When compounds of Formula (I) are prepared through a Hiyama cross coupling with the intermediates indicated in Scheme 1 , the reaction can be performed using a suitable Pd/ligand combination such as PdCI2(PPh3)2 and PPh3 or Pd(OAc)? and di(1-adamantyl)-n-butylphosphine in the presence of a suitable Cu salt such as Cul or CuBr, in the presence or absence of tetrabutylammonium fluoride in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide. The temperature of the reaction can go from room temperature to 120°C and the time of reaction from 1 h 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 three steps through a direct arylation of a compound of Formula (Villa) or (VI I lb) with halo derivative of Formula (IV) followed by reduction of the resulting N -oxide of Formula (IXa) or (IXb) and subsequent transformation of the ester or cyano derivative (IXa) or (IXb) into compounds of Formula (I), as outlined in Scheme 2.
Figure imgf000044_0001
Scheme 2
Figure imgf000044_0002
wherein 2 Z2, Z3, Z4, Z5, R1, R2, R3, R4 L1, L2, Y, m and n have the meaning described above with respect to a compound of Formula (I); A is COORa or CN; Ra is Ci-e alkyl or aryl-Cw alkyl, preferably methyl, ethyl or benzyl and X is CI or Br.
Reaction of (Villa) or (Vlllb) with (IV) can be performed using a suitable Pd/ligand combination such as PBu3 and Pd(OAc)? or PBU3-HBF4 and Pd(OAc)2, 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 (IXa) and (IXb) can easily be reduced to compound (Va) and (Vb) with hydrogen or sodium borohydnde using palladium on charcoal as a catalyst or also using phosphorous trichoride.
Compounds of Formula (Va) in Scheme 1 or 2 can be reacted directly with an amine NHR1R2 to give a compound of Formula (I). The reaction is performed in a suitable solvent such as methanol, ethanol, isopronanoi at a temperature going from room temperature to 120°C, optionally under pressure in case of volatile amines, during a time reaction from 1 h to 48h. Alternatively, compounds (Va) can be hydrolyzed to the corresponding acids by treatment with a base such as LiOH, NaOH, KOH or Me3SiO in a mixture of water and a solvent miscible with water such as dioxane, THF, MeOH, EtOH, between 0°C and room temperature for 1 to 3 days. Then, the resulting acid can be coupled with an amine of formula NHR1R2 to give compound of Formula (I) with the aid of a coupling agent in the conditions described below for the preparation of (IVa). Compounds of Formula (Vb) in Scheme 1 or 2 can be reacted with NaOH in the presence or absence of 30% H2O2 in a suitable solvent such as MeOH, EtOH, water or a mixture of them at a temperature going from room temperature to reflux for a reaction time from 1 h to 3 days, to give a compound of Formula (I). Alternatively, compounds of Formula (Vb) can be treated with a base such as KOH in a suitable solvent such as tert-butanol, at a temperature going from room temperature to reflux for a reaction time from 1h to 3 days to give a compound of Formula (i)
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 imgf000045_0001
(XIII) (XIV) (IVc)
Figure imgf000046_0001
(XVI) (IVe)
Scheme 3 wherein Z4 Z5 R3, R4, L1, L2, m and n have the meaning described above with respect to a compound of Formula (!) and X is triflate, CI, Br or I and B is CI, Br, I or alkyl or benzyl sulphonate.
For example, compounds of Formula (IVa) can be obtained by reaction of (X) with (XI) 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-(1Hbenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate(HBTU), 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU). 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, A/,/V'-dimethylformamide, tetrahydrofuran, dichloromethane or dioxane. Alternatively, carboxylic acids in (XI) are activated as mixed anhydrides or acid chlorides and then coupled with (X) 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 (X) with (XII) by means of reductive amination in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a suitable solvent such as dioxane, THF, dichloromethane or diethyl ether. Alternatively, compounds of Formula (IVb) can be obtained by means of amine aikylation of compounds of Formula (X) 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 (XIII) with (XIV) in 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 in one step by reaction of compounds of Formula (XV) with the corresponding isothiocyanate 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 THF, dioxane or DMF at a temperature from 0°C to 80°C for a time from 1 h to 24h.
For example, compounds of Formula (IVe) can be obtained by reaction of compounds of Formula
(XVI) with the corresponding pyrazoie 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 (VII) 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 adition of N-methyliminodiacetic acid; trimethyltin heterocycles can be prepared by reaction;of haloheterocycles with hexamethylditin and Pd (PPh3)4 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 trimetilsilyl heterocycles can be prepared by reaction of haoheterocycles with nBuLi in the presence of trimethylsylchloride at -78°C in THF.
The compounds of Formula (Ilia), (lllb), (Via), (Vlb), (Villa), (Vlllb), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) are commercially available or may be easily obtained from commercial compound 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 (VII), a corresponding intermediate carrying a partially elaborated (L1)m-Y-(L2)n-R4 group is used and after cross coupling step, the complete structure of (L1)m-Y-(L2)„-R4 is built by the methodologies described above in Scheme 3.
Finally, some compounds of the present invention can also be obtained from other compounds of Formula (I) by appropriate conversion reactions of functional groups in one or several steps, using well-known reactions in organic chemistry under the standard experimental conditions.
Said transformations include, for example: the substitution of a primary or secondary amine by treatment with an alkylating agent under standard conditions, or by reductive amination, i.e. by treatment with an aldehyde or a ketone in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride; the conversion of an amine into a sulfonamide by reaction with a sulfonyl halide, such as sulfonyl chloride, optionally in the presence of a base such as 4-dimethylaminopyridine, in a suitable solvent such as dioxane, chloroform, dichloromethane or pyridine, optionally in the presence of a base such as triethylamine or pyridine; the conversion of an amine into an amide or urea under standard conditions; the alkylation of an amide by treatment with an alkylating agent under basic conditions; the conversion of an alcohol into an ether under standard conditions; the partial or total oxidation of an alcohol to give a ketone under standard oxidizing conditions; the reduction of a ketone by treatment with a reducing agent such as sodium borohydride; the conversion of an alcohol into a halogen by reaction with SOC , PB¾ tetrabutylammonium bromide in the presence of P?Os, or PCb; the conversion of halogen into an amine by reaction with an amine, optionally in the presence of a suitable solvent, and preferably heating; and the conversion of a primary amide into a -CN group under standard conditions.
Likewise, any of the aromatic rings of the compounds of the present invention can undergo electrophilic aromatic substitution reactions or nucleophilic aromatic substitution reactions, widely described in the literature.
Some of these interconversion reactions are explained in greater detail in the examples. As it will be obvious to those skilled in the art, these interconversion reactions can be carried out upon the compounds of Formula (I) 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.
Compounds of formula (Va) and (Vb), as defined above, are useful as intermediates in the synthesis of compounds of Formula (I) and are also a further aspect of the present invention.
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 subfamily.
Certain compounds of the invention can be selective for KDM5 over other JmjC-KDMs. As used herein, "KD 5" refers to the KDM5 subfamily of JmjC-KDMs. "Selective" means that the compound has a greater effect on KDM5 than on other JmjC-KDMs (e.g. KDM2, KDM3, KDM4, KDM6, KDM7). In one embodiment, a selective compound may have at least a 10-fold greater effect on KDM5 than on other JmjC- KDMs, more preferably at least 20-fold greater effect, or at least 50-fold greater effect or at least 100-fold greater effect. In one embodiment, the compound of the invention is selective for KDM5.
The activity of the compounds of the invention as KD 5 inhibitors can be determined using for example the in vitro assay described in the Examples section. In particular, Example 16 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 16. As the data in Example 16 shows, compounds of the invention show in general selectivity for KDMS over KDM4 and/or KD 6. Compounds of the invention have also been shown to inhibit JmjC-KDM activity in cells, as shown by the results described in Example 17. 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.
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-methyiated 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(ll)-dependent 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 KD 2 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 KDMS subfamily in humans: KDM5A, KDM5B, KD 5C and KDM5D.
KDM5A cooperates with retinoblastoma protein (RB) and KDM5B to control respectively cellular differentiation (Benevolenskaya E.V. e a/. 2005, Mol Cell 18(6):623-35) and induction of senescence (Chicas A. ef al. 2012, PNAS 109(23):8971-6). The oncogenic role of KD 5A is highlighted by knock out studies showing that KDM5A inactivation reduces tumor formation in Rb+/- and Men-/- mice (Lin W. et 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. et al. 2014, Mol Cancer Res 12(4):571-82), temozolomide-resistant glioblastomas (Bannelli B. ef al. 2015, Cell Cycle 14(21):3418-29), gastric carcinomas (Zeng J. ef al. 2010, Gastroenterology 138(3):981-92) and cervical carcinomas (Hidalgo A. ef 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. ef al. 2016, Oncogenesis 5(8):e257). Translocations involving the human KDM5A and NUP98 gene have also been described in pediatric acute megakaryobiastic leukemias (de Rooij J.D. ef al. 2013, Leukemia 27(12):2280-8).
KDM5B-mediated histone demethylation is required for inhibiting the expression of E2F target genes during induction of senescence in murine and human embryonal fibroblasts (Chicas A. ef al. 2012, PNAS 109(23):8971-6). In cancer cell lines, KDM5B represses CDKN1A expression, effectively promoting oncogenic transformation (Wong P.P. et al. 2012, Mol Cell Biol 32(9):1633-44). Genetic inhibition of KDM5B is able to reduce proliferation, epithelial-mesenchymal transition (EMT), migration and invasion in models of hepatocellular carcinoma (Wang D. ef al. 2016, J Exp Clin Cancer Res 35:37). Similarly, the oncogenic role of KDM5B in gastric cancer is confirmed by knock down of endogenous KDM5B expression in GES-1 cells, which abolishes tumor growth and metastasis formation (Wang Z. ef al. 2014, Am J Cancer Res 5(1):87-100). Effects on invasion, migration and EMT were also described in esophageal cancer after targeting KDM5B (Kano Y. 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 Cell 25(6):762-77). At the same time, KDM5B inhibition is also relevant in basal-like (Bamodu OA et al. 2016, BMC Cancer 16(1):160) and advanced- stage breast cancers (Yamane K. et al. 2007, Mol Cell 25(6):801-12), and in multiple myeloma (Tumber A. ef al. 2017, Cell Chem Biol. 24(3):371-380). Depletion of KDM5B was also shown to inhibit cell proliferation of hepatocellular carcinoma (Wang D. et al. 2016, J Exp Clin Cancer Res. 35:37). In addition, high expression of KDM5B is associated to EMT of Non-Small-Cell Lung Cancer cells (Haley J .A. et al. 2014, Front Oncol 4:344) and reduced response to therapy and/or poorer prognosis in ovarian (Wang L. ef al. 2015, Tumour Biol 36(4):2465-72), bladder (Hayami S. ef al. 2010, Mol Cancer 9:59) and prostate cancer (Xiang Y. ef al. 2007, PNAS 104(49): 19226-31). High KDM5B expression has been observed within a small subset of melanoma cells, characterized by increased clonogenic potential and resistance to several anticancer drugs. KDM5B inhibition sensitizes melanoma cells to chemotherapy (Roesch A. ef al. 2013, Cancer Cell 23(6):811-25) and reduces tumorigenicity. High KDM5B expression was detected also in uveal melanoma (Radberger P. ef al. 2012, Invest Ophthalmol Vis Sci 53(8):4442-9). Upregulation of KDM5B has also been described following infection with Respiratory Syncytial Virus. In this setting, an increase of antiviral function and a reduction of pulmonary disease have been described when KD 5B is inhibited in dendritic cells. These results prompt the use of KDM5B inhibitors as a possible strategy to boost the efficacy of dendritic cells-based vaccines (Ptaschinski C. et 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. et al. 2005, Am J Hum Genet 76(2):227-36) and affects memory in men and mice (Simensen R.J. et 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. et al. 2013, PNAS 110Έ3027-Ε3036).
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. et 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 compounds of the invention are thus expected to be useful for treating diseases associated with activity of a JmjC-KDM, particularly a KDM5 protein. For the uses and methods of treatment described herein, any of the compounds of the invention, including any of the embodiments thereof, may be used.
Accordingly, the invention further provides a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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), or pharmaceutically acceptable salt thereof, for use in treating a disease associated with a JmjC-KDM, particularly a KDM5.
The present invention further provides the use of a compound of Formula (I), (la), (lb), (lc), (Id), (ie),
(If) or (II), preferably a compound of Formula (II), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease associated with a JmjC-KDM, particularly a KDM5.
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), or pharmaceutically acceptable salt thereof, for treating a disease associated with a JmjC-KDM, particularly a KDM5. The present invention further provides a method for treating a disease associated with a JmjC-KDM, particularly a KDM5, comprising administering a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
The present invention further provides a method of inhibiting a KDM5 activity, comprising administering to a patient in need of said treatment an amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), or pharmaceutically acceptable salt thereof, sufficient to inhibit a KDM5 activity.
The present invention further provides a method of inhibiting a KDM5 activity in a biological sample, comprising contacting said biological sample with a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), or pharmaceutically acceptable salt thereof.
The present invention further provides the use of a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), or a pharmaceutically acceptable salt thereof, as a JmjC-KDM inhibitor in research, particularly as a research tool compound for inhibiting a JmjC-KDM, particularly KDM5 . Accordingly, the invention relates to the in vitro use of a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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), the method comprising applying a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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.
The present invention further provides a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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 squamous carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, neuroendocrine tumors, melanoma, glioblastoma, neuroblastoma, multiple myeloma, and leukemia. In some embodiments, the cancer is selected from breast cancer, bladder cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, liver cancer, lung cancer, melanoma, glioblastoma, neuroblastoma, ovarian cancer, prostate cancer and leukemia. The present invention further provides the use of a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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 squamous carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, neuroendocrine tumors, melanoma, glioblastoma, neuroblastoma, multiple myeloma, and leukemia. In some embodiments, the cancer is selected from breast cancer, bladder cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, liver cancer, lung cancer, melanoma, glioblastoma, neuroblastoma, ovarian cancer, prostate cancer and leukemia.
The present invention further provides the use of a compound of Formula (I), (la), (lb), (ic), (Id), (le),
(If) or (II), preferably a compound of Formula (II), 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 squamous carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, neuroendocrine tumors, melanoma, glioblastoma, neuroblastoma, multiple myeloma, and leukemia. In some embodiments, the cancer is selected from breast cancer, bladder cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, liver cancer, lung cancer, melanoma, glioblastoma, neuroblastoma, ovarian cancer, prostate cancer 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), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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 squamous carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, neuroendocrine tumors, melanoma, glioblastoma, neuroblastoma, multiple myeloma, and leukemia. In some embodiments, the cancer is selected from breast cancer, bladder cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, liver cancer, lung cancer, melanoma, glioblastoma, neuroblastoma, ovarian cancer, prostate cancer and leukemia.
The present invention further provides a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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), (!e), (If) or (II), preferably a compound of Formula (II), 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), 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" and the like refer to any disease or condition in which a JmjC-KDM, such as a KDM5, 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 diseases or conditions the course of which can be influenced by modulating the methylation status of histones or other proteins, wherein said methylafjon status is mediated at least in part by the activity of a JmjC-KDM, such as a KDM5. 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 include, without limitation, the diseases and conditions as described herein. In some embodiments, said disease is a cancer, such as breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, iiver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, neuroendocrine tumors, melanoma, glioblastoma, neuroblastoma, multiple myeloma, and leukemia. In some embodiments, said cancer is breast cancer, bladder cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, Iiver cancer, lung cancer, melanoma, glioblastoma, neuroblastoma, ovarian cancer, prostate cancer or 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, s wince, cattle, sheep, horses, or primates, and most preferably humans. As used herein, the term "biological sample" includes, without limitation, a cell, cell cultures or extracts thereof; biopsied material obtained from an animal, e.g. a human, or extracts thereof; and blood, saliva, urine, feces, or any other body fluids or extracts thereof.
As used herein, the term "therapeutically effective amounf 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 ceil 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, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, and methyl cellulose. The pharmaceutical compositions can additionally include further pharmaceutically acceptable excipients including: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emusifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates: sweetening agents; flavouring agents; and colouring agents.
Suitable oral dosage forms include, for examples, tablets, pills, sachets or capsules of hard or soft gelatin or any other suitable material. For example, the active compound can be incorporated into a formulation that includes pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating agents (e.g., alginate, Primogel, corn starch), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). They can then be compressed into tablets or enclosed in capsules using conventional techniques. The capsules and tablets can also be coated with various coatings known in the art to modify the flavors, tastes, colors, and shapes of the capsules and tablets. In addition, liquid carriers such as fatty oil can also be included in capsules. Oral formulations can also be in the form of suspensions, solutions, syrups and the like. If desired, conventional agents for modifying flavors, tastes, color and the like can be added.
Pharmaceutical compositions suitable for parenteral administration include sterile aqueous solutions or suspensions, or can be alternatively prepared in lyophilized form for extemporaneous preparation of a solution or suspension using a sterile aqueous carrier prior to use. In such formulations, diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used. Other conventional solvents, pH buffers, stabilizers, anti-bacterial agents, surfactants, and antioxidants can all be included. For example, useful components include sodium chloride, acetates, citrates or phosphates buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like. The parenteral formulations can be stored in any conventional containers such as vials and ampoules.
Compositions for administration by inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositons may include suitable pharmaceutically acceptable excipients as described above. Such compositions maye be administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of a suitable gas. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask or the breathing chamber. Solutions, suspensions and powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
Pharmaceutical compositions for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Topical formulations can contain one or more conventional carriers. For example, ointments can contain water and one or more hydrophobic carriers selected from liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components such as cetylstearyl alcohol, glycerin monostearate and the like. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other excipients such as glycerol, hydroxyethyl cellulose and the like.
The pharmaceutical compositions, like oral and parenteral compositions, can be formulated in unit dosage forms for ease of administration and uniformity of dosage. As used herein, "unit dosage forms" refers to physically discrete units suitable as unitary dosages for administration to subjects, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with one or more suitable pharmaceutical carriers.
In therapeutic applications, pharmaceutical compositions are be administered in a manner appropriate to the disease to be treated, as determined by a person skilled in the medical arts. An appropriate dose and suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the disease, the particular form of the active ingredient, the method of administration, among others. In general, an appropriate dose and administration regimen provides the pharmaceutical composition in an amount sufficient to provide therapeutic benefit, for example an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or lessening of symptoms severity, or any other objetively identifiable improvement as noted by the clinicial. Effective doses may generally be assessed or extrapolated using experimental models like dose- response curves derived from in vitro or animal model test systems.
The pharmaceutical compositions of the invention can be included in a container, pack or dispenser together with instructions for administration.
The compounds of the invention can be administered in monotherapy (e.g., without concomitantly administering any further therapeutic agents, or without concomitantly administering any further therapeutic agents against the same disease that is to be treated with the compound of the invention). In particular, they can be used in the monotherapeutic treatment of cancer (i.e., without administering any other antineoplastic agent until the treatment with the compound of the invention is terminated). Accordingly, the invention also provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier, for use in the monotherapeutic treatment of cancer.
The compounds of the invention can also be administered in combination with another active agent as long as the other active agent does not interfere with or adversely affect the effects of the active compounds of this invention. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each additional active agent in its own separate pharmaceutical dosage formulation. If administered separately, the administration can be simultaneous, sequential or separate, and the compound of the invention and the additional therapeutic agent(s) can be administered via the same administration route or using different administration routes, for example one compound can be administered orally and the other intravenously.
Typically, for combination therapy with a compound of the invention in the field of cancer, any antineoplastic agent that has activity versus a cancer being treated or prevented with a compound of the invention may be used. As used herein, "antineoplastic agent" refers broadly to any agent used in the therapy of cancer, including chemotherapy and/or radiotherapy.
Examples of antineoplastic agents that can be used in combination with the compounds and methods of the present invention include, in general, and as appropriate, alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors. Exemplary classes of antineoplastic agents include the anthracyclines, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones, discodermolides, pteridines, diynenes and podophyllotoxins. Particularly useful members of those classes include, for example, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5- fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo- phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like. Other useful antineoplastic agents include estramustine, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11 , topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindoie derivatives, interferons and interieukins.
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 deacety!ase inhibitors, protein kinase inhibitors (such as serine, threonine and tyrosine kinase inhibitors (for example, Abelson protein tyrosine kinase)) and the various growth factors, their receptors and kinase inhibitors therefor (such as epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin-like growth factor receptor inhibitors and platelet-derived growth factor receptor kinase inhibitors)); aminopeptidase inhibitors; proteasome inhibitors; cyclooxygenase inhibitors (for example, cyclooxygenase-1 or cyclooxygenase-2 inhibitors); topoisomerase inhibitors (for example, topoisomerase I inhibitors or topoisomerase II inhibitors); or retinoid agents.
An alkylating agent which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, a nitrogen mustard (such as cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, 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 hexamethy!melamine (altretamine), triethylenemelamine, ThioTEPA (Ν,Ν'Ν'-triethylenethiophosphoramide), carboquone, or triaziquone), a hydrazine (such as procarbazine), a triazene (such as dacarbazine), or an imidazotetrazines (such as temozolomide).
A platinum coordination complex which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, or triplatin tetranitrate.
A cytotoxic drug which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, an antimetabolite, including folic acid analog antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analog antimetabolites (such as cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6- ttiioguanine), and pyrimidine analog antimetabolites (such as cytarabine, decitabine, azacytidine, 5-fluorouracil (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 docetaxel, larotaxel, ortataxei, paclitaxe!/taxol, or tesetaxel), a Vinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine, vinzolidine, or vinorelbine), an epothilone (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F) or an epothilone B analog (such as ixabepilone/azaepothilone B).
An anti-tumor antibiotic which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, an anthracycline (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin), an anthracenedione (such as mitoxantrone, or pixantrone) or an anti-tumor antibiotic isolated from Streptomyces (such as actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin).
An inhibitor of MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example a B-Raf inhibitor like vemurafenib (PLX4032), encorafenib or dabrafenib, or a EK 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, eriotinib, 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, rubitecan, or lamellarin D) or a topoisomerase II inhibitor (such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin).
Further antineoplastic agents may be used in combination with a compound of the present invention.
The antineoplastic agents may include biological or chemical molecules, such as TNF-related apoptosis- inducing ligand (TRAIL), tamoxifen, toremifene, fluoxymesterol, raloxifene, diethylstibestrol, bicalutamide, nilutamide, flutamide, aminoglutethimide, anastrozole, tetrazole, luteinizing hormone release hormone (LHRH) analogues, ketoconazole, goserelin acetate, leuprolide, megestrol acetate, prednisone, mifepristone, amsacrine, bexarotene, estramustine, irofulven, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, alvocidib, seliciclib, aminolevulinic acid, methyl aminolevulinate, efaproxiral, porfimer sodium, talaporfin, temoporfin, verteporfin, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur, celecoxib, demecolcine, elesclomol, elsamitrucin, etoglucid, ionidamine, lucanthone, masoprocol, mitobronitol, mitoguazone, mitotane, oblimersen, omacetaxine, sitimagene, 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-ketoretino) (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-5,6J,8-tetrahydro-2-naphthalenyl)-1-propenyl]-benzoic acid, 3-methyl-(E)-4-[2-(5,5,8,8-tetramethyl- 5,6J,8-tetrahydro-2-naphthaleny!)-l-propenyl]-benzoic acid, Fenretinide (N-(4-hydroxyphenyl)retinamide; 4- HPR), Etretinate ((all-E)-9-(4-methoxy-2!3,6-tn'methyfphenyl)-3J-dimethy!-2,4,6,8-nonatetraenoic acid ethyl ester; Tegison), Acitretin ((all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid; Ro 10-1670; Soriatane; Neotigason), Tazarotene (ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl] nicotinate; Tazorac; Avage; Zorac), Tocoretinate (9-cis-tretinoin; Tocoferil), Adapalene (6-[3-(1-adamantyl)-4- methoxyphenyl]-2-naphthoic acid; Differin), otretinide (trimethylmethoxyphenyl-N-ethyl retinamide; Trasmaderm), retinaldehyde (Retinal), CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl)-2-naphthalene carboxylic acid; AHPN), CD2325, ST1926 ([E-3-(4 -hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid), ST1878 (methyl 2-[3- [2-[3-(2-methoxy-1 ,1-dimethyl-2-oxoethoxy)phenoxy]ethoxy]phenoxy]isobutyrate), ST2307, ST 1898, ST2306, ST2474, MM11453, MM002 (3-CI-AHPC), MX2870-1 , MX3350-1 , MX84, and MX90-1 , docosahexaenoic acid (DHA), phytanic acid (3,7,11 , 15-tetramethyl hexadecanoic acid), MS6682 (methoprene acid), LG100268 (LG268), LG100324, SR11203 ([2-(4-carboxyphenyl)-2-(5,6J,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)-1 ,3-dithiane), SR11217 (4-(2-methyl-1-(5,6J,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)propenyl)benzoic acid)., SR11234, SR11236 (2-(4-carboxyphenyl)-2-(5,6J,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthalenyl)-1 ,3-dioxane), SR11246, AGN 194204, derivatives of 9-cis-RA such as LGD1069 (3- methyl 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-oxodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-(2R)-2-piperidinexcarbonyl]), A-161906 (7-[4-(4- cyanophenyl)phenoxy]-heptanohydroxamic acid), Scriptaid (6-(1 ,3-Dioxo-1 H,3H-benzo[de]isoquinolin-2-yl)- hexanoic acid hydroxyamide), PXD-101 (Belinostat), Panobinostat, CHAP (cyclic hydroxamic acid-containing peptide), LAQ-824 (Dacinostat), BML-EI319 (Depudecin), 03139 (Oxamflatin), NSC 696085 (Pyroxamide), MW2796; W2996, 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); Azeiaic-1 -hydroxamate-9-anilide (AAHA); 3CI-UCHA (6-(3- chlorophenylureido) caproic hydroxamic acid); and sodium butyrate, 4-phenyibutyrate, phenyl acetate, valerate, isovalerate, butyramide, isobutyramide, 3-bromopropionate, and valproate.
Also biological drugs, like antibodies, antibody fragments, antibody constructs (for example, single- chain constructs), and/or modified antibodies (like CDR-grafted antibodies, humanized antibodies, "full humanized" antibodies, etc.) directed against cancer or tumor markers/factors/cytokines involved in cancer can be employed in cotherapeutic approaches with the compounds of the invention. Examples of such biological molecules are alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, eiiizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rituximab, rovelizumab, rolizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.
Other biologic agents include, but are not limited to, immunomodulating proteins such as cytokines (such as interleukin-2 (IL-2, Aldesleukin), Epoietin-alpha.; EPO), granulocyte-CSF (G-CSF; Filgrastin), and granulocyte-macrophage-CSF (GM-CSF; Sargramostim) and interferons, (e.g., interferon-alpha, interferon-beta and interferon-gamma), bacillus Calmette-Guerin, levamisole, and octreotide, endostatin, tumor suppressor genes (e.g., DPC4, NF- 1 , NF-2, 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, gaplOO, MAGE 1 ,3 tyrosinase), papillomavirus E6 and E7 fragments, whole cells or portions/lysates of autologous tumor cells and allogeneic tumor cells.
In another aspect, the invention relates to methods of treating or preventing drug resistance in a patient using a compound as described herein. For example, a method of treating or preventing drug resistant cancer in a patient comprises administering a therapeutically effective amount of a compound of the invention to the patient alone or in combination with an antineoplastic agent. In some embodiments, the patient starts treatment comprising administration of a compound of the invention prior to treatment with the antineoplastic agent. In some embodiments, the individual concurrently receives treatment comprising the compound of the invention and the antineoplastic agent. In some embodiments, the compound of the invention increases the period of cancer sensitivity and/or delays development of cancer resistance.
Accordingly, the invention provides a method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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), 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), 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), 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), 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, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous carcinoma, liver cancer, lung cancer, melanoma, glioblastoma, neuroblastoma, ovarian cancer, prostate cancer 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 imgf000064_0001
(I)
wherein
Z1, Z2, and Z3 are each independently selected from CR5 and N, and Z4 and Z5 are each independently selected from CR3 and N, with the proviso that only one of Z1, Z2, Z3, Z4 and Z5 can be N;
R1 and R2 are each independently selected from hydrogen, 0-6 alkyl, 0-6 ha!oalkyl, -(Ci-s alkylene)-ORs, -(0-6 alkylene)-NR7R8, -CN, -lAcarbocyclyl, -L3-aryl, -LAheterocyclyl and -L3-heteroaryl, wherein the carbocyclyi in - L3-carbocyclyl, the aryl in -LAaryl, the heterocyclyl in -lAheterocyclyl and the heteroaryl in -L -heteroaryl are each optionally substituted with one or more Rs,
or R1 and R2 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, e alkyl, -s alkoxy, -OH, -NH2, -ΝΗ(0-ε alkyl), and -N(C, 6 alkyl)2;
each R3 is independently selected from hydrogen, halo, O-ε alkyl, Cu haloalkyi, Ci s alkoxy, Ο β hydroxyalkyl, -OH and -NH2;
each R5 is independently selected from hydrogen and halo;
Y is selected from -NR^C(=0)-, -NR11-, -0-, -R12- and -CH2-, wherein said -NR1CC(=0)- is linked to -(L - via the NR10 group and to -(L2)n-R4 via the C(=0) group;
U is Ci-4 alkylene, C2-4 alkenylene or C? . alkynylene, wherein said C1.4 alkylene, said C2-4 alkenylene and said C2-4 alkynylene are optionally interrupted by 0, S or NR", and wherein said C1.4 alkylene, said C2.4 alkenylene and said C2-4 alkynylene are optionally substituted with one or more R13; L2 is Ci-6 alkylene, Cu a!kenylene or C2-8 alkynylene, wherein said Cvs alkylene, said C2-6 alkenylene and said C2-6 alkynylene are optionally interrupted by 0, S or NR11, and wherein said C1-5 alkylene, said C2-3 alkenylene and said C? e alkynylene are optionally substituted with one or more R13;
m and n are each independently selected from 0 and 1 ;
R4 is -NR14R15 or R16;
R7 and R8 are each independently selected from hydrogen and C1.5 alkyl, or R7 and Rs 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, CM alkyl, -OH, -NH?, -NH(Ci 6 alkyl), and -N(Ci.6 alkyl)2;
each L3 is independently selected from a bond and C1-4 alkylene;
R10 and R11 are each independently selected from hydrogen, Ci-e alkyl and Cn haloalkyl;
-R12- 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 -R12- is linked to -(L1)m- and -(L2)n- R4 in a 1 ,3-disposition;
each R13 is independently selected from G1-6 alkyl, halo, C $ haloalkyl, -L3-carbocyclyl, -L3-aryl, -L3-heterocyclyl and -L3-heteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -lAary!, the heterocyclyl in -L3- heterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R17, and wherein two groups R1 attached to a same C atom of the alkylene group are 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 C3-6 cycloalkyi and 4- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from halo and C1-6 alkyi;
R14 and R15 are each independently selected from hydrogen, Ci-s alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-OR'8, -L3- carbocyclyl, -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 R13;
R16 is a 3- to 18-membered saturated, partially saturated or aromatic heterocyclic group which contains one N atom and optionally contains one or more further heteroatoms selected from N, 0 and S, wherein R16 is optionally substituted with one or more R20;
each R2Q is independently selected from C alkyl, C%s haloalkyl, halo, C1-3 alkoxy, C1 6 haloalkoxy, -OH, -NH¾ -NH(Ci-6 alkyl), -N(C,.6 alkyl)?, -CN, -C(=0)R21, -C(=0)NR22R23, -NR22C(=0)R21, -NR22C(=0)NR2 R23 -NR 2S02R21, -S0?NR2 R23, -S02R?1, -LAcarbocyclyl, -L3-aryl, -LAheterocyclyl and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -L3-aryf, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -L3- heteroaryl are optionally substituted with one or more R24; each R9, each R1?, each R19 and each R24 is independently selected from Ci-6 alkyl, 0.g haloalkyi, halo, 0-6 alkoxy, C,.6 haloaikoxy, -OH, -NH2, -NH(Ci-s alkyl), -N(Ci.6 alkyl)? ,-CN, -C(=0)R21, -C(=0)NR22R23, -NR22C(=0)R21, ~NR22C(=0)NR22R23, -NR22S02R21, -S02NR22R23 and -S02R2!;
each R21 is independently selected from C« alkyl; and
each R6, each R18, each R22 and each R23is independently selected from hydrogen and O e alkyl.
2.The compound of item 1 , which is a compound of Formula (II):
Figure imgf000066_0001
(il)
or a salt thereof.
3. The compound of item 1 or 2, wherein R1 and R2 are both hydrogen.
4. The compound of any one of items 1 to 3, wherein each R3 and each R5 is hydrogen.
5. The compound of any one of items 1 to 4, wherein L1 is (CH?)i ?, wherein said (CH2)i-2 is optionally substituted with one or more R13.
6. The compound of any one of items 1 to 5, wherein L2 is ((¾)ι-4, wherein said (CH?)i 4 is optionally substituted with one or more R13.
7. The compound of any one of items 1 to 6, wherein Y is selected from -NR11-, -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), - is selected from the following list:
Figure imgf000067_0001
Figure imgf000068_0001
wherein any alkylene is optionally substituted with one or more R13.
11 The compound of any one of items 1 to 10, wherein R* is -NR14R15 or R16, wherein R16 is a saturated 3- to 18-membered heterocyclic group which contains one N atom and optionally contains one or more further heteroatoms selected from N, 0 and S, wherein R16 is optionally substituted with one or more R20.
12. The compound of any one of items 1 to 11 , wherein R14 and R15 are each independently selected from hydrogen, Ci.6 alkyl, Ci « haloalkyl, -IAC3-7 cycloalkyi, and -(CH2)i-4-pnenyl, wherein the C3-7 cycloalkyi in the - LAC3.7 cycloalkyi is optionally substituted with one or more groups independently selected from CM alkyl and halo, and the phenyl in -(CH2)i-rphenyl is optionally substituted with one or more R19.
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,
Boc: tert-buty!oxycarbonyl
(Boc)jO: di-tert-butyl dicarbonate,
n-BuOH: n-butanol
DCE: 1 ,2-dichloroethane
DCM: Dichloromethane DIEA: A/,A/-diisopropylethylamine
DIPEA: N,W-Diisopropylethylamine,
DMAP; 4-{dimethylamino)pyridine
DME: 1 ,2-dimethoxyethane
DMF: A/,A -dimethylformamide
DMSO: dimethylsulfoxide,
EbO. Diethyl ether
EtOAc: ethyl acetate
EtOH: ethanol
HPLC: high performance liquid chromatography
LC-MS: liquid chromatography-mass spectroscopy
Mel: lodomethane
MeOH: methanol
Pd(PPfi3)4 : tetrakis(thphenylphosphine) palladium (0)
Pd(PPh3)2C : 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 2.1 mm, 1.7 um); Mobile Phase: B: 0.1% Formic Acid in
Water A: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B of: 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 2.1mm, 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 rrt/min.
Method 3: Column: Gemini C18 (150mm x 4.6mm, 5 μηι); 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 Acetate 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 μτη); 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 2.1 mm, 1.7 μηι); 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 7: 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 Acetonitrile; Gradient: Time/% A: 0/97, 0.4/97, 2.0/2, 5/2, 5.5/97, 6/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min.
Method 8: Column: Xbridge C18 (75mm x 4.6mm, 3.5 μιη); 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 9: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μηι); 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, 4.2/97, 4.5/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min.
Method 10: 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/% 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 11 : Column: L-Column2 (150mm x 4.6mm, 5pm); 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 12: Column: Clarity 5pm Oligo (250mm x 4.6mm); Mobile Phase: A: Acetonitrile, B: 10 mM Ammonium Bicarbonate in Aq; Gradient: Time/% A: 0/5, 5/5, 15/80, 20/90, 20.1/5; Flow Rate: 1.0 mL/min; Diluent: Acetonitri!e:Water (1 :1).
Method 13: 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/% A: 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 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: 0/5, 1/5, 3/15, 7/55, 10/98, 13/98, 13.1/5, 15/5; Flow Rate: 1.0 mL/min; Diluent: Acetonitrile:DMSO (1 :1).
Method 15: 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 16: Column: Xbridge C18 (75mm x 4.6mm, 3.5μιπ); Mobile Phase: B: Acetonitrile, A: 0.01 M Ammonium Bicarbonate in Aq; Gradient: Time/% B: 0/5, 1/5, 3/15, 7/55, 10/98, 13/98, 13.1/5, 15/5; Flow Rate: 1.0 mL/min; Diluent: Acetonitrile: H20 (1 :1).
Method 17: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μηι); 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 18: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ,um); 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 19: Column: Eclipse XDB-C18 (150mmX4.6mm, 5μπι); Mobile Phase: A: 0.01 Ammonium Bicarbonate in Aq, B: 100% Acetonitrile; Gradient: Time/% B: 0/5, 1.5/5, 3/15, 7/55, 10/95, 14/95, 17/5. 20/5; Column Temp: RT; Flow Rate: 1 mL min; Diluent: Acetonitrile: H?0: eOH (1 :2:2).
Method 20: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ,um); 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, 3.04/97, Column Temp: 35°C; Flow Rate: 0.6 mL/min;
Method 21 : Column: Gemini Phenomenex 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, 7/80, 10/98, 15/98, 15.01/10; Flow Rate: 1.0 mL/min; Diluent: AcetonitrikhbO.
Method 22: Column: Xbridge C18 (75mm x 4.6mm, 3.5 μιτι); 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, 8.01/5; Flow Rate: 1.0 mL/min.
Method 23: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 Cm); Mobile Phase: A: 0.1% Formic Acid in Water B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A of: 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 24: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 Dm); Mobile Phase: A: 0.1% Formic Acid in Water B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A of: 0/90,1/10,2.2/10,2.3/90,2.6/90; Column Temp: 50 °C; Flow Rate: 0.8 mL/min.
Method 25: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 Gm); Mobile Phase: B: 0.1% Formic Acid in Water A: 0.1 % Formic Acid in Acetonitrile; Gradient: Time/% B of: 0/97,0.3/97,2.2/2,3/2,3.01/97; Column Temp: 35 °C; Flow Rate: 0.6 mL min.
Method 26: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 3m); Mobile Phase: B: ACN, A: Ammonium Bicarbonate; Gradient: Time/% B of: 0/3, 1/3, 7/100, 7.5/100,9/3,10/3; Column Temp: 35 °C; Flow Rate: 0.500 mL/min
Method 27: Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 Dm); Mobile Phase: A: 0.1% Formic Acid in Water B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B of: 0/10, 1.8/100, 3.8/100, 4.0/10,5/10; Column Temp: 50 °C; Flow Rate: 0.7 mL/min.
Method 28: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 Dm); Mobile Phase: A: 0.1% Formic Acid in Water B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B of: 0/5,0.3/5, 2/95, 3.7/95, 4.2/5,5.7/5; Column Temp: 40 °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, 0.0116 mol) in toluene (20 mL) was added hexamethylditin (4.5 g, 0.0140 mol). the mixture was degassed with argon for 10 minutes, then Pd(PPhs)i (1.35 g, 0.00116 mol) was added and the mixture was degassed again for 5 minutes. 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 a Celite pad, washed with EtOAc, the filtrate was concentrated to get 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): R, = 1.20 min; m/z = 301.99 (Μ+Η').
Following a similar procedure to that described in reference example 1 , but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000072_0002
Terf-butyl (4'-cyano-[2,2'-bipyridin]-5-ylcarbamate
To a stirred solution of ferf-butyl 6-bromopyridin-3-ylcarbamate (2.0 g, 7.32 mmol) in 1 ,4-dioxane (20 mL) was added reference example 1a (2.15 g, 8.05 mmol), CsF (2.2 g, 14.65 mmol) and followed by Cul (0.27 g, 1.46 mmol). The resulting reaction mixture was degassed using N2 gas and then added Pd(PPh3). (0.84 g, 0.73 mmol). The reaction mixture was again degassed with 2 gas and heated to 110°C for 16h. The reaction mixture was cooled to RT and diluted with water (70 mL) and extracted with EtOAc (2 X 100 mL). The combined organic layers were dried over anhydrous
Figure imgf000072_0001
filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 20% EtOAc/ pet ether to afford the title compound (1.4 g, 65%) as an off white solid.
LC-MS (method 1): Rt = 2.31 min; m/z = 296.90 (M+H+).
Following a similar procedure to that described in reference example 2, but using the corresponding starting materia!, the following compound was obtained:
Figure imgf000072_0003
REFERENCE EXAMPLE 3
5'-Amino-[2,2'-bipyridine]-4-carbonitrile trifluoroacetate To a stirred solution of reference example 2 (1.4 g, 4.72 mmol) in DCM (3 mL) was added TFA (3 mL) at 0°C and the resulting reaction mixture was stirred at RT for 3h. The reaction mixture was evaporated under reduced pressure to obtain the title compound (1.0 g, 68%) as a pale yellow solid.
LC-MS (method 1): Rt = 1.08 min; m/z = 196.86 (M+H*).
Following a similar procedure to that described in reference example 3, but using the corresponding starting material, the following compound was obtained:
Figure imgf000073_0001
Terf-butyl (3-((6-bromopyridin-3-yl)amino)-3-oxo-1-phenylpropyl)carbamate TEA (5.83g, 0.0578 mol) followed by T3P [50% solution in EtOAc, 11.02g, 0.0346 mol) were added to a stirred solution of 6-bromo-3-amino pyridine (2g, 0.01156 mol) and 3-(Boc amino)-3-phenyl propionic acid (3.67 g, 0.011387 mol) in DCM (20 mL) at 0°C and 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) and aq.NaHCC solution (50 mL). The organic layer was dried over anhydrous NasSO*, 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 under vacuum to afford the title compound (2 g, 41%) as a brown gummy liquid.
LC-MS (method 1): Rt = 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- 3-((Terf-
346.19
4a Bromopyridin-3-yl)amino)- butoxycarbonyl)ami 18
.31 (M+H++2)
3-oxopropyl)carbamate no)propanoic acid
Terf-butyl 3-((6- 1-(Tferf- 1
bromopyridin-3- butoxycarbonyl)pipe 386.18
4b 2 2.71
yl)carbamoyl)piperidine-1 - rid i ne-3-ca rboxylic (M+H++2) carboxylate acid
A/-(6-Bromopyridin-3-y!)-1-
1-Methylpiperidine- 300.15
4c methylpiperidine-4- 1 1.04
4-carboxylic acid (M+H++2) carboxamide W-(6-Bromopy rid i n-3-y I)- 1 -
1-Methylpiperidine- 300.21
4d methylpiperidine-3- 6 1 ,41
3-carboxylic acid (M+H÷+2) carboxamide
REFERENCE EXAMPLE 5
Te/ -birtyl 3-((2-{6-bromopyridin-3-yl)ethyl)carbamoyl)piperidine-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 DC (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.NaHCOs solution and water. The organic layer was dried over anhydrous NaaSO,, 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-Bromopyridin-3-yl)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 Na2S0 . 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): R, = 1.44 min; m/z = 196.77 (M+H+).
Step c. Tert-butyl 2-(6-bromopyridin-3-yl)ethy!carbamate)
At 0°C, to a stirred solution of the compound obtained in the previous section, step b, (7.0 g, 0.035 mo!) and Boc20 (16 mL, 0.071 mol) in methanol (30 mL) was added NiCI2.6H20 (1.6 g, 0.007 mol) and followed by aBH (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 NajSO,, 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): R, = 2.02 min; m/z = 302.87 (M+H++2).
Step d. 2-(6-Bromopyridln-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 mo!) in 1 ,4-dioxane (15 mL) was added 4M HC! 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): R, = 4.80 min; m/z = 201.10 (M+H+).
Step e. Terf-butyl 3-((2-(6-bromopyridin-3-yl)ethyl)carbamoyl)piperidine-1-carboxylate
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- (feri-butoxycarbonyi)piperidine-3-carboxylic acid (2.7 g, 0.012 mol) in DCM (10 mL) was added TEA (7.0 mL, 0.05 mol) and followed by 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 I^SC , 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): R, = 2.03 min; m/z = 413.88 (M+H++2).
REFERENCE EXAMPLE 6
3-(( e/t-butoxycarbonyl)(phenyl)amino)propanoic acid
To a stirred solution of 3-(phenylamino)propanoic acid (1g, 6.06 mmol) and NaHCOs (0.509 g, 6.06 mmol) in dioxaneiH O (10:5 mL) was added Boc-anhydride (1.32 g, 6.06 mmol) 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 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 a2SO_, filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (0.9 g, 56%).
LC-MS (method 1): R, = 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 imgf000075_0001
REFERENCE EXAMPLE 7
Tert-butyl (5-bromopyrazin-2-yl)(3-(diethylamino)propyl)carbamate
Step a. WM5-Bromopyrazin-2-yl)-W "diethylpropane-1 ,3-diamine
In a microwave, to a stirred solution of 2,5-dibromopyrazine 1 (3.0 g, 12.71 mmol) in n-BuOH (10 mL) was added N1,N1-diethylpropane-1 , 3-diamine (1.652 g, 12.71 mmol) and DIPEA (1.639 g, 12.71 mmol), 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 filtered and filtrate was concentrated under reduced pressure to afford the title compound (3.0 g, crude LCMS~64%). The crude compound was used as such in the next step without further purification.
LC-MS (method 6): Rt = 1.48 min; m/z = 287.22 (M+H+).
Step b. Tert-butyl (5-bromopyrazin-2-yl)(3-(diethylamino)propyl)carbamate
To a stirred solution of 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 Boc20 (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 Na?SO,, 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 solid.
LC-MS (method 6): R, = 2.09 min; m/z = 387.39 (M+H*).
REFERENCE EXAMPLE 8
Tert-butyl (3-((6-bromopyridin-3-yl)amino)-3-oxopropyl)(phenethyl)carbamate Step a. N-(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. 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 NBISOA, filtered and concentrated under reduced pressure to afford the title compound (4.5 g, 73%) as a brown colour liquid.
Step b. W-(6"Bromopyridin-3-yl)-3-(phenethyiamino)propanamide
To a stirred solution of the compound obtained in the previous section, step b, (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 Na2SOa, 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 6): 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 Boc20 (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 a2S04, 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 7): R, = 2.57 min; m/z = 450.04 (M+H-+2).
Following a similar procedure to that described in reference example 8, but using the corresponding starting material, the following compound was obtained:
Figure imgf000077_0001
REFERENCE EXAMPLE 9
Tert-butyl 3-(1H-pyrazol-1-yl)propyl(5-bromopyrazin-2-yl)carbamate
Step a. 3-(1 H-Pyrazoi-1 -yl)propanenltrlle
A stirred solution of 1H-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 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 8): R, = 3.51 min; m/z = 122.1 (M+H+).
Step b. 3-(1 H-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 to a suspension of Raney-Nickel (1 g, wet) in methanol (15 mL) and followed by added 25% NH4OH solution (5 mL). 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 ^SC , 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, 60.3%).
LC-MS (method 1): Rt = 0.31 min; m/z = 126.15 (M+H-).
Step c. N-(3-(1H-Pyrazol-1-yl)propyl)-5-bromopyrazin-2-amine
In a microwave vial, to a solution of 2,5-dibromopyrazine (1.5 g, 6.30 mmol) in n-BuOH (10 mL) was added 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 Na2S04, 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 7): R, = 1.72 min; m/z = 281.84 (M+H*).
Step d. 7erf-butyl (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) was added TEA (2.2 mL, 15.95 mmol), Boc20 (1.73 g, 7.97 mmol) and DMAP (0.12 g, 1.06 mmol) 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 Na?S0 , 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 9): R, = 2.85 min; m/z = 384.31 (M+H++2).
REFERENCE EXAMPLE 10
3-((5-Bromopyrazin-2-yl)oxy)-N,W-diethylpropan-1-amine
To a stirred solution of 3-(diethylamino)propan-1 -ol (1.5 g, 11.43 mmol) in DMF (25 mL) was added 60% NaH (0.91 g, 22.86 mmol) 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 Na-^SO* 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): R, = 1.13 min; m/z = 290.20. ( +H++2).
Following a similar procedure to that described in reference example 10, but using the corresponding starting material, the following compound was obtained:
Figure imgf000078_0002
2-((6-Bromopyridin-3-yl)methoxy)-W,N-diethylethan-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 (5 mL) at 0 °C and stirred for 10 min, then added 2-bromo- N,rV-diethylethan-1 -amine dihydrochloride (1.38 g, 5.31 mmol) at 0°C. The reaction mixture was allowed to warm to RT and stirred for 4 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc, the separated organic layer was dried over anhydrous
Figure imgf000078_0001
filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (0.6 g, 39%).
LC-MS (method 6): R, = 1.51 min; m/z = 289.11 (M+H++2).
Following a similar procedure to that described in reference example 11 , but using in each case the corresponding starting materials, the following compounds were obtained:
Reference HPLC Rt
Compound name Startlng material m/z example met od (min)
11a 4-(2-((6-Bromopyridin-3- 6-Bromopyridin-3-ol and 4- 6 1.35 276.17 yl)oxy)ethyl)morpholine (2-bromoethyl) morpho!ine (M+H++2).
(6-Bromopyridin-3-
3-((6-Bromopyridin-3- yi)methanol and 3-chloro-
302.99
11 b yl)methoxy)-/V,rV- N,N-diethylpropan-1 -amine 1 1.13
(M+H++2 diethyipropan-1 -amine hydrochloride (reference
example 16 step a)
REFERENCE EXAMPLE 12
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-butyl 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 Na?S0 , 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 10): Rt = 2.28 min; m/z = 286.82 (M+H*+2).
Step b. 6-Bromo-W-methylpyridin-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 NaHCCb 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-bronropyridin-3-yl)(methyl)amino)-3-oxopropyl)carbarnate
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 E¾N (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 NajSC 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 13
Tert-butyl (3-((6-bromopyrldin-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) was added SOC (8.6 g, 72.72 mmol) at OX. The resulting solution was heated at 70°C for 16h. The reaction mixture was evaporated under reduced pressure, the crude compound was dissolved in DC (100 mL) and washed with saturated NaHCC>3 solution (2 x 70 mL), the organic layer were washed with brine solution (50 mL), dried over a2S04 and concentrate to obtain the title compound (3.1 g, 72%) as a colorless liquid.
LC- S (method 1): , = 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 NaHCOa (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 Na?S04 and concentrated to obtain the title compound (1.7 g, crude) as a liquid compound. The crude compound was used as such for next step without further purification.
LC-MS (method 1): R, = 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 Na2SO, 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.H?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 a2SO< and concentrated to obtain the title compound (1.2 g, 84%) as a colorless liquid.
LC-MS (method 1): Rt = 2.20 min; m/z = 291.92 (Μ-Η').
Step e. fert-butyl (3-((6-bromopyridin-3-yl)amino)-3-oxo-1-phenylpropyl)(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) was added and TEA (0.93 g, 9.21 mmol) 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 Na2S04, filtered and 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 6): R, = 2.94 min; m/z = 450.26 (M+H-+2).
REFERENCE EXAMPLE 14
3-((6-Bromopyridin-3-yI)oxy)-W,W-diethyIpropar¾-1 -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-(diethylamino)propan-1-ol (5.64 g, 43.10 mmoi),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 Na.SO-i, 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 9): Rt = 1.50 min; m/z = 287.18 (M+H*).
REFERENCE EXAMPLE 15
Tert-butyl (5-bromopyrazin-2-yl)(2-(diei yiamino)ethyl)carbamate
Step a. /T-(5-Bromopyrazin-2-yl)-W2,W2-diet ylethane-1,2"dsamine
To a stirred suspension of 60% NaH (1.0 g, 43 mmol) in DMF (30 mL) was added 5-bromopyrazin-2-amine (2.5 g, 14.45 mmol) at RT and stirred for 10 min followed by the addition of 2-bromo-W,A/-diethyiethan-1-amine dihydrochloride (3.88 g, 21.6 mmol) at RT. The reaction mixture was stirred for 16 h at RT. The reaction mixture quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous a∑S04 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) was added the compound obtained in the previous section, step a, (1.6 g, 5.86 mmol) 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 a?S0 and concentrated under reduced pressure, the obtained 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 6): R, = 1.95 min; m/z = 375.23 (M+H++2).
REFERENCE EXAMPLE 16
Tert-butyl (6-bromopyridin-3-yl)(3-(diethylamino)propyl)carbamate Step a. 3-Chloro-W,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 SOCI2 (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. Tert-butyl (6-bromopyrldin-3-yl){3-(diethylamino)propyl)carbamate
To a stirred suspension of 60% NaH (0.15 g, 6.598 mmol) in DMF (50 mL) was added a solution of ferf-butyl (6- bromopyridin-3-yl)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- S (method 15): R, = 1.55 min; m/z = 388.09 (M+H++2).
REFERENCE EXAMPLE 17
2-(1-(6-Bromopyridin-3-yl)-1H-pyrazol-4-yl)-W>W-diethyIeflian-1-amine Step a. 4-(2-Chloroethyi)-1H-pyrazole
A mixture of thionyl chloride (6.318 g, 53.55 mmol) and 2-(1H-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 9): f¾ = 1.61 min; m/z = 131.06 (M+H-).
Step b. A/,W-Diethyl-2-(1H-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)-1 H-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 K2C03 (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 Na?SO», 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): Rt = 1.69 min; m/z =323.22 (M+H+).
REFERENCE EXAMPLE 18
N-(6-Bromopyridin-3-yl)-3-(ethyl(phenethyl)amino)propanamide Step a. N-{6-Bromopyridin-3-yl)-3-(phenethylamino) 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 9): 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), 4A 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 ^SO,, 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): R, = 1.50 min; m/z = 376.36 (M+H÷).
REFERENCE EXAMPLE 19
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)2CI2 (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 Na2S04, 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): R, = 1.19 min; m/z = 266.91 ( +H*).
REFERENCE EXAMPLE 20
Tert-butyf 3-(2-bromopyrimidin-5-ylamino)-3-oxopropylcarbamate To a stirred solution of compound 2-bromopyrimidin-5-amine (950 mg, 5.46 mmol), 3-((fert- butoxycarbonyl)amino)propanoic acid (1.54 g, 8.14 mmol) in DCM (25 mL) was added TEA (3.02 mL, 21.84 mmol) and T3P (3.47 g, 10.92 mmol) at 0 °C and the reaction mixture was stirred at rt for 24 h. The mixture was diluted with DCM and washed with sat NaHCOs, the separated organic layer was dried over anhydrous feSCk The organic layer was concentrated under reduced pressure and the obtained crude compound was purified by flash column chromatography using 45 % of ethyl acetate in pet ether as an eluent to obtain the title compound (900 mg, 47%).
LC-MS (method 1): R. = 1.19 min; m/z = 344.82 (M+H++2).
REFERENCE EXAMPLE 21
1-(3-ChIoropropyl)-1H-pyrazoIe
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 NajSCv, 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- S (method 1): F¾ = 1.49 min; m/z = 144.86 (M+H+).
REFERENCE EXAMPLE 22
Tert-butyl (3·(1 H-pyrazol-1 -yl)propyl)(6-bromopyridin-3-yl)carbamate
To a stirred solution of compound tert-butyl (6-bromopyridin-3-yl)carbamate (1.0g, 1.0 equiv) in acetonitrile was added compound reference example 21 (1.2 equiv) and CsjCOs (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+).
Following a similar procedure to that described in reference example 22, but using in each case the corresponding starting materials, the following compound were obtained
Figure imgf000084_0001
REFERENCE EXAMPLE 23
N-(3-(1 H-Pyrazol-1 -yl)propyl)-6-bromo-N-methylpyridin-3-amine Step a . N-(3-(1W-Pyrazol-1-yi)propyl)-6-bromopyridin-3-amine
4M HCI in 1 , -dioxane (5 mL) was added to a solution of reference example 22 (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): Rt = 1.73 min; m/z = 283.00 (M+H++2).
Step b. N-(3-(1 H-Pyrazol-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 NaCNBH3.(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 NaHCOa 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 a2S0 , filtered and concentrated under reduced pressure to afford 700 mg of the title compound (89.5 % yield).
LC-MS (method 6): Rt = 2.48 min; m/z = 295.17 (M+H+).
REFERENCE EXAMPLE 24
4-(6-bromopyridin-3-yl)-N,N-diethylbutan-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 (Ppha^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 Na?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 4-(6- methoxy py rid in-3-yl )but-3-yn- 1 -ol , as a light brown gummy liquid.
LC-MS (method 6): F¾ = 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 eOH (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 4-(6-methoxypyridin-3-yl)butan-1 -ol , as a light brown gummy liquid. LC-MS (method 6): R, = 1.97 min; m/z = 182.17 (M+H+).
Step c . 2-bromo-5-(4-bromobutyl)pyridine
4-(6-methoxypyridin-3-yl)butan-1-ol (8 g, 1.0 eq) and POBr3 (2.0 eq) was heated at 110°C for 3 h (The progress of the reaction was monitored by LCMS). The reaction mixture was allowed to RT and the mixture was quenched with ice cold water (50 mL), neutralized with sat. Na?HCOa solution and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried over anhydrous NajSO*, 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 2-bromo-5-(4-bromobutyl)pyridine.
LC-MS (method 6): R, = 2.98 min; m/z = 292.14 (M+H+).
Step d . 4-(6-bromopyridin-3-yl)-W,W-diethylbutan-1 -amine
To a solution of the compound obtained in the previous section, step d, (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 (LCMS purity 32 % ), Purified by column chromatography using, 230-400 silica with 8% MeOH/DCM to afford 1.7 g (87.3 % yield) of 4-(6-bromopyridin-3-yl)-W,W- diethylbutan-1 -amine. 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 24, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000086_0001
REFERENCE EXAMPLE 25
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)pyridine (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 NasSO,, 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 22): R, = 4.92 min; m/z = 278.1 (M+H*).
REFERENCE EXAMPLE 26
6-Bromo-W-(3-(4,4-difluoropiperidin-1-yl)propyi)-W-methylpyridin-3-amine Step a . 6-Bromo-W-(3-(4,4-difluoropiperidin-1-yl)propyl)pyridin-3-amine
To a stirred solution of reference example 22b (4.0 g, 9.237 mmol) in DCM (30 mL), TFA (6 mL) was added at 0°C and allowed to stir at rt for 3h. The reaction mixture was basified to pH~8 using saturated NaHCOj solution and extracted with EtOAc. The separated organic layers were dried over anhydrous I^SC , filtered and concentrated under reduced pressure to afford the title compound (3.0 g, 97%) as a gummy.
LC-MS (method 23): R, = 1.37 min; m/z = 334.10 (M+H+). Step b. 6-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)propyl)-N-methylpyridin-3-amine
To a solution of the compound obtained in the previous section, step a, (3.0 g, 9.009 mmol) in formic acid (40 mL), paraformaldehyde (2.705 g, 90.09 mmol) was added and heated at 100°C for 16h. The reaction mixture was concentrated under reduced pressure: The crude residue was dissolved in water and basified to pH~8 using saturated NaHC(¾ solution and extracted with EtOAc (3x 50 mL). The separated organic layers were dried over anhydrous NajSC , filtered and concentrated under reduced pressure The crude compound was purified by silica gel column chromatography and eluted at 20% EtOAc in pet ether to afford the title compound (2.5 g, 79%) as an off-white solid.
LC-MS (method 23): Rt = 1.55 min; m/z = 348.13 (M+H+).
REFERENCE EXAMPLE 27
3-((6-Bromopyridin-3-yI)oxy)-W-ethyl- -p enethylpropan-1-amine
Step a. 3-((6-Bromopyridin-3-yl)oxy)propan-1-ol
To a stirred suspension of 6-bromopyridin-3-ol (5.0, 28.73 mmol) in DMF (40 mL), K?C03 (11.90 g, 86.20 mmol) and 3-bromo propanol (4.39 g, 31.60 mmol) were added at RT and stirred for 16h. The reaction mixture was quenched with ice cold water (150 mL) and extracted with ethyl acetate (2X60 mL). The combined organic layers were washed with water (100 mL) followed by brine solution (100 mL) and dried over anhydrous a^SC and filtered. The solution filtrated was concentrated under reduced pressure and the resulting crude compound was purified by flash column chromatography using 30 % of ethyl acetate in pet ether as the eluent to afford the title compound (3.50 g, 53%) as color less liquid.
LC-MS (method 24): R, = 0.82 min; m/z = 232.05 (M+H-).
Step b. 2-bromo-5-(3-bromopropoxy)pyridine
To a solution of the compound obtained in the previous section, step a, (3.50 g, 15.08 mmol) in DCM (50 mL), TPP (11.0 g, 30.17 mmol) and CBr. (9.98 g, 30.17 mmol) were added at 0 °C. The resulting mixture was stirred at room temperature for 6 h. The solvent was removed under reduced pressure and the crude residue was purified by silica gel column using with 10% ethyl acetate in pet ether as an eluent to afford the title compound (2.50 g, 56%) as color less liquid.
LC-MS (method 24): Rt = 1.19 min; m/z = 293.99 (Μ+Η').
Step c. 3-((6-bromopyridin-3-yl)oxy)-W-phenethylpropan-1 -amine
To a solution of the compound obtained in the previous section, step b, (2.50 g, 8.47 mmol) andd 2- phenylethanamine (1.54 g, 12.71 mmol) in ACN (50 mL), Nal (1.27 g, 8.47 mmol) and K2C03 (3.50 g, 25.42 mmol) were added. The resulting mixture was heated at 60°C for 16h. The reaction mixture was tempered, filtered and filtrate was concentrated under reduced pressure, obtained crude 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 (1.50 g, 53%) as color less liquid.
LC-MS (method 24): R, = 0.81 min; m/z = 335.20 (Μ+Η').
Step d. 3-((6-bromopyrldin-3-yl)oxy)-N-ethyl-N-phenethylpropan-1-amine To a solution of the compound obtained in the previous section, step c, (1.50 g, 4.47 mmol) in DMF (20 mL) was added K2CO3 (1.85 g, 13.43 mmol) followed by ethyl iodide 7 (1.04 g, 6.71 mmol) and stirred at room temperature for 16h. Reaction mixture was poured into ice water, extracted with ethyl acetate (2X60 mL). The combined organic layer was washed with water (100 mL) followed by brine solution (100 mL) dried over anhydrous ^SC , filtered; the filtrate was concentrated under reduced pressure and the resulting crude compound was purified by grace reverse phase column using 40 % of Acetonirile in 0.1 % aq. Formic acid an eluent to afford the title compound (1.10 g, 68%) as color less liquid.
LC-MS (method 23): R, = 1.62 min; m/z = 363.29 (M+H*).
REFERENCE EXAMPLE 28
2-Bromo-5-(3-(4,4-dif!uoropiperidin-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) was added 1-bromo-3- chloropropane (2.7 g, 17.24 mmol), K2CO3 (4.7 g, 34.48 mmol) at RT and allowed to stirred at RT. the reaction was poured in to ice water and extracted with EtOAc (2 x 20 mL) washed with water (10 mL), then brine solution (10 mL), was dried over anhydrous Na2SC , filtered and concentrated under reduced pressure to get 2.2 g (76 %) the title compound as a gummy solid.
LC-MS (method 24); Rt = 1.16 min; m/z = 251.97 (M+H++2).
Step b. 2-Bromo-5-(3-(4,4-difluoropiperidin-1-yl)propoxy}pyridine
To a solution of the compound obtained in the previous section, step a (2 g, 7.98 mmol) in acetonitrile was added 4,4-difluoropiperidine.HCI (1.88 g, 11.97 mmol), K2CO3 (3.3 g, 23.95 mmol), Nal (1.19 g, 7.98 mmol) at RT t RT and heated to 70°C for 24 h. the reaction was allowed to RT and poured into ice water (30 mL) and extracted with EtOAc (2 x 80 mL) and the separated organic layer was dried over anhydrous Na2SC<4, filtered and concentrated under reduced pressure to get crude, was washed with n-pentane and dried to afford 1.5 g (56 %) of the title compound as a gummy liquid.
LC-MS (method 24): R, = 0.66 min; m/z = 336.44 (M+H~+2).
REFERENCE EXAMPLE 29
2-Bromo-5-((2-(4I4-difluoropiperidin-1-yl)ethoxy)methyl)pyridine Step a. 2-bromo-5-(bromomethyl)pyridine
To a stirred solution of (6-Bromopyridin-3-yl) methanol (2 g, 0.01 mol) in DCM (40 mL), PBr3 (14.3 g, 0.05 mol)) was added at 0°C and allowed to stir RT for 3 h. The reaction was monitored by TLC and LC S. The crude reaction mass was diluted with 20 mL of ice cold water and basified with sat. NaHC03 solution to a pH- 8 extracted with DCM (2 X 20 mL), washed with brine, the organic layer was dried over anhydrous NaaSC^, evaporated to get crude resiude that was purified in 100-200 silica gel in 10 % EtOAc/Hexane to get 2.1 g (78%) of the title compound as an off white gummy solid.
LC-MS (method 23): R, = 1.91 min; m/z = 251.74 (M+H++2).
Step b. 2-(4,4-difluoropiperidin-1-yl)ethan-1-ol To a stirred solution of 4,4-Difluoropiperidine hydrochloride (3.0 g, 19 mmol), in acetonitri!e (30 mL) triethyiamine (9.6 g, 13.7 mL, 95 mmol) was added at 0°C and allowed to stir for 15 minutes then 2- Bromoethanol (1.9 g, 15 mmol) was added drop wise continued stirring at RT for 5 h. The reaction was monitored by TLC and LCMS. The acetonitrile was evaporated and diluted with (30 mL) ice cold water and extracted with EtOAc (2 X 30 mL), washed with brine (30 mL), dried over anhydrous Na?SO«-, concentrated to get 1.9 g (59%) crude of the title compound. No purification was done obtained crude was used as such for next step.
LC-MS (method 23): R, = 0.24 min; m/z = 166.05 (M+H*).
Step c. 2-bromo-5-({2-(4,4-difluoropiperidin-1-yl)ethoxy)methyl)pyridine
To a solution of the compound obtained in the previous section, step b (1 g, 6.1 mmol), NaH (0.72 g, 30.0 mmol) in THF at 0°C the compound obtained in the previous section, step a (1.67 g, 6.7 mmol) was added lowly at same temperature and allowed to stir for 4 h from 0°C to RT. Reaction was monitored by TLC & LCMS. The reaction mixture was diluted with 40 mL ice cold water and extracted with 2 X 50 mL EtOAC, washed with brine, dried over anhydrous Na2S04, evaporated to get crude 2-bromo-5-((2-(4,4- difluoropiperidin-1-yl)ethoxy)methyl)pyridine (3) as pale yellow liquid. The crude was purified flash column chromatography by 40% EtOAC/Hexane in 100-200 silica to get 1.3 g (64%) of of the title compound as pale yellow liquid.
LC-MS (method 27): R, = 0.41 min; m/z = 337.08 (M+H-+2).
REFERENCE EXAMPLE 30
6-Bromo-W-butyl-W-(3-(4,4-difluoropiperidin-1-yl)propyl)pyridin-3-amine Step a. N-(6-Bromopyridin-3-yl)-W-(3-(4,4-dlfiuoropiperidin-1-yl)propyl)butyramide
To a solution of the compound obtained in reference example 26, step a, (1 ,1g,3.303mmol) in DCM(15ml) was added TEA (2.3ml,13.21mmol) and butyryl chloride (0.65ml,6.606mmol) at 0°C and allowed to stir at RT for 16h and the progress of the reaction was monitored by LCMS. The reaction mixture was diluted with DCM and washed with water, 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 15% EtOAc in pet ether to afford of the title compound (1.00g,81.8%) as a yellow gummy ;
LC-MS (method 28): Rt = 2.88 min; m/z = 404.62 (M+H+).
Step b. 6-bromo-W-butyl-W-(3-(4,4-difiuoropiperidin-1 -yl)propyl)pyridin-3-amine
To a solution of the compound obtained in the previous section, step a (0.990g,2.23mmol) in THF(15ml) was added BH3.DMS (3.34ml,6.69mmol) at 0°C and heated to 75°C for 16h. The progress of the reaction was monitored by LCMS and TLC. LCMS shows of desired mass, the reaction mixture was concentrated under reduced pressure. MeOH was added to the reaction mixture and stirred at 65°C for 2h and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted at 10% EtOAc in pet ether to afford the title compound (590mg,61.7%) as a green gummy ;
LC-MS (method 23): Rt = 1.74 min; m/z = 390.27 (M+H+), EXAMPLE 1
5'-(Piperidine -carboxamido)-[2,2'-bipyridine] <arboxamide di-trlfluroacetate
Figure imgf000090_0001
Step a. Methyl 5'-(1-(fert-butoxycarbonyl)piperidine-4-carboxamido)-[2,2!-bipyridine]-4-carboxyIate To a stirred solution of compound reference example 3a (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.NaHCOs solution and extracted with DCM (3 X 10 mL). The organic layer was dried over anhydrous Na?S0.4, 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 titie compound.
LC-MS (method 1): R, = 2.21 min; m/z = 441.35 (M+H+).
Step b. Tert-butyi 4-((4'-carbamoyl-[2,2'-bipyridin]-5-yl)carbamoyl)piperidine-1-carboxyiate
In a pressure tube, to a stirred solution of the compound obtained in the previous section, step a, (200 mg, 0.4545 mmol) in MeOH (4 mL) was added saturated methanolic ammonia (10 mL). The pressure tube was sealed with Teflon screw cap and the reaction mixture was heated at 100°C for 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was triturated with Et?0 (2 X 2 mL) and dried in vacuum to afford the title compound (150 mg, 77.64%) as an off-white solid.
LC-MS (method 1): Rt = 1.70 min; m/z = 426.34 (M+H*).
Step c. 5'-(Piperidine-4-carboxamido)-[2,2'-bipyridine]-4-carboxamide di-trifluroacetate
To a stirred solution of the compound obtained in the previous section, step b, (140 mg, 0.329 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, n-pentane and dried under reduced pressure. The crude compound was dissolved in DM water and lyophilized to afford the title compound (95 mg, 88%) as a pale brown solid.
LC-MS (method 1): R, = 1.52 min; m/z = 326.27 (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:
Starting HPLC Rt
Example Compound name m/z
material method (min)
5'-(Pyrrolidine-2-carboxamido)-[2,2'- HTe t- 312.23
1a 1 1.54
bipyridine]-4-carboxamide butoxycarbony (M+H+).
Figure imgf000091_0001
Figure imgf000092_0001
• (**) Using 4M HCI in dioxane instead of TFA/DCM in step c
EXAMPLE 2
5'-{3-Amino-3-phenyipropanamido)-[2,2'-bipyridine]-4-carboxamide
Figure imgf000092_0002
Step a. Methyl 5'-(3-((fert-butoxycarbonyl)amino)-3-phenylpropanamido)-[2,2'-bipyridine]-4-carboxylate
To a stirred solution of reference example 4 (780 mg, 1.857 mmol) in 1 ,4-dioxane (15 mL) was added reference example 1 (804 mg, 2.674 mmol), CsF (566 mg, 3.714 mmol) and followed by Cul (70 mg, 0.3714 mmol). The resulting solution was degassed with nitrogen gas. then added Pd(PPhs)- (214 mg, 0.1857 mmol), the mixture was again degassed and then heated to 110 °C for 16h. The reaction mixture was cooled to RT, the reaction mixture was filtered through the Celite pad, washed with EtOAc, the filtrate was dried over anhydrous Na?SO.t and concentrated to get crude compound. The crude compound was purified by flash column chromatography using siiicagel and eiuted with 50%EtOAc/pet ether to afford the title compound (450 mg, 50%) as a pale brown solid.
LC-MS (method 1): R, = 2.32 min; m/z = 477.04 (Μ+Η').
Step b. Tert-butyl {3-((4'-carbamoyl-[2,2'-bipyridin]-5-yl)amino)-3-oxo-1-phenylpropyl)carbamate
In a sealed tube, to a solution of the compound obtained in the previous section, step a, (280mg, 0.588 mmol) in methanol (5 mL) was added NH3 in methanol (25 mL) at 0°C. The reaction mixture was allowed to stir at RT and then heated to 80°C for 16h. The reaction was continued further another 6h. The reaction mixture was cooled to RT and concentrated at reduced pressure. The crude compound was washed with aq.NaOH solution, diethyl ether and dried under reduced pressure to afford the title compound (180 mg, 66%) as an off-white solid.
LC-MS (method 1): R( = 1.84 min; m/z = 462.37 (M+H-).
Step c. 5'-(3-Amino-3-phenylpropanamido)-[2,2'-bipyridine]-4-carboxamide
To a stirred solution of the compound obtained in the previous section (95 mg, 0.206 mmol) in DCM (2 mL) was added trifluroacetic acid (1 mL) at 10SC, 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, the resulting solid was dried under reduced pressure. The crude compound was purified by preparative HPLC to afford the title compound (50 mg, 52.6 %).
LC-MS (method 1): Rt = 1.07 min; m/z = 362.33 (M+H+).
Preparative HPLC Conditions: Column: Aquity UPLC BEH, C18, 1.7 urn, 2.1x50 mm; Mobile phase: 0.1% Formic acid in H20; Time/% of B: 0/97, 3.2/2, 4/2, 4.01/97; Flow rate: 0.6 mL min; Temp: 35°C; Wave length:
215 & 254
Following a similar procedure to that described in example 2, but using in each case the corresponding starting materials, the following compounds were obtained:
Starting HPLC Rt
Example Compound name m/z
material method (min)
5'-(2-(Piperidine-3-carboxamido)ethyl)- [2, 2'-bipyridine]-4-carboxamide di- trifluoroacetate Reference
example 1 and 354.03
2a 1 0.91
Reference (M+H+). example 5
Reference
5'-(3-Aminopropanamido)-[2,2'- 286.4
2b example 1 b 4 3.56
bipyridine]-4-carboxamide (M+H*).
and Reference
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
• (*) Only steps a) and b). No Boc Deprotection step.
• (**) Using 4M HCI in dioxane instead of TFA/DCM in step c
EXAMPLE 3
5'-{(3"(1H-Pyrazol-1-yl)propy!)amino)-[2,2'-bipyridine] -carboxamide di-trifluoroacetate
Figure imgf000100_0002
Step a. Methyl 5'-((3-(1 H-pyrazol-1 -yi)propyl)(tert-butoxycarbony!)amino)-[2,2'-bipyridine]-4-carboxylate
To a stirred solution of reference example 2a (500 mg, 1.51 mmol) in acetonitrile was added the reference example 21 , (263 mg, 1.82 mmol) and Cs?COs (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 Na?S0 , filtered and concentrated under reduced pressure to get crude compound 600 mg. The crude compound was purified by Prep-HPLC and Iyophilized to afford 120 mg of the title compound (LCMS -60%).
LC-MS (method 1): R, = 2.35 min; m/z = 438.20 (M+H+).
Preparative HPLC Conditions: Column: Inertsil ODS-3 (20 x 250 mm, 5.0 Mm);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 mL/min; Wavelength: 215 nm & 254 nm.
Step b. Terf-butyl (3-{1H-pyrazol-1-yl)propyl)(4'-carbamoyl-[2,2'-bipyridin]-5-yl)carbamate
In a sealed tube, a suspension of the compound obtained in the previous section, step a, (120 mg, LCMS -64%) in saturated methanoiic-NH3 (20 mL) was heated at 80 °C for 16 h. The reaction mixture was concentrated and the residue was dissolved in EtOAc and washed with 10% aq.NaOH solution and brine solution. The separated organic layer was dried over anhydrous I^SC , filtered and filtrate was concentrated under reduced pressure to afford 90 mg of crude compound. The crude compound was purified by Preparative HPLC and Iyophilized to afford 35 mg (29.1%) of the title compound as a white solid.
LC-MS (method 1): R, = 1.79 min; m/z = 424.55 (M+H+).
Preparative HPLC Conditions: Column: X-SELECT (20 x 150 mm, 5.0 pm); Mobile phase: A: 10 mm Ammonium bicarbonate in Aq; B: Acetonitrile; Gradient Method (A / B): 0/20, 2/20, 10/45, 15/98; Flow rate: 18.0 mL/min; Wavelength: 215 nm & 254 nm.
Step c. 5!-((3-(1 H-Pyrazol-1-yl)propyl)amino)-[2,2'-bipyridine]-4-carboxamide di-trifluoracetate
To a stirred solution of the compound obtained in the previous section, step b, (35mg, 0.082 mmol) in DCM (2 mL) was added TFA (0.6 mL) at 0°C. The resulting solution was stirred at RT for 3h. The reaction mixture was evaporated under reduced pressure, the residue was triturated with diethyl ether to obtain gummy solid compound. The compound was dissolved in demineralized H20 and Iyophilized to afford 32 mg (81.7 %) of the title compound as a TFA salt.
LC-MS (method 1): Rt = 1.11 min; m/z = 323.24 (M+H~).
EXAMPLE 4
^-((a-il-Methyl-IH-pyrazol^-yiJpropyijaminoJ-^^'-bipyridinej-^rboxamide
Figure imgf000101_0001
Step a. 3-{1 -Methyt-1 H-pyrazol-4-yl)propanal
To a stirred solution of 3-(1 -methyl-1 H-pyrazol-4-yl)propan-1 -ol (500 mg, 3.571 mmol) in DCM (10 mL) was added Dess- artin periodinane (2.271 g, 5.356 mmol) 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 solution (50 mL) and brine solution (50 mL). The separated organic layer was dried over anhydrous Na2SO<, filtered and 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+).
Step b. Methyl 5'-((3-(1-methyl-1H-pyrazol -yl)propyl)amino)-[2,2'-bipyridine3-4-carboxylaie
To a stirred solution of the compound obtained in the previous section, step a, (300 mg, 2.173 mmol) in methanol (10 mL) was added reference example 3a (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 NaCNBHs (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 NaHCOa solution and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO„ filtered and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography and eiuted at 100% EtOAc to afford the title compound (250 mg, 32%) as a pale yellow solid.
LC-MS (method 1): R, = 1.47 min; m/z = 351.97 (M+H*).
Step c. 5'-(P-(1-lethyI-1H-pyrazoI -yl)propyI)amino)-[2,2'^ipyridine] -carboxamide
In a sealed tube, a suspension of methanolic-NHs (20 mL) and the compound obtained in the previous section, step b, (100 mg, 0.284 mmol) was heated to 80°C for 16h. The reaction mixture was cooled to RT and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with 10% aq.NaOH solution (50 mL) and brine solution (50 mL). The separated organic layer was dried over anhydrous NajSO-t, filtered and filtrate was concentrated under reduced pressure. The obtained compound was triturated with n-pentane and diethyl ether followed by dried under vacuum to afford the title compound (55 mg, 57%) as a pale yellow solid.
LC-MS (method 1 ): Rt = 1.15 min; m/z = 336.97 (M+H+).
Following a similar procedure to that described in example 4, but using in the corresponding starting material, the following compound was obtained:
Figure imgf000102_0001
EXAMPLE 5
5'-(Piperidine-3-carboxamido)-[2,2'-bipyrid!ne]-4-carboxamide sesqui-hydrochloride
Figure imgf000103_0001
Step a. Tert-butyl S-^'-cyano-p^'-bipyridinl-S-yllcarbamoy piperidine-l-carboxylate
To a stirred solution of reference example 4b (1.0 g, 2.61 mmol) in 1 ,4-dioxane (10 mL) was added reference example 1a (0.76 g, 2.87 mmol), CsF (0.79 g, 5.22 mmol) and followed by Cul (0.1 g, 0.52 mmol). The resulting reaction mixture was degassed using N2 gas and then added Pd(PPhj)4 (0.3 g, 0.26 mmol). The reaction mixture was again degassed and heated to 110 °C for 16h. The reaction mixture was cooled to RT and diluted with water (70 mL) and extracted with EtOAc (2 X 70 mL). The combined organic layers were dried over anhydrous filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 50% EtOAc/ pet ether to afford the title compound (0.5 g, 47%) as an off white solid.
LC-MS (method 2): R, = 2.83 min; m/z = 408.06 (M+H*).
Step b. Tert-butyl 3-((4'-carbamoyl-[2,2'-bipyridin]-5-yl)carbamoyl)piperidine-1"Carboxylate
To a stirred solution of the compound obtained in the previous section, step a, (0.2 g, 0.49 mmol) in MeOH (5 mL) was added NaOH (59 mg, 1.47 mmol) and 30% H2O2 (50 mg, 1.47 mmol) at RT. The reaction mixture was heated at 65 °C for 2h. The reaction mixture was cooled to RT and evaporated under reduced pressure. The crude compound was dissolved in EtOAc (70 mL) and washed with 10% NaOH solution (2 x 30 mL). The organic layer was dried over Na2SO<i and concentrated to obtain the title compound (95 mg, 48%) as an off white solid.
LC-MS (method 2): Rt = 2.33 min; m/z = 426.47 (M+H+).
Step c. 5'"(Piperidine-3-carboxamido)-[2,2!-bipyridine]-4-carboxamide sesqui-hydrochloride
To a stirred solution of the compound obtained in the previous section, step b, (90 mg, 0.21 mmol) in 1 ,4- dioxane (3 mL) was added 4M HCI in dioxane (3 mL) at 0 °C. The reaction mixture was stirred at RT for 5h. The reaction mixture was evaporated under reduced pressure and the crude compound was triturated with pentane (10 mL) to obtain the title compound (50 mg, 62.6 %) as a HCI salt. LC-MS (method 1): f¾ = 0.92 min; m/z = 326.27 (M+H+).
EXAMPLE 6
5'-(3-(Diethylamino)propanamido)-[2,2'-bipyridine]-4-carboxamide hemi-formate
Figure imgf000103_0002
Step a. 3-Chloro-W-(4'-cyano-[2,2'-blpyridin]-5-yl)propanamide
To a stirred solution of reference example 3 (1.0 g, 5.10 mmol) in DCM (10 mL) was added pyridine (1.20 g, 15.30 mmol) at 0°C, stirred for 10min, and then added 3-chloropropanoyl chloride (0.97 g, 7.65 mmol) at 0°C. The reaction mixture was stirred at RT for 16h. The reaction mixture was diluted with water (50 mL), and extracted with DCM (2 X 70 mL). The combined organic layers were dried over anhydrous a2S0 , filtered and concentrated under reduced pressure. The crude compound was triturated with diethyl ether (2 x 10 mL) and dried to obtain the title compound (0.5 g, 35%) as a white color solid.
LC-MS (method 1): R, = 1.84 min; m/z = 286.82 (M+H÷).
Step b. N-I '-Cyano-^.Z-bipyridinJ-S-yl^diethylaminoJpropanamide
To a stirred solution of the compound obtained in the previous section, step a, (0.5 g, 1.75 mmol) in THF (5 mL) was added diethyi amine (1.28 g, 17.50 mmol) at RT. The resulting reaction mixture was heated to 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) and dried to obtain the title compound (0.5 g, 89%) as an off white solid.
LC-MS (method 1): Rt = 1.25 min; m/z = 321.73 (M+H-).
Step c, 5'-(3-(Diethylamino)propanamido)-[2,2'-bipyridine]-4-carboxamide hems-formate
To a stirred solution of the compound obtained in the previous section, step b, (0.2 g, 0.61 mmoi) in MeOH (5 mL) was added NaOH (74 mg, 1.85 mmol) and 30% H (0.2 g, 1.85 mmol) at RT. The resulting reaction mixture was heated to 60°C for 2h. The reaction mixture was cooled to RT and evaporated under reduced pressure. The residue was suspended with 20% MeOH in DCM (50 mL), the insoluble solid was separated and the organic layer was concentrated to obtain the crude compound. The crude compound was purified by preparative HPLC to obtain the title compound (50 mg, 24%) as a formate salt.
LC-MS (method 1): R, = 1.13 min; m/z = 342.32 (M+H-).
Preparative HPLC conditions: Column : Xtimate, 250*19mm 5.0μ Pump(A) : acetonitrile, Pump(B) : 0.1%formic acid in aqueous. Flow : 20.0 ml/min Gradient : % of Pump(B)- 0/20,6/50, 6.1/100, 8/100, 8.1/20, 10/20, max : 215nm
EXAMPLE 7
5'-((3-Aminopropylamlno)- '-bipyridine]-4-carboxamide hemipenta-hydroch!oride
Figure imgf000104_0001
Step a. Tert- butyl (3-oxopropyl)carbamate
To a stirred solution of fe/f-buiyl (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 NajSA (40 mL) and saturated aqueous NaHCCh (40 mL) at RT. The precipitated solids were filtered through a pad of celite; the filtrate was extracted with DC (2 X 30 mL). The combined organic layers were washed sequentially with 20% aqueous 828203 (50 mL), saturated aqueous NaHCCh (50 mL), and brine (50 mL). The separated organic layer was dried over anhydrous NazSO-i, and concentrated under reduced pressure to afford the title compound (1.2 g, 46%) as yellow liquid.
Step b, Methyl S'-ffS-ltert-butoxycarbonyllaminoJpropylaminoJ-p^'-bipyridinel^-carboxylate
To a stirred solution of reference example 3a (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 added NaCNBH3 (406 mg, 6.55 mmol) at 0°C. The reaction mixture was stirred at RT for 24 h. The reaction mixture was added water (30 mL) and filtered through a pad of celite, the filtrate was extracted with EtOAc (3X20 ml). The combined organic layers were 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) eluting 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. Tert-butyl (3-{(4,-carbamoyl-[2,2,-bipyridin]-5-yl)amino)propyl)carbamate
To a stirred solution of the compound obtained in the previous section, step b, (200 mg, 0.51 mmol) in MeOH (2 mL) was added methanolic ammonia (20 mL) at RT and the reaction mixture was stirred at 100°C in a sealed tube for 16 h. The reaction mixture was concentrated under reduced pressure the obtained residue was dissolved in 10% Methanol in DCM (60 mL) and washed with saturated NaHC03 solution (2x25 mL) and dried over NazSO-i. The dried organic layer was concentrated under reduced pressure and the resultant crude compound was triturated with diethyl ether to afford the title compound (140 mg, 72%) as yellow solid.
LC-MS (method 1): Rt = 1.36 min; m/z = 372.51 (Μ+Η').
Step d. 5'-((3-AminopropyS)amino)-[2,2'-bipyridine]-4-carboxamide hemipenta-hydrochloride
To a stirred solution of the compound obtained in the previous section, step c, (135 mg, 0.36 mmol) in DCM: THF (10 mL:5 mL) was added 4M HCI in 1 ,4-dioxane (1.0 mL) at RT and stirred for 6 h. The mixture was concentrated under reduced pressure and the obtained crude compound was triturated with acetonitrile and diethyl ether to afford the title compound (85 mg, 77%) as yellow solid.
LC-MS (method 12): R, = 11 ,29 min; m/z = 272.3 (M+H+).
EXAMPLE 8
2-(5-(3-Amlnopropanamido}pyridin-2-yl)pyrimidine-4-carboxamide hemipenta-hydrochloride
Figure imgf000105_0001
Step a. Tert-butyl (3-oxo-3-((6-(trimethylstannyl)pyridin-3-yl)amino)propyl)carbamate To a stirred solution of reference example 4a (2 g, 5.83 mmol) and hexamethykJitin (2 mL, 9.91 mmol) in toluene (50 mL) was added Pd(PPh3)2Cb (0.205 g, 0.291 mmol) and the mixture was degassed under nitrogen for another 10 min. The reaction mixture was heated at 100°C for 16 h in a sealed tube and the reaction mixture was allowed to cool to RT, filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the resultant crude compound was purified by flash column chromatography on neutral alumina using 50% EtOAc in petroleum ether as eluent to afford the title compound (1.5 g, 60%).
LC-MS (method 1): R, = 1.51 min; m/z = 427.95 (M-H+).
Step b. Tert-butyl (3-{(6-(4-cyanopyrimidin-2-yl)pyridin-3-yl)amino)-3-oxopropyl)carbamate
To a stirred solution of 2-chioropyrimidine-4-carbonitrile (0.25 g, 1.79 mmol) and the compound obtained in the previous section, step a, (0.925 g, 2.15 mmol).in toluene (10 mL) was added Pd(PPh3)4 (0.207 g, 0.18 mmol) at RT. The resulting solution was degassed with nitrogen for 10 min. The mixture was stirred at 120 °C for 16 h in a sealed tube. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure, the obtained crude was purified by Grace column chromatography (reverse phase) using 40% acetonitrile in 0.1%TFA (aqueous) as eluent to afford the title compound (80 mg, 12%).
LC-MS (method 1): R, = 1.73 min; m/z = 369.21 ( +H+).
Step c, Tert- butyl (3-{(6-(4-carbamoylpyrimidin-2-yl)pyridin-3-yl)amino)-3-oxopropyl)
To a stirred solution of the compound obtained in the previous section, step b, (0.11 g, 0.29 mmol) in tert- butanol (10 mL) was added KOH (0.05 g, 0.89 mmol) at RT and the reaction mixture was stirred at 100°C for 45 min. The reaction mixture was concentrated under reduced pressure the obtained residue was dissolved in 20% Methanol in DCM (60 mL) and washed with saturated NaHCC solution and dried over anhydrous a2S04, filtered and the filtrate was concentrated under reduced pressure. The obtained crude compound was purified by Prep HPLC to afford the title compound (12 mg, 10%)
LC-MS (method 13): Rt = 1.25 min; m/z = 387.1 (M+H~).
Preparative HPLC Conditions: Column: XBridge C18 δ.Ομιτι (19 x 250mm), Mobile phase (Buffers): A: 10mM Ammonium Bicarbonate in Aq. B: Acetonitrile, Gradient Method (Time/ %B): 0/10, 2/10, 10/45, 15/90; Flow rate: 17.0 mL/min; Detectors (Wavelength): 215 nm & 254 nm
Step d. 2-(5-(3-Aminopropanamido)pyridin-2-yl)pyrimidine-4-carboxamide hemipenta-hydrochioride
4M HCI in 1 ,4-dioxane (1 mL) was added to a stirred solution of the compound obtained in the previous section, step c, (0.012 g, 0.031 mmol) in 1 ,4-dioxane (2 mL) at 10°C, the reaction mixture was allowed to stir 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 (4.5 mg, 51%)
LC-MS (method 14): R, = 4.55 min; m/z = 287.1 (M+H*).
EXAMPLE 9
5,-(3-(Diethylamino)-3-phenyipropanamido)-[2,2'-bipyridine]-4-carboxamide
Figure imgf000107_0001
Step a. Methyl 5'-(3-amino-3-pheny!propanamido)-[2,2'-bipyridine]-4-carboxylate hydrochloride salt 4 HCI in 1 ,4-dioxane (3 mL) was added to a stirred solution of the compound obtained in example 2 step a (640 mg) in methanol (3 mL) at 10°C, the reaction mixture was allowed to stir at RT for 4 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated; the residue was triturated with diethyl ether and dried under reduced pressure to afford the title compound as a hydrochloride salt.
LC-MS (method 1): Rt = 1.42 min; m/z = 375.05 (M-H+).
Step b. Methyl 5'-(3"(diethylamino)-3»phenylpropanamido)-[2,2'-bipyridine]-4-carboxylate
To a stirred solution of the compound obtained in the previous section, step a, (460 mg) in methanol (4 mL) was added acetaldehyde (294 mg, 6.69 mmol), 4A molecular sieves, followed by AcOH (134 mg, 2.23 mmol) at 0°C. The mixture was stirred for 10 minutes, then added NaCNBH3 (211 mg, 3.34 mmol) at 0°C. The resulting reaction mixture was allowed to stir at RT for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated; the residue was diluted with DCM (50 mL), filtered through the Celite pad, the filtrate was washed with aq.NaHCOa solution (2 x 20 mL), water (20 mL). The organic layer was dried over anhydrous a2S04, filtered and the filtrate was concentrated. The crude compound was purified by prep. HPLC to afford the titie compound (200 mg, 41%) as an off-white solid.
LC-MS (method 1): R, = 1.57 min; m/z = 433.37 (M+H*).
Preparative HPLC conditions: Column: Inertsil ODS-3 (20 x 250 mm), 5.0μιη; Mobile phase: pump (A): 10 mM NH4HCO3 in water, pump (B): Acetonitrile; Isocratic method: % of B: 78% A: 22%; Flow: 18 mL/min; Max: 215 & 254 nm.
Step c. 5'-(3-(Diet ylamino)-3-phenylpropanamido)-[2,2'-bipyridine]-4-carboxamide
To a stirred solution of the compound obtained in the previous section, step b, (80 mg, 0.185 mmol) in methanol (1 mL) was added methano!ic NH3 (5 mL) at 0°C, the reaction mixture was allowed to stir at RT for 48h. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated; the residue was washed with diethyl ether (5 mL) and dried under reduced pressure to get 65 mg of crude. The crude compound was purified by prep.HPLC and lyophilized to afford the title compound (29 mg, 37%) as a white solid.
LC-MS (method 1): Rt = 1.27 min; m/z = 418.31 (M+H*).
Preparative HPLC conditions: Column: Inertsil ODS-3 (20 x 250 mm), 5.0pm; Mobile phase: (A): 10 mM NH4HCO3 in water, (B): Acetonitrile; Isocratic method: T% of B; 2/50, 10/5, 15/50; Flow: 18 mL/min; Max: 215 nm.
EXAMPLE 10 5'-(3-(Pyrrolidin-1-yl)propanamido}-[2, 2'-bipyridine]-4-carboxamide
Figure imgf000108_0001
Step a. W- 6-Bromopyridin-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- chloropropanoyi 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 I^SC , filtered and concentrated under reduced pressure to afford 3.5 g (76.4 %) of the title compound
LC-MS (method 1): R, = 1.65 min; m/z = 263.08 (M+H+).
Step b. A/-(6-Bromopyridin-3- l)-3-(pyrrolidin-1-yi)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 a2S04, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography and eluted at 4%MeOH/DC to afford 3.0 g (quantitative yield) of the title compound
LC-MS (method 1): Rt = 0.98 min; m/z = 298.17 (M+H+).
Step c. 3-{Pyrro!idin-1 -yl)-W-(6-(trimethylstannyl)pyridin-3-yl)propanamide
To a stirred solution of 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 then Pd (PPhs^ (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/DC to afford the title 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'-bipyridine] -carboxylate
To a stirred solution of methyl 2-bromoisonicotinate (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), followed by addition of Cul (52 mg, 0.277 mmol). The resulting solution was degassed with nitrogen, then 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) filtered through Celite pad and 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- S (method 1 ): R, = 1.25 min; m/z = 355.24 (M+H*).
Step e. 5'-(3-(Pyrrolidin-1 -yl)propanamido)-[2,2'-bipyrid!ne]-4-carboxamide
In a pressure tube, methanolic-NHs (1 mL) was added to the compound obtained in the previous section, step d, (100 mg, 0.282 mmol) and stirred at RT for 16h. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by prep. HPLC to afford the title compound (15 mg, 15%) as an off-white solid.
LC-MS (method 9): R, = 1.31 min; m/z = 340.45 (M+H+).
Prep.HPLC condition: Column: Kinetex C18 (150 x 21 mm), 5.0μιη; Pump (A): 10 mM ammonium bicarbonate in aqueous, Pump (B): Acetonitrile; Gradient: time/% of B: 0/10,1/10,10730,15/98. Flow: 17.0 ml/min;
EXAMPLE 11
5'-(3-(Cyclopentylamino)propanamido)-[2,2'-bipyridine] -carboxamide hemipenta-hydrochloride
Figure imgf000109_0001
Step a. Methyl 5,-(3-((tert-butoxycarbonylKcycIopentyl)amino)propanamido)-[2,2'-bipyridine]-4- carboxyiate
To a stirred solution of reference example 3a (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.NaHCCb solution (50 mL), Brine solution (50 mL). The organic layer was dried over anhydrous NajSC , 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. Tert-butyl (3-({4'-carbamoyl-[2,2'-bipyridin]-5-yl)amino)-3-oxopropyl)(cyclopentyl) carbamate
To a stirred solution of the compound obtained in the previous step, step a (200 mg, 0.426 mmol) in MeOH (2 mL) was added methanolic ammonia (25 mL) at rt and the reaction mixture was stirred at 100°C in sealed tube for 16 h. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in 20% Methanol in DCM (75 mL) and washed with saturated NaHC03 solution (2x25 mL) and dried over anhydrous NaaSd, filtered; the filtrate was concentrated under reduced pressure. The obtained crude compound was triturated with pentane to afford the title compound (128 mg, 66%) as an off-white solid. Mass: MS (method 1): R( = 2.06 min; m/z = 454.32 (M+H+).
Step c. 5'-(3-(Cyclopentylamino)propanamido)-[2,2'-bipyridine]-4-carboxamide hemlpenta-hydrochloride
To a stirred solution of the compound obtained in the previous step, step b (100 mg, 0.22 mmol) in DCM:THF (10 ml_:5 m L) was added 4M HCI in 1 ,4-dioxane (1.3 mL) at rt and the resulting solution was stirred for 6 h. The mixture was concentrated under reduced pressure and the resultant crude compound was triturated with acetonitrile and diethyl ether to afford the title compound (53 mg, 68%). Mass: 354.26 (M+H).
MS (method 1): R, = 1.08 min; m/z = 354.26 (M+H-).
EXAMPLE 12
5'-(3-(Cyclopentyl(ethyI)amino)propanamido)-[2,2'-bipyridine]-4"Carboxamide
Figure imgf000110_0001
Step a. Methyl S'-fS-fcycIopsntylaminolpropanamidol-p^'-bipyridinel^carboxylate (3):(C2057-002) To a stirred solution of the compound obtained in example 11 , step a (310 mg, 0.66 mmol) in DCM (10 mL) was added 4M HCI in 1 ,4-dioxane (2.5 mL) at rt and resulting solution was stirred at rt for 6 h. The reaction mixture was concentrated under reduced pressure and the obtained crude compound was triturated with diethyl ether to afford the title compound (260 mg, 91%).
MS (method 6): R, = 1.82 min; m/z = 369.35 (M+H*).
Step b. Methyl 5'-(3-(cyclopentyl(ethyl)amino)propanamido)-[2,2'-bipyridine]-4-carboxylate
To a stirred solution of the compound obtained in the previous step a (260 mg, 0.705 mmol) in DMF (10 mL) was added K2C03 (291 mg, 2.115 mmol) 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 NajSO The organic layer was concentrated under reduced pressure and the obtained crude compound was purified by Grace column chromatography (reverse phase) eluted with 45 % ACN:0.1% HCOOH (aq.) and the fractions were basified using with sat NaHCOa sol and extracted EtOAc (3 X 30 mL). The organic layer was dried over Na?SO* and concentrated under reduced pressure to afford the title compound (240 mg, 60%).
MS (method 1): R, = 1.48 min; m/z = 397.16 (Μ+Η').
Step c. 5'-(3-(cyclopentyl(ethy1)amino)propanamido)-[2,2'-bipyridine]-4-carboxamide
To a stirred solution of the compound obtained in the previous step b (110 mg, 0.277 mmol) in MeOH (5 mL) was added methanolic ammonia (20 mL) at rt and the reaction mixture was stirred for 16 h in a sealed tube. The reaction mixture was concentrated under reduced pressure the obtained crude was dissolved in 20% Methanol in DC (50 mL) and washed with saturated NaHCOs solution (2x15 mL). The organic layer was dried over anhydrous I^SO*, filtered; the filtrate was concentrated under reduced pressure (at ~30°C). The obtained crude compound was purified by prep HPLC method to afford the title compound (52 mg, 49%) as an off-white solid.
MS (method 6): F¾ = 1.64 min; m/z = 382.36 (M+H+).
Prep HPLC conditions: Column: X-SELECT C18 (150*19) mm, 5.0μ Pump (A): 10M ammonium bicarbinate in aqueous. Pump (B): Acetonitrile GRADIENT: time/% of B: 2/10,10/60,15 /100 Flow : 18.0 ml/min UV : 215nm & 254 nm
EXAMPLE 13
5'-(3-(Diethylamino)propyl)-2!2'-bipyridine-4-carboxamide
Figure imgf000111_0001
Step a. Methyl 5'-(3-(diethylamino)prop-1-ynyl)-2,2'-bipyridine-4-carboxylate
To a stirred solution of reference example 19 (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(PPhs), (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 celite 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.
MS (method 1): Rt = 1.92 min; m/z = 334.32 (M+H+).
Step b. Methyl y-iS^diethylaminoJpropyl^ -bipyridine-^carboxylate
A suspension of the compound obtained in the previous section, step a (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 Celite 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.
MS (method 6): R, = 1.75 min; m/z = 328.32 (M+H+).
Step c. 5'-(3-{Diethylamino)propyl)-2,2'-bipyridine-4-carboxamide
To a stirred solution of the compound obtained in the previous section, step b (150 mg, 0.45 mmol) in MeOH (5 mL) was added methanolic ammonia (15 mL) at rt and the reaction mixture was stirred in a sealed tube for 16 h. The mixture was concentrated under reduced pressure. The obtained residue was dissolved in 20% methanol in DCM and washed with saturated NaHCC solution and dried over anhydrous a2SC . The dried organic layer was concentrated under reduced pressure and the resultant compound was triturated with diethyl ether and pentane to afford the title compound (50 mg, 35%) as an off-white solid.
MS (method 1): R, = 1.75 min; m/z = 313.17 (Μ+Η·).
EXAMPLE 14
Figure imgf000112_0001
Step a. Methyl 3-fluoro-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 Nj 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 Celite 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 eluted with 5% EtOAc/pet ether to afford 1.5 g (55.2 % yield) of the title compound.
Step b. Methyl 5'-((3-(1 H-pyrazo!-1-yI)propyl)(tert-butoxycarbonyI)amino)-3-fluoro-[2,2'-bipyridine]-4- carboxylate
To a stirred solution of reference compound 22 (1.0 g, 1 equiv) in 1 ,4-dioxane (10 mL) was added the compound obtained in the previous section, step a (1.5 equiv), CsF (2 equiv) and followed by Cul (0.2 equiv). The resulting solution was degassed with nitrogen, then added Pd(PPI¾)4 (0.1 equiv), was again degassed. The reaction mixture was heated to 110 °C for 16h. The reaction mixture was diluted with 10% MeOH/DCM and filtered through Celite pad; the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography and eluted with 30% EtOAc/ pet ether to afford 600 mg (50.0 % yield) of the title compound.
MS (method 6): R, = 2.78 min; m/z = 456.45.17 (M+H+).
Step c. Tert-butyl (3-(1 H-pyrazol-1-yl)propyl)(4'-carbamoyS-3'-fluoro-[2,2'-bipyridin]-5-yl)carbamate In a pressure tube, methanolic-Nhb was added to the compound obtained in the previous section, step b (300 mg) and stirred at rt for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure to afford 280 mg of crude product. The crude compound was purified by prep.HPLC to afford 120 mg (41.3 % yield) of the title compound.
MS (method 1): Rt = 1.72 min; m/z = 441.16 (Μ+Η').
Step d. ^-{(S-ilH-Pyrazol-l-y propy aminoJ-S-fluoro-p. -bipyridinej^carboxamide
4M HCI in 1 ,4 Dioxane was added to a stirred solution of the compound obtained in the previous section, step c (90 mg) in 1 ,4 dioxane at 0°C and allowed to stir at rt for 24h. The progress of the reaction was monitored by LCMS. The reaction was concentrated under reduced pressure and the obtained residue was triturated with pentane, diethyl ether and acetonitrile followed by dried under reduced pressure. The obtained compound further lyophilized to afford 65 mg of the title compound (96.4 % yield)
MS (method 20): Rt = 0.96 min; m/z = 341.26 (M+H+)
EXAMPLE 15
5 (2-(Diethylamino)ethoxy)methyl)-AH2^
Figure imgf000113_0001
Step a. Methyl 5'-((2-(diethylamino)ethoxy)methyl)-[2,2'-bipyndine]-4-carboxylate
Following a similar procedure to that described in example 2, step a, but using reference example 11 instead of reference example 4, the desired compound was obtained (50% yield).
LC-MS (method 25): R, = 1.12 min; m/z = 344.23 (Μ+Η').
Step b. 5'-((2-(diethylamino)ethoxy)methyl)-[2,2'-bipyridine]-4-carboxylic acid
To a stirred solution of the compound obtained in the previous section, step a (200 mg, 0.582 mmol) in DCE (10mL), trimethyltin hydroxide (526 mg, 2.91 mmol) was added at RT. The resulting solution was heated at 60°C for 16 h. The reaction mixture was concentrated to obtain 250 mg of the crude title compound as a gummy solid. The crude compound was used in subsequent reaction without further purification.
LC-MS (method 17): R, = 1.37 min; m/z = 330.39 (M+H*).
Step c. 5'-{(2-(Diethylamino)ethoxy)methyl)-^(2,2,2-trifluoroethyl)-[2,2'-bipyridine
To a stirred solution of the compound obtained in the previous section, step b (250 mg,0.75 mmol) in DMF (5 mL), HATU (285 mg, 0.75 mmol), DIPEA ( 0.4 mL, 2.27 mmol) and trifiuoroethyl amine (375 mg, 3.79 mmol) were added at RT. The resulting solution was allowed to stir at RT for 16 h. The reaction mixture was poured into cold water and extracted with EtOAc (2 x 60 mL) and washed with water (20 mL) and brine (20 mL) solution. The separated organic layers were dried over anhydrous Na2SO<, filtered and concentrated under vaccum. The crude compound was purified by prep HPLC to afford 51 mg (21 % over two steps) of the title compound as an off white solid.
LC-MS (method 17): Rt = 1.73 min; m/z = 411.43 (M+H+).
Prep HPLC Conditions: Column : X-SELECT C18(19*150mm); 5.0 μ, Pump(A) : 10mm ABC in aqueous Pump(B) : Acetonitrile, Flow : 18 ml/min, GRADIENT Method : time/% of B: 0/18,1/18,10/25,13.7/25 13.8/100; UV : 215 nm.
EXAMPLE 16
IN VITRO KDM ENZYME INHIBITION ASSAYS The ability of test compounds to inhibit the activity of KDM5B, KDM4C and KD 6B 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 inhibitorsare tested at eight logarithmic serial dilutions for IC50 determination.
Figure imgf000114_0001
General method:
The demethy!ase 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 ui 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 KD 6B: 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:
KDM5B DM4C KDM6B
KDM5B KDM4C KDM 6B
EXAMPLE % inh @ % inh @ 500 % inh @ 500
IC50 (nM) IC50 (nM) IC50 (nM) 500 nM nM nM
*
1 50
* **
1a 63
**
1 b 13 56
*
1c 90
1d 2 1433
**
1e 10 59
1f 79 *
ig 48 *
**
1 h 56 *
**
2 9 *
2a 129 *
★*
2b 55 * c 14 29 35
**
d 17 29
e 56 * **
2f 27 * ** g 130 * ** h 199
2i 220
¾ 42 * ** k 98 * **
21 9 44 39
m 279
n 14 71 81 o 36 * **
**
p 17 61
q 6 47 62
2r 122
2s 143
2t 12 * ** u 56 * ** v 108
w 98 34 * ** x 98 28 * **
2y 93 156
2z 70
aa 15 23 27
ab 19 51 32
ac 154
ad 96 * 21
ae 100 37 22
af 96 * * ag 93
ah 75
3 65 * ** 4 * **
246
5 56 44
6 1 45 32
**
7 5 267
8 463
9 *
4
10 34 * **
11 18 41
* **
12 14
13 * **
28
14 491
15 239
0 < 20 % inhibition @ 500 nM KDM4C
Γ)< 20 % inhibition @ 500 nM KDM6B
EXAMPLE 17
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-methylafjon on lysine 4 of histone 3 (H3K4me3) were assessed by western blot in the breast cancer BT474 cell line.
For this, 2x106 cells were seeded in T75 flasks and grown in RPMI-1640 medium (Sigma) supplemented with 10% FBS and 2mM glutamine (Life Technologies) without antibiotics, incubated at 37°C and 5% CO? . 24 hours after seeding, cells were treated with 1 μΜ of the test compound or vehicle (DMSO, at 0.1%), incubated for five days and harvested by trypsinisation. Pellets of 2x106 cells were used for histone purification (EpiQuick, Epigentek) following manufacturer's instructions, and 1 pg of purified histone extracts were loaded into 12% NUPAGE gels (Life Technologies) for H3K4me3 detection by Western blot (a-H3K4me3 antibody, Active Motif #39159, 1 :2000 dilution).
H3K4me3 western blot signal and total H3 intensity from ponceau staining were quantified by band densitometry using the ImageJ software. H3K4me3 signals were normalized by their corresponding total H3 levels, and made relative to the vehicle (DMSO).
The results obtained in this cell assay with compounds of the invention are shown below, wherein compounds are classified based on their potency to increase H3K4me3 levels compared to the vehicle after 5 days of incubation at 1 μΜ. Score ** means that H3 normalised H3K4me3 fold induction relative to vehicle is≥2 and score * means that H3 normalised H3K4me3 fold induction relative to vehicle is <2. Example # Score Example # Score
1d * 2aa **
2c ** 2ab **
2d * 2ad **
2g * 2af **
2j * 2ag *
2n * 13 *
2q *
2t *
2w *
2x **

Claims

1. A compound of Formula (I) or a salt thereof:
Figure imgf000119_0001
(I)
wherein
Z1, Z2, and Z3 are each independently selected from CR5 and N, and Z4 and Z6 are each independently selected from CR3 and N, with the proviso that only one of Z1, Z2, Z3, Z4 and Z5 can be N;
R1 and R2 are each independently selected from hydrogen, Ci-s alkyl, Ci-e haloalkyl, -(Ci β alkylene)-OR3, -(Ci.6 a!kylene)-NR7R8, -CN, -L3-carbocyciyl, -LAaryl, -L3-heterocyclyl and -L3-heteroaryl, wherein the carbocyclyi in - lAcarbocyclyl, the aryl in -L3-aryl, the heterocyclyl in -L3-heterocyclyl and the heteroaryl in -L3-heteroaryl are each optionally substituted with one or more R9,
or R1 and R2 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, &-s alkyl, Ci-e alkoxy, -OH, -Nhb, -NH(C-.6 alkyl), and -N(Ci-s alkyl)2;
each R3 is independently selected from hydrogen, halo, CM alkyl, Ct-e haloalkyl, Cu alkoxy, Ci-e hydroxyalkyl, -OH and -NH2;
each R5 is independently selected from hydrogen and halo;
Y is selected from -NR1<€(=0)-, -NR11-, -0-, -R12- and -CH2-, wherein said -NR 0C(=O)- is linked to -(L%- via the NR10 group and to -(L )„-R4 via the C(=0) group;
L1 is CM alkylene, C2-4 alkenylene or C2-4 alkynylene, wherein said C1-4 a!kylene, said C2-4 alkenylene and said C2-4 alkynylene are optionally interrupted by 0, S or NR11, and wherein said CM alkylene, said C2-4 alkenylene and said C2 alkynylene are optionally substituted with one or more R13; L2 is Ci-6 alkylene, C2-6 alkenylene or C? 6 alkynylene, wherein said C1.6 aikylene, said CM alkeny!ene and said C2-6 alkynylene are optionally interrupted by 0, S or NR11, and wherein said Ci e alkylene, said C?g alkenylene and said C? e alkynylene are optionally substituted with one or more R13;
m and n are each independently selected from 0 and 1 ,
R4 is -NR1 R15 or
K' and R8 are each independently selected from hydrogen and C , alkyl, or R7 and R8 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, C1 alkyl, -OH, -NH?, -NH(C,.6 alkyl), and -N(&.6 alkyl)2;
each L3 is independently selected from a bond and C1-4 alkylene;
R10 and R11 are each independently selected from hydrogen, Ci e alkyl and C1 6 haloalkyl;
-R12- 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 -R12- is linked to -{L1)m- and -(L2)n-
R4 in a 1 ,3-disposition;
each R13 is independently selected from C alkyl, halo, C1.5 haloalkyl, -L3-carbocyclyl, -L3-aryl, -LAheterocyclyl and -L3-heteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyi in -LA heterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R17, and wherein two groups R13 attached to a same C atom of the alkylene group are optionally linked together to form with said C atom a C3-6 cycloa!kyl group or a saturated 4- to 6-membered monocyclic heterocyclic ring containing 1 heteroatom selected from H, 0 and S, wherein said Cn cycloalkyl and 4- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from halo and Ci-6 alkyl;
R14 and Ri b are eacn independently selected from hydrogen, C-,-6 alkyl, C1-6 haloalkyl, -{C1-6 alkylene)-OR18, -LA carbocyclyl, -LAaryl.-LAheterocycly! and -L3-heteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyi in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are optionally substituted with one or more R19;
R16 is a 3- to 18-membered saturated, partially saturated or aromatic heterocyclic group which contains one N atom and optionally contains one or more further heteroatoms selected from N, 0 and S, wherein R15 is optionally substituted with one or more R20;
each R20 is independently selected from C e alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, d-s haloalkoxy, -OH, -NH?, -NH(C,.6 alkyl), -N(C1 6 alkyl)?, -CN, -C(=0)R?1, -C(=0)NR22R23, -NR22C(=0)R21, -NR22C(=0)NR22R23 -NR22SO?R21, -S02NR R23, -S02R?1, -LAcarbocyclyl, -L3-aryl, -L3-heterocyclyl and -L3-heteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyi in -LAheterocyclyl and the heteroaryl in -LA heteroaryl are optionally substituted with one or more R24; each Rs, each R17, each R19 and each R24 is independently selected from Ci-e alkyl, Ci-6 haloalkyl, halo, Cu5 alkoxy, Cvg haloalkoxy, -OH, -NH2, -NH(C, 6 alkyl), -N(0 6 alkyl)2 ,-CN, -C(=0)R21, -C(=0)NR22R23,
-NR22C(=0)R21, -NR 2C(=0)NR2 R23, -NR22S02R21, -S02NR 2R23 and -S02R21;
each R21 is independently selected from Ci s alkyl; and
each R6, each R18, each R22 and each R23 is independently selected from hydrogen and Ci.6 alkyl.
The compound of claim 1 , which is a compound of Formula I
Figure imgf000121_0001
or a salt thereof.
3. The compound of claim 1 , which is a compound of Formula (la) or (lb)
Figure imgf000121_0002
(la) (lb)
or a salt thereof.
4. The compound of any of claims 1 to 3, wherein R1 and R2 are each independently selected from hydrogen, Ci-e alkyl and Ci-e haloalkyl.
5. The compound of any of claims 1 to 3, wherein R1 is hydrogen and R2 is selected from hydrogen, Ci-e alkyl and C1-6 haloalkyl.
6. The compound of any of claims 1 to 3, wherein R1 and R2 are both hydrogen.
7. The compound of any of claims 1 to 3, wherein R1 is hydrogen; R2 is selected from hydrogen, Ci-c alkyl and O-s haloalkyl; and each R3 is hydrogen.
8. The compound of any of claims 1 to 7, wherein R1 and R2 are both hydrogen; and each R3 is
hydrogen.
9. The compound of any one of claims 1 to 8, wherein each R3 and each R5 is hydrogen.
10. The compound of any one of claims 1 to 9, wherein U is (CH2)i-2, wherein said (CH∑)i-2 is optionally substituted with one or more R13.
11. The compound of any one of claims 1 to 10, wherein L1 is CH2.
12. The compound of any one of claims 1 to 11 , wherein L2 is (CH2)i-4, wherein said (CH∑)u is optionally substituted with one or more R13.
13. The compound of any one of claims 1 to 12, wherein L2 is (ί¾)ι-4.
14. The compound of any one of claims 1 to 13, wherein L2 is
Figure imgf000122_0001
15. The compound of any one of claims 1 to 14, wherein Y is selected from -NR11-, -0- and -CH?-
16. The compound of any one of claims 1 to 15, wherein n is 1.
17. The compound of any one of claims 1 to 16, wherein m is 0.
18. The compound of any one of claims 1 to 9, wherein -(L -Y-{12)„- is selected from the following list:
Figure imgf000122_0002
19. The compound of claim 2 or 3, wherein:
R1 is hydrogen and R2 is selected from hydrogen, C alkyl and Ci-a haloa!kyi;
each R3 is hydrogen;
m and n are each independently selected from 0 and 1 ;
Figure imgf000123_0001
L2 is (CH2)i-6, wherein said (0Ηζ)ι-6 is optionally substituted with one or more R13,
20. The compound of claim 19, wherein R2 is hydrogen.
21. The compound of claim 19 or 20, wherein each R5 is hydrogen.
22. The compound of any of claims 19 to 21 , wherein n is 1 ; and L2 is (CH2)i-4 wherein said (CH2)i-4 is optionally substituted with one or more R13.
23. The compound of any of claims 19 to 22, wherein Y is selected from -NR11-, -0- and -CH?-.
24. The compound of any of claims 19 to 23, wherein L1 is CH?; and L2 is (CH2)i.4.
25. The compound of any of claims 19 to 24, wherein m is 0.
26. The compound of claim 2 or 3, wherein:
R1 and R2 are hydrogen;
each R3 is hydrogen;
m and n are each independently selected from 0 and 1 ;
L2 is (CH2)i-6, wherein said (CH?)i c is optionally substituted with one or more R13; and
Y is selected from -NR11-, -O- and -CH2-.
27. The compound of any one of claims 1 to 26, wherein R4 is -NR14R15 or R15, wherein R16 is a saturated 3- to 18-membered heterocyclic group which contains one N atom and optionally contains one or more further heteroatoms selected from N, O and S, wherein R16 is optionally substituted with one or more R20.
28. The compound of any one of claims 1 to 27, wherein R4 is a saturated 4- to 7-membered heterocyclic group which contains one N atom and optionally contains one further heteroatom selected from N, 0 and S, wherein R4 is optionally substituted with one or more R20.
29. The compound of any one of claims 1 to 27, wherein R4 is selected from 1-piperidinyl, 1-pyrrolidinyl and 1-morpholinyl, wherein R4 is optionally substituted with one or more R20.
30. The compound of any one of claims 27 to 29, wherein each R20 is independently selected from Ci-e alkyl, C-,.6 haloalkyl and halo.
31. The compound of any one of claims 1 to 27, wherein R4 is 1-piperidinyl substituted with one or more fluoro.
32. The compound of any one of claims 1 to 27, wherein R4 is 4,4-difluono-1-piperidinyl.
33. The compound of any one of claims 1 to 27, wherein R4 is -NR 4R15.
34. The compound of any one of claims 1 to 27 or 33, wherein R14 and R15 are each independently selected from hydrogen, C-.g alkyl, Ci e haloalkyl, -LAC 3-7 cycloalkyi, and -(CH2) -phenyl, wherein the C3-7 cycioalkyi in the -LAC3-7 cycloalkyi is optionally substituted with one or more groups independently selected from C1-6 alkyl and halo, and the phenyl in -(CH2)i~i-phenyl is optionally substituted with one or more R19,
35. The compound of any one of claims 27 to 34, wherein:
R1 and R2 are hydrogen;
each R3 is hydrogen;
m and n are each independently selected from 0 and 1;
U is {CH2)1-2;
L2 is (Chb e, wherein said (CH?)-,6 is optionally substituted with one or more R13; and
Y is selected from -NR11-, -0- and ~CH2-.
36. The compound of any one of claims 28 to 32, wherein:
R1 and R2 are hydrogen;
each R3 is hydrogen;
m and n are each independently selected from 0 and 1 ;
L2 is (CH2)i-6, wherein said (CH2)i-6 is optionally substituted with one or more R13; and
Y is selected from -NR11-, -0- and -CHr.
37. The compound of claim 1 , wherein the compound is selected from:
5'-(Piperidine-4-carboxamido)-[2,2'-bipyridine]-4-carboxamide;
5'-(Pyrrolidine-2-carboxamido)-[2,2'-bipyridine]-4-carboxamide;
5'-(2-(Piperidin-2-yl)acetamido)-[2,2'-bipyridine)-4-carboxamide; 5'-(3-(Phenyiamino)propanamido)-[2,2'-bipyridine]-4-carboxamide;
5'-(3-(Benzylamino)propanamido)-[2,2'-bipyridine]-4-carboxamide;
5'-(4-(Dimethylamino)butanamido)-[2,2'-bipyridine]-4-carboxamide;
5'-(2-(Diethylamino)acetamido)-[2!2'-bipyridine]-4-carboxamide;
5'-(3-Amino-2-benzylpropanamido)-[2,2'-bipyridine]-4-carboxamide;
5'-(4-Amino-3-phenylbutanamido)-[2,2'-bipyridine]-4-carboxamide;
5'-(3-Amino-3-pheny!propanamido)-[2,2'-bipyridine]-4-carboxamide;
5'-(2-(Piperidine-3-carboxamido)ethyl)-[2, 2'-bipyridine]-4-carboxamide;
5'-(3-Aminopropanamido)-[2.2'-bipyridine]-4-carboxamide;
2-(5-((3-(Diethy! amino)propyl)amino) pyrazin-2-yl) isonicotinamide;
5'-(3-(Phenethylamino) propanamido)-[2, 2'-bipyridine]-4-carboxamide;
S -il-Methylpiperidine^carboxamidoJ-p^'-bipyndineJ^-carboxamide;
5'-{1- ethylpiperidine-3-carboxamido)-[2,2'-bipyridine]-4-carboxamide;
2-(5-(3-(Diethylamino)propoxy)pyrazin-2-yl)isonicotinamide;
2-(5-({3-(1 H-Pyrazol-1-yl)propyi)amino)pyrazin-2-yl)isonicotinamide;
2-(5-(2-(Diethylamino)ethoxy)pyrazin-2-yl)isonicotinamide;
5'-((2-(Diethylamino)eihoxy)methyl)-[2,2'-bipyridine]-4-carboxamide;
5'-(3-Amino-A/-methylpropanamido)-[2,2'-bipyridine] -carboxamide;
5'-(3-(Ethylamino)-3-phenylpropanamido)-[2,2'-bipyridine]-4-carboxamide;
5'-(2-Morpholinoeihoxy)-[2,2'-bipyridine]-4-carboxamide;
5'-(3-(Diethylamino)propoxy)-[2,2'-bipyridine]-4-carboxamide;
5'-(3-(Ethylamino)propanamido)-[2J2'-bipyridine]-4-carboxamide;
2-(5-(2-(Diethyiamino)ethylamino)pyrazin-2-yl)isonicotinamide;
5'-((3-(Diethylamino)propyi)amino)-[2,2'-bipyridine]-4-carboxamide;
5'-((3-(Diethylamino)propoxy)methy!)-[2,2'-bipyridine]-4-carboxamide;
5'-(4-(2-(Diethylamino}ethyl)-1W^yrazol-1-yl)-[2,2'-bipyridineJ-4-carboxamide;
5'-(3-(Ethyl{phenethyi)amino)propanamkjoH2!2'-bipyridine] -carboxamide;
2-(5-(3-Aminoprapanamido)pyrimidin-2-yl)isonicotinamide;
5,-((3-(1H-Pyrazol-1-yl)propyl)(meihyl)amino)-[2,2'-bipyridine]-4-carboxamide;
5'-(4-(Diethylamino)butyl)-[2)2'-bipyridine]-4-carboxamide;
5'-(4-(4,4-Difiuoropiperidin-1-yl)butyl)-[2,2'-bipyridine]-4-carboxamide;
5'-(4-(1 H-Pyrazol-1 -yl)buty l)-[2,2'-bipyridine]4-carboxamide;
5'-((2-(Pyridin-2-yl)ethyl)amino)-[2,2'-bipyridine]4-carboxamide;
5'-((3- orpholinopropyl)amino)-[2,2'-bipyridineH-carboxamide;
5^(3-(4,4 ifluoropiperidin4-yi)propyl)amino)-[2,2 -bipyridine]4-carboxarnide;
5'-(4-(Pyridin-3-ylamino)butyl)-[2,2'-bipyridine]4-carboxamide; 325
5l-((3-{4,4-Difluoropiperidin-1-yI)propyl)(methyl)amino)-[2,2'-bipyridine]-4-carboxa
5'-(3-(Ethyl(phenethyl)amino)propoxy)-[2,2'-bipyridine]-4-carboxarnide;
5'-(3-(4,4-Difluoropiperidin-1-yl)propoxy)-[2,2'-bipyridine]-4-carboxamide;
5'-((2-{4,4-Difluoropiperidin-1-yl)ethoxy}methyl)-[2,2!-bipyridine] -carboxamide;
5'-(butyl{3-(4,4-difluoropiperidin-1-yl)propyl)amino)-[2,2'-bipyridine]-4-carboxamide;
5'-((3-{1W-Pyrazol-1-yi)propyl)amino)-[2,2'-bipyridine] -carboxamide;
5,-((3-{1-Methyl-1 H-pyrazol-4-yl)propyl)amino}-[2,2,-bipyridine]-4-carboxamide;
5'-((3-Aminopropyl)amirso)-[2,2'-bipyridine]-4-carboxamide;
5'-{Piperidine-3-carboxamido)-[2,2'-bipyridine]-4-carboxarnide;
5'-(3-(Dieihylamino)propanamido)-[2,2'-bipyridine]-4-carboxamide;
5'-((3-Aminopropylamino)-[2,2'-bipyridine]-4-carboxamide;
2-(5-(3-Aminopropanamido)pyridin-2-yl)pyrirnidine-4-carboxamide;
5'-(3-(Diethylamino)-3^henylpropanamido)-[2,2'-bipyridine] -carboxamide;
5'-(3-(Pyrrolidin-1-yl)propanamido)-[2, 2'-bipyridine]-4-carboxamide;
5'-(3-(Cyclopentylamino)propanamido) 2,2'-bipyridine]-4-carboxarnide;
5'-(3-{Cyclopentyl{ethyl)amino)propanamido) 2)2'-bipyridine]-4-carboxamide;
5'-(3-(Diethylamino)propyl)-2,2'-bipyridine -carboxamide;
5'-((3-(1 H-Pyrazol-1-yl)propyl)amino)-3-fluoro-[2.2'-bipyridineH-carboxamide;
5'-((2-(Diethylamino)ethoxy)methyl)-W-(2,2,2 rifluoroethyi)-[2,2'-bipy
or a salt thereof.
38. The compound of claim 1 or 2, wherein the compound is selected from:
5'-((3-(4,4-Difluoropiperidin-1-yl)propyl)amino)-[2,2'-bipyridine]-4-carboxamide;
5'-(3-(4!4-Difluoropiperidin-1-yl)propoxy)-[2!2'-bipyridsne]-4-carboxamide;
5'-{4-(4,4-Difluoropiperidin-1-yl)butyl)-[2,2'-bipyridine]-4-carboxamide:
5'-((3-Morphoiinopropyl)arnino)-[2,2'-bipyridine]-4-carboxamide;
2-(5-((3-(Diethyl amino)propyl)amino) pyrazin-2-yl) isonicotinamide;
5'-((3-(4,4-Difluoropiperidin-1-yl)propyl)(methyl)amino)-[2,2'-bipyridine]-4-carboxamide;
5'-(3-{Ethyi(phenethyl)amino)propoxy)-[2,2'-bipyridine]-4-carboxamide;
or a salt thereof.
39. A pharmaceutical composition which comprises a compound of any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
40. A compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use as a medicament.
41. A compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 39, for use in the treatment of a disease associated with a JmjC-KDM.
42. A compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 39 for use in the treatment of cancer.
43. A compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 39, for use in the treatment of a viral infection.
44. 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 38, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
45. A method for treating cancer, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
46. A method for treating a viral infection, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
47. Use of a compound of any one of claims 1 to 38, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease associated with a JmjC-KDM.
48. Use of a compound of any one of claims 1 to 38, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.
49. Use of a compound of any one of claims 1 to 38, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a viral infection.
50. In vitro use of a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, as a JmjC-KDM inhibitor
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