WO2016120808A1 - Heteroarylaminoisoquinolines, methods for their preparation and therapeutic uses thereof - Google Patents

Heteroarylaminoisoquinolines, methods for their preparation and therapeutic uses thereof Download PDF

Info

Publication number
WO2016120808A1
WO2016120808A1 PCT/IB2016/050413 IB2016050413W WO2016120808A1 WO 2016120808 A1 WO2016120808 A1 WO 2016120808A1 IB 2016050413 W IB2016050413 W IB 2016050413W WO 2016120808 A1 WO2016120808 A1 WO 2016120808A1
Authority
WO
WIPO (PCT)
Prior art keywords
diamine
alkyl
group
chloroisoquinolin
hydrogen
Prior art date
Application number
PCT/IB2016/050413
Other languages
French (fr)
Inventor
Ana María GARCÍA COLLAZO
Marc Martinell Pedemonte
Marc REVÉS VILAPLANA
Rodolfo Lavilla Grifols
Laura RODRÍGUEZ PASCAU
Elena CUBERO JORDÀ
Original Assignee
Minoryx Therapeutics S.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Minoryx Therapeutics S.L. filed Critical Minoryx Therapeutics S.L.
Publication of WO2016120808A1 publication Critical patent/WO2016120808A1/en

Links

Classifications

    • 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
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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

Definitions

  • the present invention is related to heteroarylaminoisoquinolines, with new processes for their preparation and to the use thereof for the treatment and/or prevention of conditions associated with the alteration of the activity of beta galactosidase, specially galactosidase beta-1 or GLB1 , including GM1 gangliosidoses and Morquio syndrome, type B.
  • GM1 gangliosidosis and Morquio B syndrome both arising from beta- galactosidase (GLB1 ) deficiency, are very rare lysosomal storage diseases with an incidence of about 1 :100,000-1 :200,000 live births worldwide (Caciotti A. et al Biochim Biophys Acta 201 1 July; 1812(7) 782-890). Said conditions associated with GLB1 are known to be caused by a deficiency of the enzyme ⁇ - galactosidase due to mutations in the GLB1 gene.
  • ⁇ -galactosidase cleaves ⁇ -galactose from different substrates, and deficiencies in its activity cause said substrates (i.e. gangliosides, and oligosaccharides carrying terminal ⁇ -linked galactose, such as ganglioside GM- 1 and glycosaminoglycans such as keratin sulfate) to accumulate in patients suffering from conditions associated with GLB1 activity such as GM1 gangliosidosis and Morquio B syndrome.
  • substrates i.e. gangliosides, and oligosaccharides carrying terminal ⁇ -linked galactose, such as ganglioside GM- 1 and glycosaminoglycans such as keratin sulfate
  • small molecules capable of binding allosterically to mutated ⁇ - galactosidase enzyme thereby stabilizing the enzyme against degradation constitute an important therapeutic target in conditions associated with the alteration of the activity of beta galactosidase, specially galactosidase beta-1 or GLB1 .
  • the present disclosure provides compounds represented by formulae (IA), (MA), and (I), and the salts and solvates thereof, collectively referred to herein as "Compounds of the Invention” (each individually referred to hereinafter as a “Compound of the Invention”).
  • the present disclosure provides compounds of formula (IA),
  • R 11 , R 12 , R 13 , R 4 , R 5 , A 1 , A 2 , A 3 , and n are as defined below.
  • each of A 1 is independently selected from the group consisting of nitrogen and C(R 2 );
  • each of A 2 and A 3 is independently selected from the group consisting of nitrogen, C(R 3 ) and C(NH 2 );
  • a 2 and A 3 are C(NH 2 ) and wherein no less than one and no more than two of A 1 , A 2 and A 3 are nitrogen;
  • each R 1 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORb, and -Ci -4 alkyl, wherein said -Ci -4 alkyl group is optionally substituted by 1 , 2 or 3 halogen atoms, with the proviso that at least one R 1 is not hydrogen;
  • R 2 is selected from the group consisting of hydrogen, fluorine, -CN, methyl and trifluoromethyl;
  • each one of R 3 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -Ci -4 alkyl, -C3-i o cycloalkyl, and 5- to 10- membered-C2-i o-heterocyclyl, said alkyl, cycloalkyl and heterocyclyl groups being optionally substituted with 1 , 2 or 3 groups each independently selected from the group consisting of halogen, hydroxy, -Ci -4 alkyl optionally substituted with 1 , 2 or 3 halogen atoms, -N(Rb) 2 and methoxy, optionally substituted with 1 , 2 or 3 halogen atoms;
  • n has a value selected from 0, 1 or 2; • each Ra is independently selected from the group consisting of hydrogen, -Ci -4 alkyl, -C-3- ⁇ cycloalkyl, -Ci -4 alkyl-C3-i o cycloalkyl, -C-6-10 aryl, -Ci -4 alkyl-C6-i o aryl, 5- to 10-membered-Ci-io heteroaryl, -Ci -4 alkyl- 5- to 10- membered-C-i-10 heteroaryl, 5- to l
  • heterocyclyl -Ci -4 alkyl-5- to 10-membered-C 2- io heterocyclyl; said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups optionally being substituted with 1 , 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, -CN , -ORb, -SRb, -N(Rb) 2 , -Ci -4 alkyl optionally substituted with 1 , 2, or 3 halogen atoms, optionally substituted C-6-10 aryl, optionally substituted 5- to 10-membered-Ci-io heteroaryl and 5- to 10- membered-C2-i o heterocyclyl; and
  • each Rb independently represents, on each occasion when used herein hydrogen, -Ci -4 alkyl, -C 3- i 0 cycloalkyl, 5- to 10-membered-C 2- io heterocyclyl; said alkyl, cycloalkyl or heterocyclyl groups optionally being substituted by 1 , 2 or 3 fluorine atoms,
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any one of formulae (IA), (IIA), or (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein and at least one pharmaceutically acceptable excipient.
  • the present disclosure provides compounds of formulae (IA), (IIA), and (I) as defined herein, or pharmaceutically acceptable salts or solvates thereof, for use in the prevention or treatment of a condition associated with the alteration of the activity of GLB1 .
  • the present disclosure provides use of a compound of any one of formulae (IA), (IIA), or (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the preparation of a medicament for the prevention or treatment of a condition associated with the alteration of the activity of GLB1.
  • the present disclosure provides a method for the prevention or treatment of a condition associated with the alteration of the activity of GLB1 , which comprises the administration to a patient needing such prevention or treatment, of a therapeutically effective amount of at least one compound of any one of formulae (IA), (IIA), and (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein.
  • the present disclosure provides a method of treating or preventing a condition associated with the alteration of the activity of GLB1 in a patient, comprising administering to the patient in need thereof an effective amount of a Compound of the Invention, or a pharmaceutically acceptable salt or solvate thereof.
  • the present disclosure provides a method of treating GM1 ganglisidosis or Morquio B syndrome in a patient, comprising administering to the patient in need thereof an effective amount of a Compound of the Invention, or a pharmaceutically acceptable salt or solvate thereof.
  • the present disclosure provides a method of increasing ⁇ -galactosidase activity in a patient in need thereof, comprising administering to the patient an effective amount of a Compound of the Invention, or a pharmaceutically acceptable salt or solvate thereof.
  • One aspect of the invention is based on the use of Compounds of the Invention for binding allosterically to mutated ⁇ -galactosidase enzyme and, thereby, stabilizing the enzyme against denaturation.
  • Compounds of the Invention are useful for preventing or treating conditions associated with the alteration of the activity of ⁇ -galactosidase, and especially galactosidase beta-1 or GLB1 , including GM1 gangliosidoses and Morquio syndrome, type B.
  • Compounds of the Invention are compounds of formula (IA):
  • each A 1 is independently selected from the group consisting of nitrogen and C(R 2A );
  • each of A 2 and A 3 is independently selected from the group consisting of nitrogen, C(R 3A ) and C(NH 2 ); provided that
  • a 2 and A 3 is C(NH 2 ) and wherein no less than one and no more than two of A 1 , A 2 and A 3 are nitrogen;
  • R 11 , R 12 , and R 13 are each independently selected from the group consisting of hydrogen, halogen, -CN, -ORb A , and -Ci -4 alkyl, wherein said -Ci -4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, with the proviso that at least one R 11 , R 12 , and R 13 is other than hydrogen;
  • R 2A is selected from the group consisting of hydrogen, halogen, -CN, Ci -4 alkyl, and halo(Ci -4 )alkyl;
  • each one of R 3A is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa A , -Ci -4 alkyl, -C3-io cycloalkyl, and 5- to 10- membered heterocyclyl, said alkyl, cycloalkyl and heterocyclyl groups are optionally substituted with 1 , 2 or 3 groups each independently selected from the group consisting of halogen, hydroxy, -Ci -4 alkyl optionally substituted with 1 , 2 or 3 halogen atoms, -N(Rb A ) 2 , and Ci -4 alkoxy optionally substituted with 1 , 2 or 3 independently selected halogen atoms;
  • each R 4 is independent selected from the group consisting of halogen
  • R 5 is hydrogen or Ci -4 alkyl
  • n has a value selected from 0, 1 or 2;
  • each Ra A is independently selected from the group consisting of hydrogen, -Ci -4 alkyl, -C3-10 cycloalkyl, -Ci -4 alkyl-(C3-io)cycloalkyl, -C6-10 aryl, -Ci -4 alkyl-(C 6- i o)aryl, 5- to 10-membered heteroaryl, -Ci -4 alkyl-(5- to 10-membered heteroaryl), 5- to 10-membered heterocyclyl, -Ci -4 alkyl- (5- to 10-membered heterocyclyl), wherein any of which, when other than hydrogen, is optionally being substituted with 1 , 2 or 3 groups each independently selected from the group consisting of halogen, -CN, -ORb A (for example OH), -SRb A , -N(Rb A ) 2 , -Ci -4 alkyl optionally substituted with 1 , 2, or 3 independently selected halogen atoms
  • each Rb A is independently selected from the group consisting of hydrogen, -Ci -4 alkyl, -(C3-i o)cycloalkyl, 5- to 10-membered heterocyclyl; wherein said alkyl, cycloalkyl or heterocyclyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms.
  • Compounds of the Invention are compounds of formula (IA), and the salts and solvates thereof, wherein one of A 1 , A 2 and A 3 is nitrogen.
  • one of A 1 is nitrogen.
  • one of A 2 is nitrogen.
  • a 3 is nitrogen.
  • Compounds of the Invention are compounds represented by formula (I IA):
  • R 4 , R 5 , R 11 , R 12 , and R 13 are as defined above for formula (IA), n is 0 or 1 , and
  • Het is selected from the group consisting of
  • Compounds of the Invention are compounds of formula (IIA), and the salts and solvates thereof, wherein Het is selected from the group consisting of
  • R and R are as defined above for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen. In another embodiment, R 2A is hydrogen and R 3A is as defined for formula (IA).
  • Het is Het1 , Het3, Het5, or Het6, wherein R 2A and R 3A are as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen. In another embodiment, R 2A is hydrogen and R 3A is as defined for formula (IA).
  • Het is Het2 or Het4, wherein R 2A and R 3A are as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen. In another embodiment, R 2A is hydrogen and R 3A is as defined for formula (IA).
  • Compounds of the Invention are compounds of formula (IIA), and the salts and solvates thereof, wherein Het is Het1 , wherein R 2A and R 3A are as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen. In another embodiment, R 2A is hydrogen and R 3A is as defined for formula (IA). In another embodiment, Compounds of the Invention are compounds of formula (IIA), and the salts and solvates thereof, wherein Het is Het2, wherein R 2A and R 3A are as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen. In another embodiment, R 2A is hydrogen and R 3A is as defined for formula (IA).
  • Compounds of the Invention are compounds of formula (IIA), and the salts and solvates thereof, wherein Het is Het4, wherein R 2A and R 3A are as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen. In another embodiment, R 2A is hydrogen and R 3A is as defined for formula (IA).
  • Compounds of the Invention are compounds of formula (IIA), and the salts and solvates thereof, wherein Het is Het6, wherein R 2A and R 3A are as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen. In another embodiment, R 2A is hydrogen and R 3A is as defined for formula (IA).
  • Compounds of the Invention are compounds of formula (IA), and the salts and solvates thereof, wherein two of A 1 , A 2 and A 3 are nitrogen.
  • Compounds of the Invention are compounds of formula (IIA), and the salts and solvates thereof, wherein Het is selected from the group consisting of
  • R and R are as defined above for formula (IA).
  • R 2A and R 3A are each hydrogen.
  • R 2A is hydrogen and R 3A is as defined for formula (IA).
  • R 2A is hydrogen and R 3A is -ORa A , wherein Ra A is -Ci -4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRb A , -N(Rb A ) 2 , and optionally substituted C 6- io aryl, wherein Rb A is each independently hydrogen or Ci -4 alkyl.
  • Het is Het7, Het10, Het11 , Het12, Het13, or Het16, wherein R 2A and R 3A are as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen. In another embodiment, R 2A is hydrogen and R 3A is as defined for formula (IA).
  • R 2A is hydrogen and R 3A is -ORa A , wherein Ra A is -Ci -4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRb A , -N(Rb A ) 2 , and optionally substituted C6-io aryl, wherein Rb A is each independently hydrogen or Ci -4 alkyl.
  • Het is Het8, Het9, Het14, or Het15, wherein R 2A and R 3A are as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen.
  • R 2A is hydrogen and R 3A is as defined for formula (IA).
  • R 2A is hydrogen and R 3A is -ORa A , wherein Ra A is -Ci -4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRb A , - N(Rb A ) 2 , and optionally substituted C-6-10 aryl, wherein Rb A is each independently hydrogen or Ci -4 alkyl.
  • Compounds of the Invention are compounds of formula (IIA), and the salts or solvates thereof, wherein Het is Het8, wherein each R 3A is independently as defined for formula (IA).
  • each R 3A is hydrogen.
  • one R 3A is hydrogen and the other one is -ORa A , wherein Ra A is -Ci -4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRb A , -N(Rb A ) 2 , and optionally substituted C 6- i o aryl, wherein Rb A is each independently hydrogen or Ci -4 alkyl.
  • Compounds of the Invention are compounds of formula (IIA), and the salts or solvates thereof, wherein Het is Het9, wherein R 2A and R 3A are as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen. In another embodiment, R 2A is hydrogen and R 3A is as defined for formula (IA).
  • R 2A is hydrogen and R 3A is -ORa A , wherein Ra A is -Ci -4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRb A , -N(Rb A ) 2 , and optionally substituted C-6-10 aryl, wherein Rb A is each independently hydrogen or Ci -4 alkyl.
  • Compounds of the Invention are compounds of formula (IIA), and the salts or solvates thereof, wherein Het is Het12, wherein R 2A and R 3A are as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen. In another embodiment, R 2A is hydrogen and R 3A is as defined for formula (IA).
  • R 2A is hydrogen and R 3A is -ORa A , wherein Ra A is -Ci -4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRb A , -N(Rb A ) 2 , and optionally substituted C-6-10 aryl, wherein Rb A is each independently hydrogen or Ci -4 alkyl.
  • Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein n is 0 or 1 , R 11 and R 12 are both hydrogen and R 13 is selected from the group consisting of halogen, -CN, -ORb A , and -Ci -4 alkyl, wherein said -Ci -4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein Rb A is as defined above for formula (IA).
  • n is 0.
  • Rb A is hydrogen or Ci -4 alkyl optionally substituted by 1 , 2 or 3 independently selected halogen atoms.
  • Het is Het1 , Het2, Het3, Het4, Het5, or Het6.
  • Het is Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16.
  • Het is Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R 2A is hydrogen and R 3A is as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen.
  • Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein n is 0 or 1 , R 11 and R 13 are both hydrogen and R 12 is selected from the group consisting of halogen, -CN, -ORb A , and -Ci -4 alkyl, wherein said -Ci -4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein Rb A is as defined above for formula (IA).
  • n is 0.
  • Rb A is hydrogen or Ci -4 alkyl optionally substituted by 1 , 2 or 3 independently selected halogen atoms.
  • Het is Het1 , Het2, Het3, Het4, Het5, or Het6.
  • Het is Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16.
  • Het is Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R 2A is hydrogen and R 3A is as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen.
  • Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein n is 0 or 1 , R 12 and R 13 are both hydrogen and R 11 is selected from the group consisting of halogen, -CN, -ORb A , and -Ci -4 alkyl, wherein said -Ci -4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein Rb A is as defined above for formula (IA).
  • n is 0.
  • Rb A is hydrogen or Ci -4 alkyl optionally substituted with 1 , 2, or 3 independently selected halogen atoms.
  • Het is Het1 , Het2, Het3, Het4, Het5, or Het6.
  • Het is Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16.
  • Het is Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R 2A is hydrogen and R 3A is as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen.
  • Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein n is 0 or 1 , R 11 is hydrogen and R 12 and R 13 are each independently selected from the group consisting of halogen, -CN, -ORb A , and -Ci -4 alkyl, wherein said -Ci -4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein Rb A is as defined above for formula (IA).
  • n is 0.
  • Rb A is hydrogen or Ci -4 alkyl optionally substituted with 1 , 2, or 3 independently selected halogen atoms.
  • Het is Het1 , Het2, Het3, Het4, Het5, or Het6.
  • Het is Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16.
  • Het is Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R 2A is hydrogen and R 3A is as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen.
  • Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein n is 0 or 1 , R 12 is hydrogen and R 11 and R 13 are each independently selected from the group consisting of halogen, -CN, -ORb A , and -Ci -4 alkyl, wherein said -Ci -4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein Rb A is as defined above for formula (IA).
  • n is 0.
  • Rb A is hydrogen or Ci -4 alkyl optionally substituted with 1 , 2, or 3 independently selected halogen atoms.
  • Het is Het1 , Het2, Het3, Het4, Het5, or Het6.
  • Het is Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16.
  • Het is Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R 2A is hydrogen and R 3A is as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen.
  • Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein n is 0 or 1 , R 13 is hydrogen and R 11 and R 12 are each independently selected from the group consisting of halogen, -CN, -ORb A , and -Ci -4 alkyl, wherein said -Ci -4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein Rb A is as defined above for formula (IA).
  • n is 0.
  • Rb A is hydrogen or Ci -4 alkyl optionally substituted with 1 , 2, or 3 independently selected halogen atoms.
  • Het is Het1 , Het2, Het3, Het4, Het5, or Het6.
  • Het is Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16.
  • Het is Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R 2A is hydrogen and R 3A is as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen.
  • Compounds of the Invention are compounds of formula (I IA), and the salts and solvates thereof, wherein n is 0 or 1 , R 11 , R 12 and R 13 are each independently selected from the group consisting of halogen, -CN, -ORb A , and -Ci -4 alkyl, wherein said -Ci -4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein Rb A is as defined above for formula (IA). In one embodiment, n is 0.
  • Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein R 11 , R 12 , and R 13 , when other than hydrogen, are each independently selected from the group consisting of chlorine, fluorine, -CN, unsubstituted Ci -4 alkyl (such as methyl or ethyl), Ci -4 alkyl substituted with 1 , 2 or 3 fluorine atoms (such as fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 1 , 1 -difluoroethyl, or 1 , 1 , 1 - trifluoroethyl), and -ORb A , wherein Rb A is hydrogen, unsubstituted Ci -4 alkyl (such as methyl or ethyl) or Ci -4 alkyl substituted with 1 , 2 or 3 fluorine atoms (such as fluoromethyl, difluoromethyl,
  • R 11 , R 12 , and R 13 when other than hydrogen, are each independently selected from the group consisting of chlorine and -ORb A , wherein Rb A is hydrogen or unsubstituted Ci -4 alkyl. In one embodiment, Rb A is hydrogen or Ci -4 alkyl. In one embodiment, n is 0.
  • Het is Het1 , Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16, and preferably Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R 2A is hydrogen and R 3A is as defined for formula (IA). In one embodiment, both R 2A and R 3A are hydrogen.
  • Compounds of the Invention are compounds of any of formulae (IA) and (MA), and the salts and solvates thereof, wherein R 5 is hydrogen.
  • Compounds of the Invention are compounds of any of formulae (IA) and (MA), and the salts and solvates thereof, wherein R 5 is Ci -4 alkyl.
  • R 5 is methyl or ethyl, and preferably methyl.
  • Compounds of the Invention are compounds of any one of formulae (IA) and (MA), and the salts and solvates thereof, wherein n is 0. In another embodiment, n is 1 or 2, and preferably n is 1 .
  • Compounds of the Invention are compounds of any one of formulae (IA) and (MA), and the salts and solvates thereof, wherein n is 1 and R 4 is selected from the group consisting of chlorine, fluorine, bromine, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, methoxy, ethoxy, tert- butoxy, CN and hydroxy.
  • R 4 is fluorine.
  • Compounds of the Invention are compounds of any one of formulae (IA) and (IIA), and the salts and solvates thereof, wherein R 2A is hydrogen, fluorine, chlorine, -CN, Ci -4 alkyl, fluoro(Ci -4 )alkyl, di-fluoro(C-
  • Compounds of the Invention are compounds of any one of formulae (IA) and (IIA), and the pharmaceutically acceptable salts and solvates thereof, wherein each R 3A is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa A , -Ci -4 alkyl, -C3-io cycloalkyl, and 5- to 10- membered heterocyclyl, said alkyl, cycloalkyl and heterocyclyl groups being optionally substituted with 1 , 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, -Ci -4 alkyl optionally substituted with 1 , 2 or 3 halogen atoms, -N(Rb A ) 2 and methoxy, optionally substituted with 1 , 2 or 3 halogen atoms, wherein each Rb A independently is hydrogen, Ci -4 alkyl, C3-io cycloalkyl, 5- to 10-membered heterocyclyl,
  • each R 3A is independently selected from hydrogen, fluorine, -CN, -ORa A , and Ci -4 alkyl, wherein Ra A is as defined for formula (IA).
  • Ra A is selected from the group consisting of hydrogen, -Ci -4 alkyl, -C-3- ⁇ cycloalkyl, -Ci -4 alkyl- (C 3- io)cycloalkyl, -C 6- io aryl, -Ci -4 alkyl-(C 6 -io)aryl, 5- to 10-membered heteroaryl, -Ci -4 alkyl-(5- to 10-membered heteroaryl), 5- to 10-membered heterocyclyl, -Ci -4 alkyl-(5- to 10-membered heterocyclyl); said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocycl
  • Ra A is -Ci -4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRb A , -N(Rb A ) 2 , and optionally substituted C-6-10 aryl, wherein Rb A is each independently hydrogen or Ci -4 alkyl.
  • Ra A is selected from the group consisting of hydrogen, unsubstituted Ci -4 alkyl, C 3- i 0 cycloalkyl, -Ci -4 alkyl-(C3-io)cycloalkyl, C-6-10 aryl, and -Ci -4 alkyl-(C6-io)aryl, and preferably, hydrogen, unsubstituted Ci -4 alkyl (such as, for example, methyl, ethyl, iso- propyl, and tert-butyl), C6-10 aryl (such as, for example, phenyl and naphthyl), and -Ci -4 alkyl-(C6-io)aryl (such as, for example, benzyl, phenethyl, and naphthylmethyl), and more preferably hydrogen or Ci -4 alkyl.
  • R 3A is hydrogen or -ORa A , wherein Ra A is as defined above.
  • Ra A is as defined
  • Compounds of the Invention are compounds of formula (IA) represented by the formula (I),
  • each of A 1 is independently selected from the group consisting of nitrogen and C(R 2 );
  • each of A 2 and A 3 is independently selected from the group consisting of nitrogen, C(R 3 ) and C(NH 2 );
  • a 2 and A 3 are C(NH 2 ) and wherein no less than one and no more than two of A 1 , A 2 and A 3 are nitrogen;
  • each R 1 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORb, and -Ci -4 alkyl, wherein said -Ci -4 alkyl group is optionally substituted by 1 , 2 or 3 halogen atoms, with the proviso that at least one R 1 is not hydrogen;
  • R 2 is selected from the group consisting of hydrogen, fluorine, -CN, methyl and trifluoromethyl;
  • each one of R 3 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -Ci -4 alkyl, -C 3- i 0 cycloalkyl, and 5- to 10- membered-C2-i o heterocyclyl, said alkyl, cycloalkyl and heterocyclyl groups being optionally substituted with 1 , 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, -Ci -4 alkyl optionally substituted with 1 , 2 or 3 halogen atoms, -N(Rb) 2 and methoxy, optionally substituted with 1 , 2 or 3 halogen atoms;
  • n has a value selected from 0, 1 or 2;
  • each Ra independently is selected from the group consisting of hydrogen, -Ci -4 alkyl, -C3-10 cycloalkyl, -Ci -4 alkyl-(C3-i o)cycloalkyl, -C6-10 aryl, -Ci -4 alkyl-(C6-i o)aryl, 5- to 10-membered-Ci -i o heteroaryl, -Ci -4 alkyl-5- to 10-membered-Ci -i o heteroaryl, 5- to 10-membered-C2-i o heterocyclyl, -Ci -4 alkyl-5- to 10-membered-C 2- i o heterocyclyl; said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups optionally being substituted with 1 , 2 or 3 groups independently selected from
  • each Rb independently represents, on each occasion when used herein hydrogen, -Ci -4 alkyl, -C3-i o cycloalkyl, 5- to 10-membered-C2-i o heterocyclyl; said alkyl, cycloalkyl or heterocyclyl groups optionally being substituted by 1 , 2 or 3 independently fluorine atoms;
  • Compounds of the Invention are compounds of formula (I), wherein:
  • each of A 1 is independently selected from the group consisting of nitrogen and C(R 2 ), each of A 2 and A 3 is independently selected from the group consisting of nitrogen, C(R 3 ) and C(NH 2 ),
  • a 2 and A 3 are C(NH 2 ) and wherein no less than one and not more than two of A 1 , A 2 and A 3 are nitrogen,
  • each R 1 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORb, and -Ci -4 alkyl wherein said -Ci -4 alkyl group is optionally substituted by 1 , 2 or 3 halogen atoms, with the proviso that at least one R 1 is not hydrogen,
  • R 2 is selected from the group consisting of hydrogen, fluorine, -CN, methyl and trifluoromethyl,
  • each one of R 3 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -Ci -4 alkyl, -C3-i o cycloalkyl, and 5- to 10- membered-C 2- 9 heterocyclyl, said alkyl, cycloalkyl and heterocyclyl groups being optionally substituted with 1 , 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, -Ci -4 alkyl optionally substituted with 1 , 2 or 3 halogen atoms, -N(Rb) 2 and methoxy, optionally substituted with 1 , 2 or 3 halogen atoms;
  • n has a value selected from 0, 1 or 2;
  • each Ra independently is selected from the group consisting of hydrogen, -Ci -4 alkyl, -C3-10 cycloalkyl, -Ci -4 alkyl-(C3-io)cycloalkyl, -C6-10 aryl, -Ci -4 alkyl-(C6-io)aryl, 5- to 10-membered-C 1-9 heteroaryl, -Ci -4 alkyl- 5- to I O-membered-C-i-9 heteroaryl, 5- to 10-membered-C 2- 9 heterocyclyl, -Ci -4 alkyl-5- to 10-membered-C 2- 9 heterocyclyl; said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups optionally being substituted with 1 , 2 or 3 groups independently selected from halogen, hydroxy, -CN,
  • each Rb independently represent, on each occasion when used herein hydrogen, -Ci -4 alkyl, -C3-io cycloalkyl,- 5- to 10-membered-C 2- 9 heterocyclyl; said alkyl, cycloalkyl or heterocyclyl groups optionally being substituted by 1 , 2 or 3 independently fluorine atoms
  • the present invention relates to a compound of formula (I) as defined above, wherein n has a value of zero. In another embodiment, n has a value of 1 .
  • the present invention relates to a compound of formula (I) as defined above, wherein one of A 1 is nitrogen. In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein both of A 1 are nitrogen. In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein when A 1 is C(R 2 ) and R 2 is as defined for formula (I). In another embodiment, R 2 is hydrogen or fluorine. In another embodiment, R 2 is hydrogen.
  • the present invention relates to a compound of formula (I) as defined above, wherein one of A 2 is C(NH 2 ).
  • the present invention relates to a compound of formula (I) as defined above, wherein A 3 is C(NH 2 ). In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein one of A 2 is C(R 3 ), wherein R 3 is as defined above for formula (I). In one embodiment, R 3 is selected from the group consisting of hydrogen, fluorine, CN, -ORa, and Ci -4 alkyl. In another embodiment, R 3 is hydrogen or -ORa.
  • Ra is selected from the group consisting of hydrogen, Ci -4 alkyl, C-3- ⁇ cycloalkyl, -Ci -4 alkyl-(C3- i o)cycloalkyl, C-6-10 aryl, and -Ci -4 alkyl-(C6-i o)aryl, and more preferably selected from the group consisting of hydrogen, Ci -4 alkyl, C 6- i o aryl, and -Ci -4 alkyl-(C 6- i o)aryl.
  • Ra is hydrogen or Ci -4 alkyl.
  • the present invention relates to a compound of formula (I) as defined above, wherein A 3 is C(R 3 ), wherein R 3 is as defined above for formula (I).
  • R 3 is selected from the group consisting of hydrogen, fluorine, CN, -ORa, and Ci -4 alkyl. In another embodiment, R 3 is hydrogen or -ORa.
  • Ra is selected from the group consisting of hydrogen, Ci -4 alkyl, C3-io cycloalkyl, -Ci -4 alkyl-(C3- i o)cycloalkyl, C-6-10 aryl, and -Ci -4 alkyl-(C6-i o)aryl, and more preferably selected from the group consisting of hydrogen, Ci -4 alkyl, C 6- i o aryl, and -Ci -4 alkyl-(C 6- i o)aryl.
  • Ra is hydrogen or Ci -4 alkyl.
  • the present invention relates to a compound of formula (I) as defined above, wherein one only of A 1 , A 2 and A 3 is nitrogen.
  • the present invention relates to a compound of formula (I) as defined above, wherein two of A 1 , A 2 and A 3 are nitrogen.
  • compounds of formula (I) include those where R 1 is selected from the group consisting of hydrogen, halogen, CN , -ORb, and Ci -4 alkyl, and preferably selected from the group consisting of hydrogen, chlorine, CN , and -ORb. More preferably, R 1 is chlorine or -ORb. In one embodiment, Rb is hydrogen or Ci -4 alkyl, wherein the Ci -4 alkyl is optionally substituted with 1 , 2, or 3 fluorine atoms.
  • the present invention relates to a compound of formula (I) as defined above, wherein one or two of R 1 are hydrogen.
  • the present invention relates to a compound of formula (I) as defined above, wherein the substituents R 1 at positions 5 and 6 of the isoquinoline ring are hydrogen and the substituent R 1 at position 7 of the isoquinoline ring is as defined above for formula (I), and preferably is selected from the group consisting of chlorine, methyl, trifluoromethyl and -ORb wherein Rb is selected from the group consisting of methyl and trifluoromethyl.
  • the present invention relates to a compound of formula (I) as defined above, wherein the substituents R 1 at positions 6 and 7 of the isoquinoline ring are hydrogen and the substituent R 1 at position 5 of the isoquinoline ring is as defined above for formula (I), and preferably is selected from the group consisting of chlorine and -ORb wherein Rb is selected from the group consisting of methyl and trifluoromethyl.
  • the present disclosure provides a compound selected from the group consisting of: N 2 -(5-chloroisoquinolin-1 -yl)pyridine-2,6-diamine,
  • the present disclosure provides a compound selected from the group consisting of:
  • the present disclosure provides compounds useful as synthesis intermediates in the preparation of Compounds of the Invention.
  • These compounds for use as synthesis intermediates are compounds of formulae (IA), (IIA), and (I), and their salts or solvates thereof, wherein at least one amino group is protected by an amine protecting group.
  • amine protecting group or "amino protecting group” as used herein refers to a group that blocks (i.e., protects) the amine functionality while reactions are carried out on other functional groups or parts of the molecule.
  • amine protecting group or "amino protecting group” as used herein refers to a group that blocks (i.e., protects) the amine functionality while reactions are carried out on other functional groups or parts of the molecule.
  • Those skilled in the art will be familiar with the selection, attachment, and cleavage of amine protecting groups and will appreciate that many different protective groups are know in the art, the suitability of one protective group or another being dependent on the particular synthetic scheme planned. Treatises on the subject are available for consultation, such as Wuts, P. G. M. & Greene, T. W., Greene's Protective Groups in Organic Synthesis, 4rd Ed. (J. Wiley & Sons, 2007), herein incorporated by reference in its entirety.
  • Suitable amine protecting groups include methyl carbamate, fe/f-butyloxycarbonyl (tert-butyl carbamate; BOC), 9-fluorenylmethyl carbamate, benzyl carbamate, 2- (trimethylsilyl)ethyl carbamate, trifluoroacetamide, benzylamine, allylamine, tritylamine, trichloroacetyl, trifluoroacetyl, p-toluenesulfonyl, and allyl carbamate.
  • the protected amino group can be a phthalimide-protected amino group (NPhth).
  • the compounds of formulae (IA), (IIA), and (I) can be in the form of solvates or salts, preferably wherein the solvating agents and/or the salt's counter-ions are pharmaceutically acceptable species.
  • halogen or halo refer to -F, -CI, -Br or -I.
  • hydroxyl or “hydroxy” refers to the group -OH
  • alkyl refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, which is attached to the rest of the molecule by a single bond and, unless otherwise specified, an alkyl radical typically has from 1 to 4 carbon atoms.
  • exemplary alkyl groups can be methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, i-butyl and sec-butyl.
  • the alkyl is d-2 alkyl (methyl or ethyl).
  • halo(Ci -4 )alkyl refers to any of the above- mentioned Ci -4 alkyl groups, substituted by one or more halogen atoms (fluorine, chlorine, bromine or iodine atoms) (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1 ,1 -difluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups).
  • halogen atoms fluorine, chlorine, bromine or iodine atoms
  • halo(Ci -4 )alkyl is monohalo(Ci -4 )alkyl.
  • the term "monohalo(Ci -4 )alkyl” indicates that the Ci -4 alkyl group is substituted by exactly one halogen atom.
  • the term "dihalo(Ci -4 )alkyl” means that the Ci -4 alkyl group is substituted by two halogen atoms.
  • trihalo(Ci -4 )alkyl means that the Ci -4 alkyl group is substituted by three halogen atoms.
  • the halogen atoms can be attached to the same or different carbon atoms.
  • the one or more halogen atoms can be the same or different.
  • Ci -4 alkoxy refers to oxygen substituted by one of the Ci -4 alkyl groups mentioned above (e.g., methoxy, ethoxy, propoxy, iso-propoxy, butoxy, tert-butoxy, iso-butoxy, and sec-butoxy), preferably by one of the C-i-2 alkyl groups.
  • cycloalkyl embraces saturated carbocyclic radicals and, unless otherwise specified, a cycloalkyl radical typically has from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the cycloalkyl group is C-3- ⁇ ⁇ cycloalkyl.
  • alkylcycloalkyl when employed in the definition of a substituent refers to a cycloalkyl group which is linked through an alkylene radical with the core structure which it substitutes.
  • a cyclopentylethyl substituent is a substituent consisting of a cyclopentyl group linked through an ethylene group to the core structure which it substitutes.
  • heterocyclyl or “heterocyclic group” embrace typically a monocyclic or polycyclic, non-aromatic, saturated or unsaturated C2- 10 carbocyclic ring, such as a 5 to 10 membered radical, in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S.
  • a heterocyclyl is a C3 -7 heterocyclyl.
  • a heterocyclic radical may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom.
  • the substituents may be the same or different.
  • a said optionally substituted heterocyclyl is typically unsubstituted or substituted with 1 , 2 or 3 substituents which may be the same or different.
  • heterocyclic radicals include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazolinyl, pyrazolidinyl, quinuclidinyl, tetrazolyl, cromanyl, isocromanyl, imidazolidinyl, oxiranyl, azaridinyl, 4,5- dihydro-oxazolyl and 3-aza-tetrahydrofuranyl.
  • alkylheterocyclyl when employed in the definition of a substituent refers to a heterocyclyl group as defined above which is linked through an alkylene radical with the core structure which it substitutes.
  • aryl designates typically a C-6-10 monocyclic or polycyclic aryl radical such as phenyl and naphthyl. Phenyl is preferred.
  • a said optionally substituted aryl radical is typically unsubstituted or substituted with 1 , 2 or 3 substituents which may be the same or different.
  • the substituents are preferably selected from halogen atoms, preferably fluorine or chlorine atoms, hydroxy groups, alkoxycarbonyl groups in which the alkyl moiety has from 1 to 4 carbon atoms, hydroxycarbonyl groups, carbamoyl groups, nitro groups, cyano groups, Ci -4 alkyl groups optionally substituted by one or more halogen atoms, Ci -4 alkoxy groups, optionally substituted by one or more halogen atoms and d. 4 hydroxyalkyl groups.
  • halogen atoms preferably fluorine or chlorine atoms
  • hydroxy groups alkoxycarbonyl groups in which the alkyl moiety has from 1 to 4 carbon atoms, hydroxycarbonyl groups, carbamoyl groups, nitro groups, cyano groups
  • Ci -4 alkyl groups optionally substituted by one or more halogen atoms
  • Ci -4 alkoxy groups optionally substituted by one or more halogen atoms and d
  • alkylaryl when employed in the definition of a substituent refers to an aryl group as defined above which is linked through an alkylene radical with the core structure which it substitutes.
  • heteroaryl designates typically a 5- to 10- membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N, typically 1, 2, 3 or 4 heteroatoms.
  • a heteroaryl group may comprise a single ring or two or more fused rings wherein at least one ring contains a heteroatom.
  • a said optionally substituted heteroaryl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different.
  • the substituents are preferably selected from halogen atoms, preferably fluorine, chlorine or bromine atoms, alkoxycarbonyl groups in which the alkyl moiety has from 1 to 4 carbon atoms, carbamoyl groups, nitro groups, hydroxy groups, Ci -4 alkyl groups, optionally substituted by one or more halogen atoms and Ci -4 alkoxy groups, optionally substituted by one or more halogen atoms.
  • an heteroaryl radical carries 2 or more substituents, the substituents may be the same or different. Unless otherwise specified, the substituents on a heteroaryl radical are typically themselves unsubstituted.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, tetrazolyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, pyridinyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl
  • heteroaryl radicals or rests within the present invention is intended to cover the N-oxides obtainable from these radicals when they comprise N-atoms.
  • alkylheteroaryl when employed in the definition of a substituent refers to an heteroaryl group as defined above which is linked through an alkylene radical with the core structure which it substitutes.
  • pharmaceutically acceptable species refers to compositions and molecular entities that are physiologically tolerable and do not typically produce an allergic reaction or a similar unfavorable reaction as gastric disorders, dizziness and suchlike, when administered to a human or animal.
  • pharmaceutically acceptable means it is approved by a regulatory agency of a state or federal government or is included in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • treatment refers to administering a therapy in an amount, manner or mode effective to improve a condition, symptom, or parameter associated with a condition or to prevent progression of a condition, to either a statistically significant degree or to a degree detectable to one skilled in the art.
  • An effective amount, manner, or mode can vary depending on the subject and may be tailored to the patient.
  • the term “about”, as used herein in connection with a measured quantity refers to the normal variations in that measured quantity, as expected by the skilled artisan making the measurement and exercising a level of care commensurate with the objective of measurement and precision of the measuring equipment. Typically, the term “about” includes the recited number ⁇ 10%. Thus, “about 10" means 9 to 1 1 .
  • the term "optionally substituted” refers to a group that may be unsubstituted or substituted.
  • solvate means any form of the active compound of the invention which has another molecule (for example a polar solvent such as water or ethanol, a cyclodextrin or a dendrimer) attached to it through noncovalent bonds. Methods of solvation are known within the art.
  • the invention also provides salts of the compounds of the invention.
  • Non-limiting examples are sulphates; hydrohalide salts; phosphates; lower alkane sulphonates; arylsulphonates; salts of d-2o aliphatic mono-, di- or tribasic acids which may contain one or more double bonds, an aryl nucleus or other functional groups such as hydroxy, amino, or keto; salts of aromatic acids in which the aromatic nuclei may or may not be substituted with groups such as hydroxyl, lower alkoxyl, amino, mono- or di- lower alkylamino sulphonamido.
  • quaternary salts of the tertiary nitrogen atom with lower alkyl halides or sulphates, and oxygenated derivatives of the tertiary nitrogen atom, such as the N-oxides are also included within the scope of the invention.
  • quaternary salts of the tertiary nitrogen atom with lower alkyl halides or sulphates are also included within the scope of the invention.
  • oxygenated derivatives of the tertiary nitrogen atom such as the N-oxides.
  • those skilled in the art will select the pharmaceutically acceptable salts.
  • Solvates and salts can be prepared by methods known in the state of the art. Note that the non-pharmaceutically acceptable solvates also fall within the scope of the invention because they can be useful in preparing pharmaceutically acceptable salts and solvates.
  • the compounds of the invention also seek to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a carbon enriched in 11 C, 13 C or 14 C or the replacement of a nitrogen by a 15 N enriched nitrogen are within the scope of this invention.
  • Some of the compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, such as epimers.
  • the present invention is meant to encompass the uses of all such possible forms, as well as their racemic and resolved forms and mixtures thereof.
  • the individual enantiomers may be separated according to methods known to those of ordinary skill in the art in view of the present disclosure.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention as well.
  • stereoisomers is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
  • chiral center refers to a carbon atom to which four different groups are attached.
  • epimer refers to diastereomers that have opposite configuration at only one of two or more tetrahedral streogenic centres present in the respective molecular entities.
  • stereoisomer is an atom, bearing groups such that an interchanging of any two groups leads to a stereoisomer.
  • enantiomer and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.
  • racemic refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.
  • resolution refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
  • a and an refer to one or more.
  • Another aspect of the invention refers to procedures to obtain compounds of general formulae (IA), (IIA), and (I).
  • Compounds of the Invention can be prepared using methods known to those skilled in the art in view of this disclosure, or by illustrative methods shown in the schemes below.
  • Scheme 1 illustrates the different synthetic paths to obtain compounds of formula (I) wherein one of A 2 is C(NH 2 ). These compounds have formula (la).
  • Scheme 2 illustrates the different synthetic paths to obtain compounds of formula (I) wherein one of A 3 is C(NH 2 ). These compounds have formula (lb).
  • Reaction A is used to prepare compounds of formulae (Via) or (Vlb) by reaction of a compound of formulae (Ilia) or (lllb) respectively with a compound of formula (II) wherein LG 1 represents a leaving group such as iodo, bromo, chloro or a sulphonate group (e.g. -OS(0) 2 CF 3 , -OS(0) 2 CH 3 or -OS(0) 2 PhMe).
  • LG 1 represents a leaving group such as iodo, bromo, chloro or a sulphonate group (e.g. -OS(0) 2 CF 3 , -OS(0) 2 CH 3 or -OS(0) 2 PhMe).
  • Said reaction may be performed under standard conditions in the presence of a suitable base such as pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, or mixtures thereof, and an appropriate solvent such as pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, dimethylsulphoxide, water or mixtures thereof and, for example, at around room temperature or above, or under microwave irradiation reaction conditions.
  • a suitable base such as pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, or mixtures thereof
  • an appropriate solvent such as pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, dimethylsulphoxide, water or mixtures thereof and, for example, at around room temperature or above, or under microwave irradiation reaction conditions.
  • the reaction may also be carried out in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc) 2 , Cul (or Cul/diamine complex) copper tris(triphenyl-phosphine)bromide, Pd(OAc) 2 , tris(dibenzylideneacetone) dipalladium(O) (Pd 2 (dba) 3 ) or N 1CI2 and also optionally in the presence of an additive such as Ph 3 P, 2,2'- bis(diphenylphosphino)-1 , 1 '-binaphthyl, xantphos, Nal or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as sodium hydride, triethylamine, pyridine, N,N'-dimethylethylenediamine, sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, sodium tert-butoxide or potassium tert
  • dichloromethane dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran) or a mixture thereof.
  • This reaction may be carried out under microwave irradiation reaction conditions.
  • the reaction mixture may be stirred at room temperature or heated until the starting materials have been consumed.
  • the reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3rd Edition, New York, 1999).
  • reaction B is carried out with a suitable reducing agent such as Fe, SnC , Raney Nickel and H 2 /Pt02.
  • a suitable reducing agent such as Fe, SnC , Raney Nickel and H 2 /Pt02.
  • the reaction may be carried out in the presence of and acid such as acetic acid and in a suitable solvent such as ethyl acetate, water, methanol, ethanol and/or tetrahydrofuran.
  • acid such as acetic acid
  • a suitable solvent such as ethyl acetate, water, methanol, ethanol and/or tetrahydrofuran.
  • Other reducing agents or acids may be employed, as is known by the person skilled in the art.
  • the reaction mixture is stirred at room temperature, or heated until the starting materials have been consumed.
  • the reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction.
  • Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3rd Edition, New York, 1999).
  • Reaction C is carried out under standard amine arylation conditions such as those explained for step 1 of method 1 described above.
  • a suitable leaving group such as such as iodo, bromo, chloro or a sulphonate group
  • Reaction D is carried out under standard amine arylation conditions such as those explained for step 1 of method 1 described above.
  • the leaving group in the compound of formulae (Vila) or (Vllb) is subsequently replaced by a group -NH-PG 1 wherein PG 1 is an amino protecting group such as methyl carbamate, tert-butyl carbamate, 9-fluorenylmethyl carbamate, benzyl carbamate, 2-(trimethylsilyl)ethyl carbamate, trifluoroacetamide, benzylamine, allylamine, tritylamine, trichloroacetyl, trifluoroacetyl, p-toluenesulfonyl or allyl carbamate to yield the compound of formulae (Villa) or (VI I lb) respectively according to the invention as illustrated in reaction E of the schemes above.
  • PG 1 is an amino protecting group such as methyl carbamate, tert-butyl carbamate, 9-fluorenylmethyl carbamate, benzyl carbamate, 2-(trimethyls
  • the reaction E is carried out by causing compound of formulae (Vila) or (Vllb) respectively to react with a compound of formula PGi-NH 2 wherein PG 1 is as hereinabove defined.
  • the reaction may be carried out under standard conditions in the presence of a suitable base (e.g. pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, or mixtures thereof), and appropriate solvent (e.g. pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, triethylamine, dimethylsulphoxide, water or mixtures thereof) and for example at around room temperature or above, or under microwave irradiation reaction conditions.
  • a suitable base e.g. pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, or mixtures thereof
  • solvent e.g. pyridine, dichloromethane
  • an appropriate metal catalyst such as Cu, Cu(OAc) 2 , Cul (or Cul/diamine complex) copper tris(triphenyl-phosphine)bromide, Pd(OAc) 2 , tris(dibenzylideneacetone)dipalladium (0) (Pd 2 (dba) 3 ) or NiCI 2 and of optional additive such as Ph 3 P, 2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthyl, xantphos, Nal or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as sodium hydride, triethylamine, pyridine, ⁇ , ⁇ '-dimethylethylenediamine, sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, sodium tert-butoxide or potassium tert-butoxide (or
  • dichloromethane dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N- methylpyrrolidinone, tetrahydrofuran or a mixture thereof).
  • This reaction may be carried out under microwave irradiation reaction conditions.
  • the reaction mixture may be stirred at room temperature or heated until the starting materials have been consumed.
  • the reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3rd Edition, New York, 1999).
  • Step 3 In a final step, the amino protecting group (PGi) of the compound of formulae (Villa) or (Vlllb) is cleaved to yield the compound of formulae (la) or (lb) respectively as illustrated in reaction F of the scheme above.
  • Said reaction may be carried under standard conditions known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3rd Edition, New York, 1999).
  • a tert- butyl carbamate amine protecting group can be performed in the presence of a strong protic acid (e.g. 3M HCI or CF 3 COOH) or TMS-I;
  • a 2-(trimethylsilyl)ethyl carbamate amine protecting group can be removed in the presence of a fluoride ion (e.g.
  • a 9-fluorenylmethyl carbamate amine protecting group by treatment with a mild base (e.g piperidine or morpholine); a benzyl carbamate amine protecting group by hydrogenolysis, treatment with BBr 3 or Na/NH 3 , PdC and Et 3 SiH; a trifluoroacetamide amine protecting group can be removed by treatment with a base (e.g. K2CO3) or NH 3 ; p-toluenesulfonyl protecting group can be cleaved with a strong acid or Na(Hg); allyl carbamate amine protecting group is cleaved with Pd(0) and a reducing agent (e.g.
  • a mild base e.g piperidine or morpholine
  • a benzyl carbamate amine protecting group by hydrogenolysis, treatment with BBr 3 or Na/NH 3 , PdC and Et 3 SiH
  • a trifluoroacetamide amine protecting group can
  • benzylamine can be cleaved by hydrogenolysis (e.g. H 2 , Pd/C and HCI); a tritylamine can be cleaved with HCI or H 2 , Pd/C; an allylamine can be cleaved by treatment with polymethylhydrosiloxane (PMHS), ZnCI 2 and Pd(PPh 3 ) 4 or in oxydative conditions (e. g.
  • hydrogenolysis e.g. H 2 , Pd/C and HCI
  • a tritylamine can be cleaved with HCI or H 2 , Pd/C
  • an allylamine can be cleaved by treatment with polymethylhydrosiloxane (PMHS), ZnCI 2 and Pd(PPh 3 ) 4 or in oxydative conditions (e. g.
  • NMO, Os0 4 and Nal0 4 NMO, Os0 4 and Nal0 4 ); a trichloroacetyl amine protecting group can be removed with NaBH 4 ; a trifluoroacetyl amine protecting group can be cleaved with a base (e.g. K 2 C0 3 Na 2 C0 3 ).
  • R 3 represents a group -ORa a compound of formulae (IXa), (IXa2), (IXa3), (IXa4), (IXb1 ) or (IXb2), wherein LG 3 represents a leaving group such as iodo, bromo, chloro or a sulphonate group (e.g. -OS(O) 2 CF 3 , -OS(O) 2 CH 3 or -OS(O) 2 PhMe) is caused to react with a compound of formula H-R 3 wherein R 3 represents -ORa and Ra is as defined above.
  • LG 3 represents a leaving group such as iodo, bromo, chloro or a sulphonate group
  • Said reaction may be performed under standard conditions in the presence of a suitable base such as pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, or mixtures thereof), and an appropriate solvent such as pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, triethylamine, dimethylsulphoxide, water or mixtures thereof and, for example, at around room temperature or above, or under microwave irradiation reaction conditions.
  • a suitable base such as pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, or mixtures thereof
  • an appropriate solvent such as pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, triethylamine, dimethylsulphoxide, water or mixtures thereof and, for example, at around room temperature or above, or under microwave irradiation reaction conditions.
  • the reaction may also be carried out in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc) 2 , Cul (or Cul/diamine complex) copper tris(triphenyl-phosphine)bromide, Pd(OAc) 2 , tris(dibenzylideneacetone) dipalladium (0) (Pd 2 (dba) 3 ) or N 1CI2 and also optionally in the presence of an additive such as Ph 3 P, 2,2'- bis(diphenylphosphino)-1 , 1 '-binaphthyl, xantphos, Nal or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as sodium hydride, triethylamine, pyridine, N, N'-dimethylethylenediamine, sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, sodium tert-butoxide or potassium tert-
  • dichloromethane dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or a mixture thereof.
  • This reaction may be carried out under microwave irradiation reaction conditions
  • the reaction mixture may be stirred at room temperature or heated until the starting materials have been consumed.
  • the reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3rd Edition, New York, 1999).
  • R 3 represents a group selected from -C-u ⁇ alkyl, -C3 ⁇ 4-R
  • -OS(0) 2 CF 3 , -OS(0) 2 CH 3 or -OS(0) 2 PhMe is caused to react with a compound of formula Q-R 3 wherein Q represents a suitable group such as alkali metal group (e.g. lithium), a Grignard reagent (e.g. MgX), - B(OH) 2 , -B(OR) 2 or -Sn(R) 3 , wherein each R independently represents an alkyl group, or, in the case of -B(OR) 2 , the respective R groups may be linked together to form a 4- to 6- membered cyclic group.
  • the reaction may be performed, for example in the presence of a suitable catalyst system, e.g.
  • a metal such as Pd, Cu, Pd/C, PdCI 2 , Pd(OAc) 2 , Pd(Ph 3 P) 4 , Pd(Ph 3 P) 2 CI 2 (i.e.
  • a suitable base such as, sodium carbonate, potassium phosphate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium fluoride, triethylamine, diisopropylethylamine, sodium tert-butoxide, or potassium tert-butoxide (or mixtures thereof) in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, ethylene glycol di
  • the initial compounds and starting materials e.g. the compounds of formula (II), (Ilia), (lllb), (IVa), (IVb), (Va), and (Vb), are either commercially available or can be obtained following procedures described in the literature.
  • Compounds of formula (IXa1 ), (IXa2), (IXa3), (IXa4), (IXb1 ) and (IXb2), can also be obtained following anyone of methods 1 , 2 or 3 described above.
  • Compounds of the Invention have the ability to bind allosterically to mutated ⁇ -galactosidase enzyme and, thereby, stabilizing the enzyme against denaturation. Therefore Compounds of the Invention can be used/administered to treat an/or prevent conditions associated with the alteration of the activity of ⁇ -galactosidase, specifically galactosidase ⁇ -1 or GLB1 , including GM1 gangliosidoses and Morquio syndrome, type B, in a patient suffering from said condition.
  • the present invention is directed to a method of treating or preventing a condition associated with the alteration of the activity of GLB1 in a patient, comprising administering to the patient in need thereof an effective amount of a compound of any one of formulae (IA), (IIA), or (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention is also directed to a method of treating GM1 ganglisidosis or Morquio B syndrome in a patient, comprising administering to the patient in need thereof an effective amount of a compound of any one of formulae (IA), (IIA), or (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention is also directed to a method of increasing ⁇ - galactosidase activity in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of defined formulae (IA), (IIA), or (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention is also directed to the use of a compound represented by any of defined formulae (IA), (IIA), or (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating and/or preventing a condition associated with the alteration of the activity of ⁇ -galactosidase, specifically galactosidase ⁇ -1 or GLB1 , including GM1 gangliosidoses and Morquio syndrome, type B, in a patient suffering from said condition.
  • Pharmaceutical compositions represented by any of defined formulae (IA), (IIA), or (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating and/or preventing a condition associated with the alteration of the activity of ⁇ -galactosidase, specifically galactosidase ⁇ -1 or GLB1 , including GM1 gangliosidoses and Morquio syndrome, type B, in a patient suffering from said condition.
  • the Compounds of the Invention can be used in human medicine. As described above, the Compounds of the Invention are useful for treating or preventing a condition associated with the alteration of the activity of ⁇ -galactosidase.
  • the Compounds of the Invention can be administered to any patient suffering said condition.
  • patient refers to any human that may experience the beneficial effects of a Compound of the Invention.
  • a Compound of the Invention When administered to a patient, a Compound of the Invention can be administered as a component of a composition that comprises a pharmaceutically acceptable excipient or carrier.
  • excipient refers to a vehicle, diluent, or adjuvant that is administered with the active ingredient.
  • Such pharmaceutical excipients can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and similar. Water or saline queous solutions and aqueous dextrose and glycerol solutions, particularly for injectable solutions, are preferably used as vehicles.
  • Suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences” by E.W. Martin, 21 st Edition, 2005; or "Handbook of Pharmaceutical Excipients," Rowe C.R.; Paul J.S.; Marian E.Q., sixth Edition, incorporated herein by reference.
  • compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid compositions (solutions, suspensions or emulsions) for oral, topical or parenteral administration.
  • the pharmaceutical compositions are in an oral delivery form.
  • Pharmaceutical forms suitable for oral administration can be tablest and capsules, and can contain conventional excipients known in the art, such as binders, for example syrup, gum Arabic, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, cornstarch, calcium phosphate, sorbitol, or glycine; lubricants for the preparation of tablets, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents, such as sodium lauryl sulphate.
  • Solid oral compositions can be prepared by conventional methods of blending, filling or preparation of tablets.
  • the tablets can be prepared, for example, by dry or wet granulation and optionally can be coated by well known methods in normal pharmaceutical practice, in particular using enteric coating.
  • compositions can also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the appropriate unit dosage form.
  • Suitable excipients such as fillers, buffering agents or surfactants, can be used.
  • the mentioned formulations can be prepared using standard methods, such as those described or referred to in the Spanish and U.S. Pharmacopoeias and similar reference texts.
  • the effective amount of a Compound of the Invention to be administered depends on the relative efficacy of the compound chosen, the severity of the condition or disorder being treated, and the patient's weight.
  • the active compound can be administered one or more times a day, for example 1 , 2, 3, or 4 times daily, with typical total daily doses in the range from about 0.01 mg/kg of body weight/day to about 1000 mg/kg of body weight/day.
  • the effective dosage amount of a Compound of the Invention is about 500 mg/kg of body weight/day or less.
  • the effective dosage amount of a Compound of the Invention is about 100 mg/kg of body weight/day or less.
  • the effective dosage amount ranges from about 0.01 mg/kg of body weight/day to about 100 mg/kg of body weight/day of a Compound of the Invention; in another embodiment, from about 0.02 mg/kg of body weight/day to about 50 mg/kg of body weight/day of a Compound of the Invention; and in another embodiment, from about 0.025 mg/kg of body weight/day to about 20 mg/kg of body weight/day of a Compound of the Invention.
  • a composition of the invention can be prepared by a method comprising admixing a Compound of the Invention with a pharmaceutically acceptable excipient or carrier. Admixing can be accomplished using methods known for admixing a compound and a pharmaceutically acceptable excipient or carrier.
  • the Compound of the Invention is present in the composition in an effective amount.
  • h means hours, “eq” means equivalents, "min” means minutes, "Pd 2 (dba) 3 " means tn ' s(dibenzylideneacetone)-dipalladium(0), "XantPhos” means 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; "SnC " means tin(ll) chloride; "TLC” means thin layer chromatography; and "HPLC” means high-performance liquid chromatography.
  • HPLC measurements were performed using a HPLC Waters Alliance HT comprising a pump (Edwards RV12) with degasser, an autosampler, a diode array detector and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer.
  • the MS detector was configured with an eletrospray ionization source (micromass ZQ4000), Nitrogen was used as the nebulizer gas. Data acquisition was performed with MassLynx software.
  • HPLC method A The reverse phase HPLC purifications were carried out on a YMC-Pack ODS-AQ (50x4.6 mm, D S. 3 ⁇ , 12 nm) column.
  • Solvent A water 0.1 % formic acid
  • Solvent B acetonitrile with 0.1 % formic acid.
  • Gradient 5% of B to 100% of B within 3.5 min.
  • Flux 1 .6 mL/min at 50°C.
  • HPLC method B Column: Agilent Zorbax 3.5 ⁇ , SB-C8 (4.6x75 mm); wavelength: 210/254 nm; flow: 1 mL/min; run time: 7 min; Time & mobile phase- gradient (time in min/B): 0/5, 3.5/90, 5/90, 5.5/5, 7/5 [B: acetonitrile; A: formic acid (0.1 % in water)]; MASS: Agilent-single quad-multimode-APCI-ESI.
  • HPLC method C Column: Agilent Zorbax 3.5 ⁇ , SB-C8 (4.6x75 mm); wavelength: 210/254 nm; flow: 1 mL/min; run time: 7 min; Time & mobile phase- gradient (time in min/B): 0/30, 3.5/95, 5/95, 5.5/30, 7/30 [B: acetonitrile; A: formic acid (0.1 % in water)]; MASS: Agilent-single quad-multimode-APCI- ESI.
  • HPLC method D Column: Waters Symmetry C-18 Column (4.6x75 mm) 3.5 pm, flow 1 mL/min, runtime: 5 min, Time & mobile phase-isocratic (time in min/B): 0/80, 5/80 [B: acetonitrile, A: formic acid (0.1 % in water)]; LC/MS/MS module Applied Biosystem-API 3200 with Shimadzu LC.
  • HPLC method E Direct mass: Time & mobile phase-isocratic (time in min/B) using union: 0/80, 1/80 [B: acetonitrile, formic acid (0.1 % in water)]; LC/MS/MS module Applied Biosystems-API-2000 with Agilent LC. MW calculated is an isotopic average and the "found mass" is referring to the most abundant isotope detected in the LC-MS.
  • Trifluoroacetic acid (2 mL) was added to a solution of the appropriate carbamate (Vila) or (Vllb) (ex: tert-butyl (4-((7-chloroisoquinolin-1 - yl)amino)pyridin-2-yl)carbamate) in dichloromethane (2 mL). The solution was stirred at room temperature for 3-5h and concentrated under vacuum. The resultant residue was purified by flash column chromatography (dichloromethane/methanol) to obtain the desired amine product (la) or (lb) (ex: /V 4 -(7-chloroisoquinolin-1-yl)pyridine-2,4-diamine).
  • TFA Trifluoroacetic acid
  • the aqueous layer was extracted with ethyl acetate (x2), and the combined organic layers were dried (magnesium sulphate), filtered and concentrated under vacuum to give the desired protected amine (ex: 2-(6-((7-methylisoquinolin-1 -yl)amino)pyridazin-3- yl)isoindoline-1 ,3-dione).
  • the resultant crude was quenched with ice-cold water and the pH was adjusted to ⁇ 8 using ammonium hydroxide solution to afford a solid, which was filtered, washed with water and dried under reduced pressure.
  • the -NH 2 group in compounds of formulae (lAa) and (lAb) wherein R 5 is hydrogen can be protected by reacting, for example, with tert-butyl carbamate to obtain a protected group -N(BOC)BOC.
  • lodomethane (1.5 eq.) was added to a solution of the appropriate amine (1 eq) (ex: 2-(6-((7-methylisoquinolin-1 -yl)amino)pyridazin-3-yl)isoindoline-1 ,3-dione) and cesium carbonate (1 .5 eq) in dimethylformamide at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature during 72 h. The mixture was concentrated under reduced pressure. The resultant crude was dissolved in ethyl acetate and washed with water.
  • the resultant residue was purified by flash column chromatography (dichloromethane/methanol) to obtain the desired free amine(ex: /V 3 -methyl-/V 3 -(7-methylisoquinolin-1 -yl)pyridazine-3,6-diamine).
  • Pd 2 (dba) 3 (0.05 eq) was added to a solution of the appropriate chloro derivative (1 .0 eq) (ex: 7-chloro-/V-(6-chloropyridazin-3-yl)-/V-methylisoquinolin-1 -amine), 4-methoxybenzyl amine (3.0 eq), BINAP (0.1 eq) and sodium tert-butoxide (1.5 eq) in dioxane (20 ml), and the reaction mixture was heated to 100°C for 2-3 hrs. The mixture was cooled and diluted with water (50 ml) and extracted with ethyl acetate (2 ⁇ 100 ml).
  • Trifluoroacetic acid (5 ml) was added to a solution of the appropriate protected amine (1 eq) (ex: ⁇ -(Z-Chloroisoquinolin-l -y -A ⁇ -methoxybenzy -A/ 3 - methylpyridazine-3,6-diamine) at RT and the reaction mixture was stirred at 60°C for 5-6 hrs. Trifluoroacetic acid was evaporated under reduced pressure, the resultant crude was poured in to ice-cold water and the mixture was basified using saturated sodium hydrogen carbonate solution (pH ⁇ 9).
  • tert-Butyl (5-nitropyridin-2-yl)carbamate (1 eq), Pd/C (10% w/w) and ethyl acetate was added to a flask under H 2 atmosphere. The mixture was stirred at room temperature overnight. The mixture was filtered through a celite pad and the filtrate concentrated under reduced pressure to obtain tert-butyl (5- aminopyridin-2-yl)carbamate.
  • Pd/C (10% w/w) and ethyl acetate were mixed and stirred at room temperature overnight under H 2 atmosphere.
  • the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to obtain tert-butyl (5- aminopyrimidin-2-yl)carbamate (Crude contains approximately 20% of tert-butyl (5-aminopyrimidin-2-yl)dicarbamate. Was used in the next step without purification).
  • Phosphorous pentabromide (42 g) was added to chelidemic acid (5.0 g, 0.025 mol) and heated 80°C for 3 hours. After consumption of starting materials (TLC), the reaction mixture was cooled to room temperature, diluted with chloroform (400 mL) and filtered. The filtrate was cooled to -10°C and methanol (75 mL) was added drop wise and the mixture was stirred at -10°C. After 1 h, the reaction mixture was brought to room temperature and concentrated under vacuum. The resulting residue was diluted with ice-cold water (300 mL) to afford a precipitate. The solid precipitate was filtered, washed with water and dried under vacuum to afford dimethyl 4-bromopyridine-2,6-dicarboxylate., which was taken to the next step without further purification. Crude yield: 5.2 g.
  • the obtained residue was purified by semi-preparative HPLC (Column: CHEMSIL, SEMI- PREP-ODS-C18, 10 micron (20 x 250 mm); wavelength: 210 nm; flow: 15 mL/min; run time: 15 min; time & mobile phase-gradient (time in min/B): 0/23, 9.5/23, 9.6/90, 14/90, 14.1/23, 15/23 [B: acetonitrile: methanol (50:50); A: 10 mM Ammonium acetate]) to afford compound 2,6-diaminoisonicotinonitrile (6.0 mg).
  • Intermediate 64 was prepared from intermediate 63 using general procedures A 2 , C 2 , and D 2 .
  • Compounds according to the present invention are capable of binding allosterically to mutated ⁇ -galactosidase enzyme thereby stabilizing the enzyme against denaturation and enhancing its catalytic activity.
  • the coding region of human wild-type ⁇ -galactosidase cDNA was amplified by PCR in two fragments that were ligated and cloned in a pUC18 vector. Mutations p.T420K, p.R457Q, p.Y83C and p.R201 H were generated by site- directed mutagenesis using the QuickChangeTM Site-Directed Mutagenesis XL kit (Stratagene, La Jolla, CA) according to the manufacturer's instructions. The constructs were resequenced to ensure that no spurious mutation had been introduced. For protein expression, the wild-type and mutated cDNAs were subcloned into the pcDNA3.1 expression vector.
  • COS-7 cells were cultured in 100 mm diameter tissue culture dishes with DMEM (Sigma-Aldrich, St. Louis, MO), 10% fetal bovine serum (Life Technologies S.A., Carlsbad, CA), and antibiotics.
  • DMEM Sigma-Aldrich, St. Louis, MO
  • 10% fetal bovine serum Life Technologies S.A., Carlsbad, CA
  • antibiotics for transfection with wild- type and mutant ⁇ -galactosidase cDNAs, 8x10 4 cells per well were plated in 12- well microplates. Twenty-four hours later, 1 .6 g of the corresponding plasmid mixed with 2.5 ⁇ of LipofectamineTM 2000 Reagent (Life Technologies S.A., Carlsbad, CA) was added to each well.
  • a negative control a pcDNA vector carrying antisense ⁇ -galactosidase cDNA was transfected.
  • Lysates were resuspended in 200 ⁇ of 0.9% NaCI containing 0.01 % triton X-100 lysis buffer to promote membrane disruption.
  • the cell suspension was sonicated and centrifuged at 13000 rpm 2 min to remove insoluble materials.
  • the liberated 4-MU was measured with a fluorescence reader (excitation 340 nm, emission 460 nm, Modulus Microplate Multimode Reader, Turner Biosystems). Protein quantification was determined using BCA protein assay kit (Pierce BCA Protein Assay Kit, Thermo Fisher Scientific Inc., Waltham, MA).

Abstract

The application is directed to compounds of formula (IA) : and specifically compounds of formula (I) and their salts and solvates, wherein R1, R11, R12, R13, R4, R5, n, A1, A2, and A3 are as set forth in the specification, as well as to a method for their preparation, pharmaceutical compositions comprising the same, and use thereof for the treatment and/or prevention of conditions associated with the alteration of the activity of β-galactosidase, specially galactosidase beta-1 or GLB1, including GM1 gangliosidoses and Morquio syndrome, type B.

Description

HETEROARYLAMINOISOQUINOLINES, METHODS FOR THEIR PREPARATION AND THERAPEUTIC USES THEREOF
FIELD OF THE INVENTION
The present invention is related to heteroarylaminoisoquinolines, with new processes for their preparation and to the use thereof for the treatment and/or prevention of conditions associated with the alteration of the activity of beta galactosidase, specially galactosidase beta-1 or GLB1 , including GM1 gangliosidoses and Morquio syndrome, type B.
BACKGROUND OF THE INVENTION GM1 gangliosidosis and Morquio B syndrome, both arising from beta- galactosidase (GLB1 ) deficiency, are very rare lysosomal storage diseases with an incidence of about 1 :100,000-1 :200,000 live births worldwide (Caciotti A. et al Biochim Biophys Acta 201 1 July; 1812(7) 782-890). Said conditions associated with GLB1 are known to be caused by a deficiency of the enzyme β- galactosidase due to mutations in the GLB1 gene. β-galactosidase cleaves β-galactose from different substrates, and deficiencies in its activity cause said substrates (i.e. gangliosides, and oligosaccharides carrying terminal β-linked galactose, such as ganglioside GM- 1 and glycosaminoglycans such as keratin sulfate) to accumulate in patients suffering from conditions associated with GLB1 activity such as GM1 gangliosidosis and Morquio B syndrome.
Suzuki et al. (Cell. Mol. Life Sci. 65 (2008) 351 -353) reported that the mutations of the GLB1 gene result in an unstable mutant β-galactosidase enzyme protein with normal or near-normal biological activity. The mutant enzyme protein seems to be unstable at neutral pH in the endoplasmic reticulum (ER)/Golgi apparatus, and rapidly degraded because of inappropriate molecular folding and this is the reason for its impaired activity. The authors also reported that the use of a competitive inhibitor binding to misfolded mutant protein as a molecular chaperone (i.e. a small molecule that interacts with a misfolded protein to achieve a recovery on its activity) resulted in the formation of a stable molecular complex at neutral pH. The protein-chaperone complex was safely transported to the lysosome, where it dissociated under the acidic conditions. In this way the mutant enzyme remained stabilized, and its catalytic function was enhanced.
Several patents and publications have since then explored the use of chaperones to treat conditions associated with the alteration of the activity of GLB1 : WO 2008/034575 A, WO 2006/100586 A, WO 2009/049421 A, WO 2010/046517, EP 1 433 776 A and Ogawa S. et al., Bioorg. Med. Chem. 10(6), 1967-1972 (2002).
Therefore, small molecules capable of binding allosterically to mutated β- galactosidase enzyme thereby stabilizing the enzyme against degradation (chaperones) constitute an important therapeutic target in conditions associated with the alteration of the activity of beta galactosidase, specially galactosidase beta-1 or GLB1 .
The inventors have now surprisingly found that compounds of general formula (I) are capable of binding to beta galactosidase thereby stabilizing the enzyme against denaturation.
BRIEF SUMMARY OF THE INVENTION In one aspect, the present disclosure provides compounds represented by formulae (IA), (MA), and (I), and the salts and solvates thereof, collectively referred to herein as "Compounds of the Invention" (each individually referred to hereinafter as a "Compound of the Invention").
In one aspect, the present disclosure provides compounds of formula (IA),
Figure imgf000004_0001
and salts and solvates thereof (preferably pharmaceutically acceptable salts and solvates thereof), wherein R11, R12, R13, R4, R5, A1 , A2, A3, and n are as defined below.
In another aspect of the invention, the present disclosure provides compounds of general formula I),
wherein:
Figure imgf000005_0001
• each of A1 is independently selected from the group consisting of nitrogen and C(R2);
• each of A2 and A3 is independently selected from the group consisting of nitrogen, C(R3) and C(NH2);
• wherein exactly one of A2 and A3 is C(NH2) and wherein no less than one and no more than two of A1 , A2 and A3 are nitrogen;
• each R1 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORb, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 halogen atoms, with the proviso that at least one R1 is not hydrogen;
• R2 is selected from the group consisting of hydrogen, fluorine, -CN, methyl and trifluoromethyl;
• each one of R3 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -Ci-4 alkyl, -C3-i o cycloalkyl, and 5- to 10- membered-C2-i o-heterocyclyl, said alkyl, cycloalkyl and heterocyclyl groups being optionally substituted with 1 , 2 or 3 groups each independently selected from the group consisting of halogen, hydroxy, -Ci-4 alkyl optionally substituted with 1 , 2 or 3 halogen atoms, -N(Rb)2 and methoxy, optionally substituted with 1 , 2 or 3 halogen atoms;
• n has a value selected from 0, 1 or 2; • each Ra is independently selected from the group consisting of hydrogen, -Ci-4 alkyl, -C-3-ιο cycloalkyl, -Ci-4 alkyl-C3-i o cycloalkyl, -C-6-10 aryl, -Ci-4 alkyl-C6-i o aryl, 5- to 10-membered-Ci-io heteroaryl, -Ci-4 alkyl- 5- to 10- membered-C-i-10 heteroaryl, 5- to l
Figure imgf000006_0001
heterocyclyl, -Ci-4 alkyl-5- to 10-membered-C2-io heterocyclyl; said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups optionally being substituted with 1 , 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, -CN , -ORb, -SRb, -N(Rb)2, -Ci-4alkyl optionally substituted with 1 , 2, or 3 halogen atoms, optionally substituted C-6-10 aryl, optionally substituted 5- to 10-membered-Ci-io heteroaryl and 5- to 10- membered-C2-i o heterocyclyl; and
• each Rb independently represents, on each occasion when used herein hydrogen, -Ci-4 alkyl, -C3-i0 cycloalkyl, 5- to 10-membered-C2-io heterocyclyl; said alkyl, cycloalkyl or heterocyclyl groups optionally being substituted by 1 , 2 or 3 fluorine atoms,
and solvates and salts thereof.
In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of any one of formulae (IA), (IIA), or (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein and at least one pharmaceutically acceptable excipient.
In another aspect, the present disclosure provides compounds of formulae (IA), (IIA), and (I) as defined herein, or pharmaceutically acceptable salts or solvates thereof, for use in the prevention or treatment of a condition associated with the alteration of the activity of GLB1 .
In another aspect, the present disclosure provides use of a compound of any one of formulae (IA), (IIA), or (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the preparation of a medicament for the prevention or treatment of a condition associated with the alteration of the activity of GLB1. In another aspect, the present disclosure provides a method for the prevention or treatment of a condition associated with the alteration of the activity of GLB1 , which comprises the administration to a patient needing such prevention or treatment, of a therapeutically effective amount of at least one compound of any one of formulae (IA), (IIA), and (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein.
In another aspect, the present disclosure provides a method of treating or preventing a condition associated with the alteration of the activity of GLB1 in a patient, comprising administering to the patient in need thereof an effective amount of a Compound of the Invention, or a pharmaceutically acceptable salt or solvate thereof.
In another aspect, the present disclosure provides a method of treating GM1 ganglisidosis or Morquio B syndrome in a patient, comprising administering to the patient in need thereof an effective amount of a Compound of the Invention, or a pharmaceutically acceptable salt or solvate thereof.
In another aspect, the present disclosure provides a method of increasing β-galactosidase activity in a patient in need thereof, comprising administering to the patient an effective amount of a Compound of the Invention, or a pharmaceutically acceptable salt or solvate thereof. Other aspects and advantages of the invention will be readily apparent from the following detailed description of the invention. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the invention is based on the use of Compounds of the Invention for binding allosterically to mutated β-galactosidase enzyme and, thereby, stabilizing the enzyme against denaturation. In view of this property, Compounds of the Invention are useful for preventing or treating conditions associated with the alteration of the activity of β-galactosidase, and especially galactosidase beta-1 or GLB1 , including GM1 gangliosidoses and Morquio syndrome, type B.
In one embodiment, Compounds of the Invention are compounds of formula (IA):
Figure imgf000008_0001
and the salts and solvates thereof, wherein:
• each A1 is independently selected from the group consisting of nitrogen and C(R2A);
• each of A2 and A3 is independently selected from the group consisting of nitrogen, C(R3A) and C(NH2); provided that
o exactly one of A2 and A3 is C(NH2) and wherein no less than one and no more than two of A1, A2 and A3 are nitrogen;
• R11, R12, and R13 are each independently selected from the group consisting of hydrogen, halogen, -CN, -ORbA, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, with the proviso that at least one R11 , R12, and R13 is other than hydrogen;
• R2A is selected from the group consisting of hydrogen, halogen, -CN, Ci-4 alkyl, and halo(Ci-4)alkyl;
• each one of R3A is independently selected from the group consisting of hydrogen, halogen, -CN, -ORaA, -Ci-4 alkyl, -C3-io cycloalkyl, and 5- to 10- membered heterocyclyl, said alkyl, cycloalkyl and heterocyclyl groups are optionally substituted with 1 , 2 or 3 groups each independently selected from the group consisting of halogen, hydroxy, -Ci-4 alkyl optionally substituted with 1 , 2 or 3 halogen atoms, -N(RbA)2, and Ci-4 alkoxy optionally substituted with 1 , 2 or 3 independently selected halogen atoms;
each R4 is independent selected from the group consisting of halogen,
Ci-4 alkyl, Ci-4 alkoxy, CN and hydroxy;
R5 is hydrogen or Ci-4 alkyl;
n has a value selected from 0, 1 or 2;
each RaA is independently selected from the group consisting of hydrogen, -Ci-4 alkyl, -C3-10 cycloalkyl, -Ci-4 alkyl-(C3-io)cycloalkyl, -C6-10 aryl, -Ci-4 alkyl-(C6-i o)aryl, 5- to 10-membered heteroaryl, -Ci-4 alkyl-(5- to 10-membered heteroaryl), 5- to 10-membered heterocyclyl, -Ci-4 alkyl- (5- to 10-membered heterocyclyl), wherein any of which, when other than hydrogen, is optionally being substituted with 1 , 2 or 3 groups each independently selected from the group consisting of halogen, -CN, -ORbA (for example OH), -SRbA, -N(RbA)2, -Ci-4alkyl optionally substituted with 1 , 2, or 3 independently selected halogen atoms, optionally substituted C-6-10 aryl, optionally substituted 5- to 10-membered heteroaryl, and optionally substitututed 5- to 10-membered heterocyclyl; and
each RbA is independently selected from the group consisting of hydrogen, -Ci-4 alkyl, -(C3-i o)cycloalkyl, 5- to 10-membered heterocyclyl; wherein said alkyl, cycloalkyl or heterocyclyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms.
In another embodiment, Compounds of the Invention are compounds of formula (IA), and the salts and solvates thereof, wherein one of A1 , A2 and A3 is nitrogen. In one embodiment of this aspect of the invention, one of A1 is nitrogen. In another embodiment, one of A2 is nitrogen. In another embodiment, A3 is nitrogen.
In another embodiment, Compounds of the Invention are compounds represented by formula (I IA):
Figure imgf000010_0001
(IIA)
and the salts and solvates thereof, wherein:
R4, R5, R11, R12, and R13 are as defined above for formula (IA), n is 0 or 1 , and
Het is selected from the group consisting of
Figure imgf000010_0002
Figure imgf000011_0001
Figure imgf000011_0002
wherein R and R are as defined above for formula (IA).
In one embodiment, Compounds of the Invention are compounds of formula (IIA), and the salts and solvates thereof, wherein Het is selected from the group consisting of
Figure imgf000011_0003
R and R are as defined above for formula (IA). In one embodiment, both R2A and R3A are hydrogen. In another embodiment, R2A is hydrogen and R3A is as defined for formula (IA).
In another embodiment of this aspect of the invention, Het is Het1 , Het3, Het5, or Het6, wherein R2A and R3A are as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen. In another embodiment, R2A is hydrogen and R3A is as defined for formula (IA).
In another embodiment, Het is Het2 or Het4, wherein R2A and R3A are as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen. In another embodiment, R2A is hydrogen and R3A is as defined for formula (IA).
In another embodiment, Compounds of the Invention are compounds of formula (IIA), and the salts and solvates thereof, wherein Het is Het1 , wherein R2A and R3A are as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen. In another embodiment, R2A is hydrogen and R3A is as defined for formula (IA). In another embodiment, Compounds of the Invention are compounds of formula (IIA), and the salts and solvates thereof, wherein Het is Het2, wherein R2A and R3A are as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen. In another embodiment, R2A is hydrogen and R3A is as defined for formula (IA).
In another embodiment, Compounds of the Invention are compounds of formula (IIA), and the salts and solvates thereof, wherein Het is Het4, wherein R2A and R3A are as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen. In another embodiment, R2A is hydrogen and R3A is as defined for formula (IA).
In another embodiment, Compounds of the Invention are compounds of formula (IIA), and the salts and solvates thereof, wherein Het is Het6, wherein R2A and R3A are as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen. In another embodiment, R2A is hydrogen and R3A is as defined for formula (IA).
In another embodiment, Compounds of the Invention are compounds of formula (IA), and the salts and solvates thereof, wherein two of A1, A2 and A3 are nitrogen.
In one embodiment of this aspect of the invention, Compounds of the Invention are compounds of formula (IIA), and the salts and solvates thereof, wherein Het is selected from the group consisting of
Figure imgf000013_0001
Figure imgf000013_0002
wherein R and R are as defined above for formula (IA). In one embodiment, R2A and R3A are each hydrogen. In another embodiment, R2A is hydrogen and R3A is as defined for formula (IA). In another embodiment, R2A is hydrogen and R3A is -ORaA, wherein RaA is -Ci-4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRbA, -N(RbA)2, and optionally substituted C6-io aryl, wherein RbA is each independently hydrogen or Ci-4 alkyl.
In another embodiment of this aspect of the invention, Het is Het7, Het10, Het11 , Het12, Het13, or Het16, wherein R2A and R3A are as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen. In another embodiment, R2A is hydrogen and R3A is as defined for formula (IA). In another embodiment, R2A is hydrogen and R3A is -ORaA, wherein RaA is -Ci-4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRbA, -N(RbA)2, and optionally substituted C6-io aryl, wherein RbA is each independently hydrogen or Ci-4 alkyl. In another embodiment, Het is Het8, Het9, Het14, or Het15, wherein R2A and R3A are as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen. In another embodiment, R2A is hydrogen and R3A is as defined for formula (IA). In another embodiment, R2A is hydrogen and R3A is -ORaA, wherein RaA is -Ci-4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRbA, - N(RbA)2, and optionally substituted C-6-10 aryl, wherein RbA is each independently hydrogen or Ci-4 alkyl.
In another embodiment, Compounds of the Invention are compounds of formula (IIA), and the salts or solvates thereof, wherein Het is Het8, wherein each R3A is independently as defined for formula (IA). In one embodiment, each R3A is hydrogen. In another embodiment, one R3A is hydrogen and the other one is -ORaA, wherein RaA is -Ci-4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRbA, -N(RbA)2, and optionally substituted C6-i o aryl, wherein RbA is each independently hydrogen or Ci-4 alkyl.
In another embodiment, Compounds of the Invention are compounds of formula (IIA), and the salts or solvates thereof, wherein Het is Het9, wherein R2A and R3A are as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen. In another embodiment, R2A is hydrogen and R3A is as defined for formula (IA). In another embodiment, R2A is hydrogen and R3A is -ORaA, wherein RaA is -Ci-4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRbA, -N(RbA)2, and optionally substituted C-6-10 aryl, wherein RbA is each independently hydrogen or Ci-4 alkyl.
In another embodiment, Compounds of the Invention are compounds of formula (IIA), and the salts or solvates thereof, wherein Het is Het12, wherein R2A and R3A are as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen. In another embodiment, R2A is hydrogen and R3A is as defined for formula (IA). In another embodiment, R2A is hydrogen and R3A is -ORaA, wherein RaA is -Ci-4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRbA, -N(RbA)2, and optionally substituted C-6-10 aryl, wherein RbA is each independently hydrogen or Ci-4 alkyl.
In another embodiment, Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein n is 0 or 1 , R11 and R12 are both hydrogen and R13 is selected from the group consisting of halogen, -CN, -ORbA, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein RbA is as defined above for formula (IA). In one embodiment, n is 0. In one embodiment, RbA is hydrogen or Ci-4 alkyl optionally substituted by 1 , 2 or 3 independently selected halogen atoms. In one embodiment of this aspect of the invention, Het is Het1 , Het2, Het3, Het4, Het5, or Het6. In another embodiment, Het is Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16. In another embodiment, Het is Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R2A is hydrogen and R3A is as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen.
In another embodiment, Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein n is 0 or 1 , R11 and R13 are both hydrogen and R12 is selected from the group consisting of halogen, -CN, -ORbA, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein RbA is as defined above for formula (IA). In one embodiment, n is 0. In one embodiment, RbA is hydrogen or Ci-4 alkyl optionally substituted by 1 , 2 or 3 independently selected halogen atoms. In one embodiment of this aspect of the invention, Het is Het1 , Het2, Het3, Het4, Het5, or Het6. In another embodiment, Het is Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16. In another embodiment, Het is Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R2A is hydrogen and R3A is as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen. In another embodiment, Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein n is 0 or 1 , R12 and R13 are both hydrogen and R11 is selected from the group consisting of halogen, -CN, -ORbA, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein RbA is as defined above for formula (IA). In one embodiment, n is 0. In one embodiment, RbA is hydrogen or Ci-4 alkyl optionally substituted with 1 , 2, or 3 independently selected halogen atoms. In one embodiment of this aspect of the invention, Het is Het1 , Het2, Het3, Het4, Het5, or Het6. In another embodiment, Het is Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16. In another embodiment, Het is Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R2A is hydrogen and R3A is as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen. In another embodiment, Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein n is 0 or 1 , R11 is hydrogen and R12 and R13 are each independently selected from the group consisting of halogen, -CN, -ORbA, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein RbA is as defined above for formula (IA). In one embodiment, n is 0. In one embodiment, RbA is hydrogen or Ci-4 alkyl optionally substituted with 1 , 2, or 3 independently selected halogen atoms. In one embodiment of this aspect of the invention, Het is Het1 , Het2, Het3, Het4, Het5, or Het6. In another embodiment, Het is Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16. In another embodiment, Het is Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R2A is hydrogen and R3A is as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen.
In another embodiment, Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein n is 0 or 1 , R12 is hydrogen and R11 and R13 are each independently selected from the group consisting of halogen, -CN, -ORbA, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein RbA is as defined above for formula (IA). In one embodiment, n is 0. In one embodiment, RbA is hydrogen or Ci-4 alkyl optionally substituted with 1 , 2, or 3 independently selected halogen atoms. In one embodiment of this aspect of the invention, Het is Het1 , Het2, Het3, Het4, Het5, or Het6. In another embodiment, Het is Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16. In another embodiment, Het is Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R2A is hydrogen and R3A is as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen.
In another embodiment, Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein n is 0 or 1 , R13 is hydrogen and R11 and R12 are each independently selected from the group consisting of halogen, -CN, -ORbA, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein RbA is as defined above for formula (IA). In one embodiment, n is 0. In one embodiment, RbA is hydrogen or Ci-4 alkyl optionally substituted with 1 , 2, or 3 independently selected halogen atoms. In one embodiment of this aspect of the invention, Het is Het1 , Het2, Het3, Het4, Het5, or Het6. In another embodiment, Het is Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16. In another embodiment, Het is Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R2A is hydrogen and R3A is as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen.
In another embodiment, Compounds of the Invention are compounds of formula (I IA), and the salts and solvates thereof, wherein n is 0 or 1 , R11, R12 and R13 are each independently selected from the group consisting of halogen, -CN, -ORbA, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein RbA is as defined above for formula (IA). In one embodiment, n is 0. In another embodiment, Compounds of the Invention are compounds of formula (MA), and the salts and solvates thereof, wherein R11 , R12, and R13, when other than hydrogen, are each independently selected from the group consisting of chlorine, fluorine, -CN, unsubstituted Ci-4 alkyl (such as methyl or ethyl), Ci-4 alkyl substituted with 1 , 2 or 3 fluorine atoms (such as fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 1 , 1 -difluoroethyl, or 1 , 1 , 1 - trifluoroethyl), and -ORbA, wherein RbA is hydrogen, unsubstituted Ci-4 alkyl (such as methyl or ethyl) or Ci-4 alkyl substituted with 1 , 2 or 3 fluorine atoms (such as fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 1 , 1 - difluoroethyl, or 1 , 1 , 1 -trifluoroethyl). Preferably, R11, R12, and R13, when other than hydrogen, are each independently selected from the group consisting of chlorine and -ORbA, wherein RbA is hydrogen or unsubstituted Ci-4 alkyl. In one embodiment, RbA is hydrogen or Ci-4 alkyl. In one embodiment, n is 0. In one embodiment of this aspect of the invention, Het is Het1 , Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9, Het10, Het11, Het12, Het13, Het14, Het15, or Het16, and preferably Het1, Het2, Het4, Het6, Het8, Het9, or Het12, wherein R2A is hydrogen and R3A is as defined for formula (IA). In one embodiment, both R2A and R3A are hydrogen.
In another embodiment, Compounds of the Invention are compounds of any of formulae (IA) and (MA), and the salts and solvates thereof, wherein R5 is hydrogen. In another embodiment, Compounds of the Invention are compounds of any of formulae (IA) and (MA), and the salts and solvates thereof, wherein R5 is Ci-4 alkyl. In one embodiment, R5 is methyl or ethyl, and preferably methyl.
In another embodiment, Compounds of the Invention are compounds of any one of formulae (IA) and (MA), and the salts and solvates thereof, wherein n is 0. In another embodiment, n is 1 or 2, and preferably n is 1 .
In another embodiment, Compounds of the Invention are compounds of any one of formulae (IA) and (MA), and the salts and solvates thereof, wherein n is 1 and R4 is selected from the group consisting of chlorine, fluorine, bromine, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, methoxy, ethoxy, tert- butoxy, CN and hydroxy. In another embodiment, R4 is fluorine. In another embodiment, Compounds of the Invention are compounds of any one of formulae (IA) and (IIA), and the salts and solvates thereof, wherein R2A is hydrogen, fluorine, chlorine, -CN, Ci-4 alkyl, fluoro(Ci-4)alkyl, di-fluoro(C-|. 4)alkyl, and trifluoro(Ci-4)alkyl; and preferably R2A is hydrogen, fluorine, -CN, methyl, and trifluoromethyl; and more preferably R2A is hydrogen or fluorine; and more preferably R2A is hydrogen.
In another embodiment, Compounds of the Invention are compounds of any one of formulae (IA) and (IIA), and the pharmaceutically acceptable salts and solvates thereof, wherein each R3A is independently selected from the group consisting of hydrogen, halogen, -CN, -ORaA, -Ci-4 alkyl, -C3-io cycloalkyl, and 5- to 10- membered heterocyclyl, said alkyl, cycloalkyl and heterocyclyl groups being optionally substituted with 1 , 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, -Ci-4 alkyl optionally substituted with 1 , 2 or 3 halogen atoms, -N(RbA)2 and methoxy, optionally substituted with 1 , 2 or 3 halogen atoms, wherein each RbA independently is hydrogen, Ci-4 alkyl, C3-io cycloalkyl, 5- to 10-membered heterocyclyl, said, alkyl, cycloalkyl and heterocyclyl groups optionally being substituted by 1 , 2, or 3 fluorine atoms. In another embodiment, each R3A is independently selected from hydrogen, fluorine, -CN, -ORaA, and Ci-4 alkyl, wherein RaA is as defined for formula (IA). In one embodiment, RaA is selected from the group consisting of hydrogen, -Ci-4 alkyl, -C-3-ιο cycloalkyl, -Ci-4 alkyl- (C3-io)cycloalkyl, -C6-io aryl, -Ci-4 alkyl-(C6-io)aryl, 5- to 10-membered heteroaryl, -Ci-4 alkyl-(5- to 10-membered heteroaryl), 5- to 10-membered heterocyclyl, -Ci-4 alkyl-(5- to 10-membered heterocyclyl); said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are optionally substituted with 1 , 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORbA, -SRbA, -N(RbA)2, -Ci-4alkyl optionally substituted with 1 , 2, or 3 halogen atoms, optionally substituted C-6-10 aryl, optionally substituted, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl, wherein RbA is hydrogen or Ci-4 alkyl. In another embodiment, RaA is -Ci-4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRbA, -N(RbA)2, and optionally substituted C-6-10 aryl, wherein RbA is each independently hydrogen or Ci-4 alkyl. In another embodiment, RaA is selected from the group consisting of hydrogen, unsubstituted Ci-4 alkyl, C3-i0 cycloalkyl, -Ci-4 alkyl-(C3-io)cycloalkyl, C-6-10 aryl, and -Ci-4 alkyl-(C6-io)aryl, and preferably, hydrogen, unsubstituted Ci-4 alkyl (such as, for example, methyl, ethyl, iso- propyl, and tert-butyl), C6-10 aryl (such as, for example, phenyl and naphthyl), and -Ci-4 alkyl-(C6-io)aryl (such as, for example, benzyl, phenethyl, and naphthylmethyl), and more preferably hydrogen or Ci-4 alkyl. In another embodiment, R3A is hydrogen or -ORaA, wherein RaA is as defined above. In another embodiment, R3A is hydrogen, fluorine, -CN, and Ci-4 alkyl. In another embodiment, R3A is hydrogen.
In another embodiment, Compounds of the Invention are compounds of formula (IA) represented by the formula (I),
Figure imgf000020_0001
wherein:
• each of A1 is independently selected from the group consisting of nitrogen and C(R2);
• each of A2 and A3 is independently selected from the group consisting of nitrogen, C(R3) and C(NH2);
• wherein exactly one of A2 and A3 is C(NH2) and wherein no less than one and no more than two of A1, A2 and A3 are nitrogen;
• each R1 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORb, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 halogen atoms, with the proviso that at least one R1 is not hydrogen; • R2 is selected from the group consisting of hydrogen, fluorine, -CN, methyl and trifluoromethyl;
• each one of R3 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -Ci-4 alkyl, -C3-i 0 cycloalkyl, and 5- to 10- membered-C2-i o heterocyclyl, said alkyl, cycloalkyl and heterocyclyl groups being optionally substituted with 1 , 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, -Ci -4 alkyl optionally substituted with 1 , 2 or 3 halogen atoms, -N(Rb)2 and methoxy, optionally substituted with 1 , 2 or 3 halogen atoms;
• n has a value selected from 0, 1 or 2;
• each Ra independently is selected from the group consisting of hydrogen, -Ci-4 alkyl, -C3-10 cycloalkyl, -Ci -4 alkyl-(C3-i o)cycloalkyl, -C6-10 aryl, -Ci -4 alkyl-(C6-i o)aryl, 5- to 10-membered-Ci -i o heteroaryl, -Ci-4 alkyl-5- to 10-membered-Ci -i o heteroaryl, 5- to 10-membered-C2-i o heterocyclyl, -Ci-4 alkyl-5- to 10-membered-C2-i o heterocyclyl; said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups optionally being substituted with 1 , 2 or 3 groups independently selected from halogen, hydroxy, -CN, -ORb, -SRb, -N(Rb)2, -C1 -4alkyl optionally substituted with 1 , 2, or 3 halogen atoms, optionally substituted C-6-10 aryl, optionally substituted, 5- to 10-membered-Ci -i o heteroaryl and 5- to 10-membered-C2-i o heterocyclyl; and
• each Rb independently represents, on each occasion when used herein hydrogen, -Ci -4 alkyl, -C3-i o cycloalkyl, 5- to 10-membered-C2-i o heterocyclyl; said alkyl, cycloalkyl or heterocyclyl groups optionally being substituted by 1 , 2 or 3 independently fluorine atoms;
or a solvate or a salt thereof.
In another embodiment, Compounds of the Invention are compounds of formula (I), wherein:
• each of A1 is independently selected from the group consisting of nitrogen and C(R2), each of A2 and A3 is independently selected from the group consisting of nitrogen, C(R3) and C(NH2),
wherein exactly one of A2 and A3 is C(NH2) and wherein no less than one and not more than two of A1, A2 and A3 are nitrogen,
each R1 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORb, and -Ci-4 alkyl wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 halogen atoms, with the proviso that at least one R1 is not hydrogen,
R2 is selected from the group consisting of hydrogen, fluorine, -CN, methyl and trifluoromethyl,
each one of R3 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -Ci-4 alkyl, -C3-i o cycloalkyl, and 5- to 10- membered-C2-9 heterocyclyl, said alkyl, cycloalkyl and heterocyclyl groups being optionally substituted with 1 , 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, -Ci-4 alkyl optionally substituted with 1 , 2 or 3 halogen atoms, -N(Rb)2 and methoxy, optionally substituted with 1 , 2 or 3 halogen atoms;
n has a value selected from 0, 1 or 2;
each Ra independently is selected from the group consisting of hydrogen, -Ci-4 alkyl, -C3-10 cycloalkyl, -Ci-4 alkyl-(C3-io)cycloalkyl, -C6-10 aryl, -Ci-4 alkyl-(C6-io)aryl, 5- to 10-membered-C 1-9 heteroaryl, -Ci-4 alkyl- 5- to I O-membered-C-i-9 heteroaryl, 5- to 10-membered-C2-9 heterocyclyl, -Ci-4 alkyl-5- to 10-membered-C2-9 heterocyclyl; said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups optionally being substituted with 1 , 2 or 3 groups independently selected from halogen, hydroxy, -CN, -ORb, -SRb, -N(Rb)2, -Ci-4alkyl optionally substituted with 1 , 2, or 3 halogen atoms, optionally substituted C6-io aryl, optionally substituted 5- to 10- membered-C-i-9 heteroaryl and 5- to 10-membered-C2-9 heterocyclyl. each Rb independently represent, on each occasion when used herein hydrogen, -Ci-4 alkyl, -C3-io cycloalkyl,- 5- to 10-membered-C2-9 heterocyclyl; said alkyl, cycloalkyl or heterocyclyl groups optionally being substituted by 1 , 2 or 3 independently fluorine atoms
or a solvate or a salt thereof.
As defined above for compounds of any one of formulae (IA), (IIA), and (I), it is required that exactly one of A2 and A3 is C(NH2) and this means that the six-membered aromatic ring attached to the isoquinolin-1 -ylamine moiety comprises one and only one C(NH2) rest at one of the ring's meta (A2) or para (A3) positions with respect to the carbon atom through which said ring is attached to said isoquinolin-1 -ylamine moiety. In the above mentioned definitions for compounds of any one of formulae
(IA), (IIA), and (I), it is also required that no less than one and no more than two of A1 , A2 and A3 are nitrogen and this intends to limit the six-membered aromatic ring attached to the isoquinolin-1 -ylamine moiety to optionally substituted pyridine or optionally substituted pyrimidine rings. In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein n has a value of zero. In another embodiment, n has a value of 1 .
In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein one of A1 is nitrogen. In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein both of A1 are nitrogen. In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein when A1 is C(R2) and R2 is as defined for formula (I). In another embodiment, R2 is hydrogen or fluorine. In another embodiment, R2 is hydrogen.
In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein one of A2 is C(NH2).
In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein A3 is C(NH2). In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein one of A2 is C(R3), wherein R3 is as defined above for formula (I). In one embodiment, R3 is selected from the group consisting of hydrogen, fluorine, CN, -ORa, and Ci-4 alkyl. In another embodiment, R3 is hydrogen or -ORa. Preferably, Ra is selected from the group consisting of hydrogen, Ci-4 alkyl, C-3-ιο cycloalkyl, -Ci-4 alkyl-(C3- i o)cycloalkyl, C-6-10 aryl, and -Ci-4 alkyl-(C6-i o)aryl, and more preferably selected from the group consisting of hydrogen, Ci-4 alkyl, C6-i o aryl, and -Ci-4 alkyl-(C6- i o)aryl. In another embodiment, Ra is hydrogen or Ci-4 alkyl. In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein A3 is C(R3), wherein R3 is as defined above for formula (I). In one embodiment, R3 is selected from the group consisting of hydrogen, fluorine, CN, -ORa, and Ci-4 alkyl. In another embodiment, R3 is hydrogen or -ORa. Preferably, Ra is selected from the group consisting of hydrogen, Ci-4 alkyl, C3-io cycloalkyl, -Ci-4 alkyl-(C3- i o)cycloalkyl, C-6-10 aryl, and -Ci-4 alkyl-(C6-i o)aryl, and more preferably selected from the group consisting of hydrogen, Ci-4 alkyl, C6-i o aryl, and -Ci-4 alkyl-(C6- i o)aryl. In another embodiment, Ra is hydrogen or Ci-4 alkyl. In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein one only of A1 , A2 and A3 is nitrogen.
In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein two of A1 , A2 and A3 are nitrogen.
In another embodiment, compounds of formula (I) include those where R1 is selected from the group consisting of hydrogen, halogen, CN , -ORb, and Ci-4 alkyl, and preferably selected from the group consisting of hydrogen, chlorine, CN , and -ORb. More preferably, R1 is chlorine or -ORb. In one embodiment, Rb is hydrogen or Ci-4 alkyl, wherein the Ci-4 alkyl is optionally substituted with 1 , 2, or 3 fluorine atoms.
In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein one or two of R1 are hydrogen. In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein the substituents R1 at positions 5 and 6 of the isoquinoline ring are hydrogen and the substituent R1 at position 7 of the isoquinoline ring is as defined above for formula (I), and preferably is selected from the group consisting of chlorine, methyl, trifluoromethyl and -ORb wherein Rb is selected from the group consisting of methyl and trifluoromethyl.
In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein the substituents R1 at positions 6 and 7 of the isoquinoline ring are hydrogen and the substituent R1 at position 5 of the isoquinoline ring is as defined above for formula (I), and preferably is selected from the group consisting of chlorine and -ORb wherein Rb is selected from the group consisting of methyl and trifluoromethyl.
In another embodiment, the present disclosure provides a compound selected from the group consisting of: N2-(5-chloroisoquinolin-1 -yl)pyridine-2,6-diamine,
N4-(7-chloroisoquinolin-1 -yl)pyrimidine-2,4-diamine,
N2-(7-chloroisoquinolin-1 -yl)pyridine-2,6-diamine,
N2-(5,7-dichloroisoquinolin-1 -yl)pyridine-2,6-diamine,
N2-(5-(trifluoromethyl)isoquinolin-1 -yl)pyridine-2,6-diamine,
N2-(7-(trifluoromethoxy)isoquinolin-1 -yl)pyridine-2,6-diamine,
N2-(5-(trifluoromethoxy)isoquinolin-1 -yl)pyridine-2,6-diamine,
N2-(7-methoxyisoquinolin-1 -yl)pyridine-2,6-diamine,
N2-(7-chloroisoquinolin-1 -yl)pyrazine-2,5-diamine,
N2-(7-chloroisoquinolin-1 -yl)-4-(pyridin-3-yloxy)pyridine-2,6-diamine, N4-(7-chloroisoquinolin-1 -yl)pyridine-2,4-diamine,
N4-(5-chloroisoquinolin-1 -yl)pyridine-2,4-diamine,
N2-(7-chloroisoquinolin-1 -yl)-3-fluoropyridine-2,6-diamine,
N2-(7-chloroisoquinolin-1 -yl)pyrimidine-2,4-diamine,
N5-(7-chloroisoquinolin-1 -yl)pyridine-2,5-diamine, and
N2-(7-chloroisoquinolin-1 -yl)pyridine-2,5-diamine,
and the salts and solvates thereof. In another embodiment, the present disclosure provides a compound selected from the group consisting of:
/V3-(7-chloroisoquinolin-1 -yl)pyridine-3,5-diamine,
/V3-(7-chloroisoquinolin-1 -yl)pyridazine-3,6-diamine,
/V4-(7-chloroisoquinolin-1 -yl)pyrimidine-4,6-diamine,
/V2-(7-chloroisoquinolin-1 -yl)pyrazine-2,5-diamine,
/V2-(7-methylisoquinolin-1 -yl)pyridine-2,6-diamine,
/V3-(7-methylisoquinolin-1 -yl)pyridazine-3,6-diamine,
/V2-(7-methoxyisoquinolin-1 -yl)pyrazine-2,6-diamine,
/V3-(7-methoxyisoquinolin-1 -yl)pyridazine-3,6-diamine,
/V2-(5-(trifluoromethyl)isoquinolin-1 -yl)pyrazine-2,6-diamine,
/V3-(5-chloroisoquinolin-1 -yl)pyridazine-3,6-diamine,
/V2-(6-chloroisoquinolin-1 -yl)pyridine-2,6-diamine,
/V3-(6-chloroisoquinolin-1 -yl)pyridazine-3,6-diamine,
/V2-(5,6-dichloroisoquinolin-1 -yl)pyridine-2,6-diamine,
/V2-(5-methoxyisoquinolin-1 -yl)pyridine-2,6-diamine,
/V2-(5-methoxyisoquinolin-1 -yl)pyrazine-2,6-diamine,
/V2-(7-chloroisoquinolin-1 -yl)-4-methylpyridine-2,6-diamine,
1 -((6-aminopyridin-2-yl)amino)isoquinoline-7-carbonitrile,
1 - ((6-aminopyrazin-2-yl)amino)isoquinoline-7-carbonitrile,
2- amino-6-((7-chloroisoquinolin-1 -yl)amino)isonicotinonitrile,
/V2-(5-chloroisoquinolin-1 -yl)pyrazine-2,6-diamine,
/V2-(7-chloroisoquinolin-1 -yl)-4-methoxypyridine-2,6-diamine,
/V2-(7-chloroisoquinolin-1 -yl)-4-(4-chlorophenoxy)pyridine-2,6-diamine, /V5-(7-chloroisoquinolin-1 -yl)pyrimidine-2,5-diamine,
/V4-(7-methoxyisoquinolin-1 -yl)pyridine-2,4-diamine,
/V5-(7-methylisoquinolin-1 -yl)pyridine-2,5-diamine,
/V5-(7-methoxyisoquinolin-1 -yl)pyridine-2,5-diamine,
/V5-(5-chloroisoquinolin-1 -yl)pyridine-2,5-diamine,
/V4-(7-chloroisoquinolin-1 -yl)-/V4-methylpyridine-2,4-diamine,
/V5-(7-chloroisoquinolin-1 -yl)-/V5-methylpyridine-2,5-diamine,
/V2-(7-chloroisoquinolin-1 -yl)pyrimidine-2,5-diamine, /V2-(7-chloroisoquinolin-1 -yl)pyridine-2,4-diamine,
/V2-(7-methoxyisoquinolin-1 -yl)pyndine-2,5-diamine,
/V2-(7-methoxyisoquinolin-1 -yl)pynmidine-2,5-diamine,
/V2-(5-chloroisoquinolin-1 -yl)pyridine-2,5-diamine,
/V2-(5-methoxyisoquinolin-1 -yl)pyrimidine-2,5-diamine,
/V4-(7-chloroisoquinolin-1 -yl)-6-(2-(methylamino^
diamine;
/V3-methyl-/V3-(7-methylisoquinolin-1 -yl)pyndazine-3,6-diamine,
/V2-(7-chloroisoquinolin-1 -yl)-/V2-methylpyridine-2,6-diamine,
/V2-(7-methoxyisoquinolin-1 -yl)-/V2-methylpyridine-2,6-diamine,
1 - ((6-aminopyridin-2-yl)(methyl)amino)isoquinoline-7-carbonitnle,
/V2-(7-chloroisoquinolin-1 -yl)-/V2-methylpyrazine-2,6-diamine,
/V3-(7-chloroisoquinolin-1 -yl)-/V3-methylpyridazine-3,6-diamine,
/V3-(7-methoxyisoquinolin-1 -yl)-/V3-methylpyridazine-3,6-diamine,
1 -((6-aminopyridazin-3-yl)(methyl)amino)isoquinoline-7-carbonitnle, and
2- amino-6-((7-chloroisoquinolin-1 -yl)amino)pyridin-4-ol,
and the salts and solvates thereof.
In another aspect, the present disclosure provides compounds useful as synthesis intermediates in the preparation of Compounds of the Invention. These compounds for use as synthesis intermediates are compounds of formulae (IA), (IIA), and (I), and their salts or solvates thereof, wherein at least one amino group is protected by an amine protecting group.
The term "amine protecting group" or "amino protecting group" as used herein refers to a group that blocks (i.e., protects) the amine functionality while reactions are carried out on other functional groups or parts of the molecule. Those skilled in the art will be familiar with the selection, attachment, and cleavage of amine protecting groups and will appreciate that many different protective groups are know in the art, the suitability of one protective group or another being dependent on the particular synthetic scheme planned. Treatises on the subject are available for consultation, such as Wuts, P. G. M. & Greene, T. W., Greene's Protective Groups in Organic Synthesis, 4rd Ed. (J. Wiley & Sons, 2007), herein incorporated by reference in its entirety. Suitable amine protecting groups include methyl carbamate, fe/f-butyloxycarbonyl (tert-butyl carbamate; BOC), 9-fluorenylmethyl carbamate, benzyl carbamate, 2- (trimethylsilyl)ethyl carbamate, trifluoroacetamide, benzylamine, allylamine, tritylamine, trichloroacetyl, trifluoroacetyl, p-toluenesulfonyl, and allyl carbamate. In one embodiment, the protected amino group can be a phthalimide-protected amino group (NPhth).
The compounds of formulae (IA), (IIA), and (I) can be in the form of solvates or salts, preferably wherein the solvating agents and/or the salt's counter-ions are pharmaceutically acceptable species.
As used herein, the terms "halogen" or "halo" refer to -F, -CI, -Br or -I.
As used herein, the term "hydroxyl" or "hydroxy" refers to the group -OH,
As used herein, the term "alkyl" refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, which is attached to the rest of the molecule by a single bond and, unless otherwise specified, an alkyl radical typically has from 1 to 4 carbon atoms. Exemplary alkyl groups can be methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, i-butyl and sec-butyl. In one embodiment, the alkyl is d-2 alkyl (methyl or ethyl). As used herein, the term "halo(Ci-4)alkyl" refers to any of the above- mentioned Ci-4 alkyl groups, substituted by one or more halogen atoms (fluorine, chlorine, bromine or iodine atoms) (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1 ,1 -difluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups). In one embodiment, halo(Ci-4)alkyl is monohalo(Ci-4)alkyl. The term "monohalo(Ci-4)alkyl" indicates that the Ci-4 alkyl group is substituted by exactly one halogen atom. The term "dihalo(Ci-4)alkyl" means that the Ci-4 alkyl group is substituted by two halogen atoms. The term "trihalo(Ci-4)alkyl" means that the Ci-4 alkyl group is substituted by three halogen atoms. The halogen atoms can be attached to the same or different carbon atoms. The one or more halogen atoms can be the same or different. As used herein, the term "Ci-4 alkoxy" refers to oxygen substituted by one of the Ci-4 alkyl groups mentioned above (e.g., methoxy, ethoxy, propoxy, iso-propoxy, butoxy, tert-butoxy, iso-butoxy, and sec-butoxy), preferably by one of the C-i-2 alkyl groups. As used herein, the term "cycloalkyl" embraces saturated carbocyclic radicals and, unless otherwise specified, a cycloalkyl radical typically has from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. It is preferably cyclopropyl, cyclopentyl and cyclohexyl. In one embodiment, the cycloalkyl group is C-3-ι ο cycloalkyl. As used herein, the term "alkylcycloalkyl" when employed in the definition of a substituent refers to a cycloalkyl group which is linked through an alkylene radical with the core structure which it substitutes. As an example, a cyclopentylethyl substituent is a substituent consisting of a cyclopentyl group linked through an ethylene group to the core structure which it substitutes. As used herein, the terms "heterocyclyl" or "heterocyclic group" embrace typically a monocyclic or polycyclic, non-aromatic, saturated or unsaturated C2- 10 carbocyclic ring, such as a 5 to 10 membered radical, in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S. In one embodiment, a heterocyclyl is a C3-7 heterocyclyl.
Saturated heterocyclyl radicals are preferred. A heterocyclic radical may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom. When a heterocyclyl radical carries one or more substituents, the substituents may be the same or different. A said optionally substituted heterocyclyl is typically unsubstituted or substituted with 1 , 2 or 3 substituents which may be the same or different. Examples of heterocyclic radicals include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazolinyl, pyrazolidinyl, quinuclidinyl, tetrazolyl, cromanyl, isocromanyl, imidazolidinyl, oxiranyl, azaridinyl, 4,5- dihydro-oxazolyl and 3-aza-tetrahydrofuranyl. As used herein, the term "alkylheterocyclyl" when employed in the definition of a substituent refers to a heterocyclyl group as defined above which is linked through an alkylene radical with the core structure which it substitutes.
As used herein, the term "aryl" designates typically a C-6-10 monocyclic or polycyclic aryl radical such as phenyl and naphthyl. Phenyl is preferred. A said optionally substituted aryl radical is typically unsubstituted or substituted with 1 , 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine or chlorine atoms, hydroxy groups, alkoxycarbonyl groups in which the alkyl moiety has from 1 to 4 carbon atoms, hydroxycarbonyl groups, carbamoyl groups, nitro groups, cyano groups, Ci-4 alkyl groups optionally substituted by one or more halogen atoms, Ci-4 alkoxy groups, optionally substituted by one or more halogen atoms and d. 4 hydroxyalkyl groups. When an aryl radical carries 2 or more substituents, the substituents may be the same or different. Unless otherwise specified, the substituents on an aryl group are typically themselves unsubstituted.
As used herein, the term "alkylaryl" when employed in the definition of a substituent refers to an aryl group as defined above which is linked through an alkylene radical with the core structure which it substitutes.
As used herein, the term "heteroaryl" designates typically a 5- to 10- membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N, typically 1, 2, 3 or 4 heteroatoms.
A heteroaryl group may comprise a single ring or two or more fused rings wherein at least one ring contains a heteroatom. A said optionally substituted heteroaryl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine, chlorine or bromine atoms, alkoxycarbonyl groups in which the alkyl moiety has from 1 to 4 carbon atoms, carbamoyl groups, nitro groups, hydroxy groups, Ci-4 alkyl groups, optionally substituted by one or more halogen atoms and Ci-4 alkoxy groups, optionally substituted by one or more halogen atoms. When an heteroaryl radical carries 2 or more substituents, the substituents may be the same or different. Unless otherwise specified, the substituents on a heteroaryl radical are typically themselves unsubstituted.
Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, tetrazolyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, pyridinyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl, 1 H-pyrazolo[3,4- d]pyrimidinyl, thieno[2,3-d]pyrimi-dinyl and the various pyrrolopyridyl radicals.
The mention of optionally substituted heteroaryl radicals or rests within the present invention is intended to cover the N-oxides obtainable from these radicals when they comprise N-atoms. As used herein, the term "alkylheteroaryl" when employed in the definition of a substituent refers to an heteroaryl group as defined above which is linked through an alkylene radical with the core structure which it substitutes.
The term "pharmaceutically acceptable species" refers to compositions and molecular entities that are physiologically tolerable and do not typically produce an allergic reaction or a similar unfavorable reaction as gastric disorders, dizziness and suchlike, when administered to a human or animal. Preferably, the term "pharmaceutically acceptable" means it is approved by a regulatory agency of a state or federal government or is included in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
The term "treatment" or "treating" refers to administering a therapy in an amount, manner or mode effective to improve a condition, symptom, or parameter associated with a condition or to prevent progression of a condition, to either a statistically significant degree or to a degree detectable to one skilled in the art. An effective amount, manner, or mode can vary depending on the subject and may be tailored to the patient. The term "about", as used herein in connection with a measured quantity, refers to the normal variations in that measured quantity, as expected by the skilled artisan making the measurement and exercising a level of care commensurate with the objective of measurement and precision of the measuring equipment. Typically, the term "about" includes the recited number ± 10%. Thus, "about 10" means 9 to 1 1 .
As used herein, the term "optionally substituted" refers to a group that may be unsubstituted or substituted.
The term "solvate" means any form of the active compound of the invention which has another molecule (for example a polar solvent such as water or ethanol, a cyclodextrin or a dendrimer) attached to it through noncovalent bonds. Methods of solvation are known within the art.
The invention also provides salts of the compounds of the invention. Non-limiting examples are sulphates; hydrohalide salts; phosphates; lower alkane sulphonates; arylsulphonates; salts of d-2o aliphatic mono-, di- or tribasic acids which may contain one or more double bonds, an aryl nucleus or other functional groups such as hydroxy, amino, or keto; salts of aromatic acids in which the aromatic nuclei may or may not be substituted with groups such as hydroxyl, lower alkoxyl, amino, mono- or di- lower alkylamino sulphonamido. Also included within the scope of the invention are quaternary salts of the tertiary nitrogen atom with lower alkyl halides or sulphates, and oxygenated derivatives of the tertiary nitrogen atom, such as the N-oxides. In preparing dosage formulations, those skilled in the art will select the pharmaceutically acceptable salts. Solvates and salts can be prepared by methods known in the state of the art. Note that the non-pharmaceutically acceptable solvates also fall within the scope of the invention because they can be useful in preparing pharmaceutically acceptable salts and solvates.
The compounds of the invention also seek to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a carbon enriched in 11C, 13C or 14C or the replacement of a nitrogen by a 15N enriched nitrogen are within the scope of this invention.
Some of the compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, such as epimers. The present invention is meant to encompass the uses of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers may be separated according to methods known to those of ordinary skill in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention as well. As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
The term "chiral center" refers to a carbon atom to which four different groups are attached.
The term "epimer" refers to diastereomers that have opposite configuration at only one of two or more tetrahedral streogenic centres present in the respective molecular entities.
The term "stereogenic center" is an atom, bearing groups such that an interchanging of any two groups leads to a stereoisomer.
The terms "enantiomer" and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction. The term "racemic" refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.
The term "resolution" refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule. The terms "a" and "an" refer to one or more.
Synthesis of Compounds of the Invention
Another aspect of the invention refers to procedures to obtain compounds of general formulae (IA), (IIA), and (I). Compounds of the Invention can be prepared using methods known to those skilled in the art in view of this disclosure, or by illustrative methods shown in the schemes below.
The following methods describe the procedures for obtaining compounds of general formula (I), or solvates or salts thereof.
Scheme 1 illustrates the different synthetic paths to obtain compounds of formula (I) wherein one of A2 is C(NH2). These compounds have formula (la). Scheme 2 illustrates the different synthetic paths to obtain compounds of formula (I) wherein one of A3 is C(NH2). These compounds have formula (lb).
The two schemes are virtually identical with the exception of the position of the amino group in the six membered ring attached to the aminoisoquinoline. Therefore the different reactions A to G and their conditions will be described together for the two Schemes.
Compounds of formulae (IA) and (IIA) can be prepared similarly following the procedures A to G. Compounds of formulae (IA) and (IIA) where R5 is Ci-4 alkyl can be prepared, for example, by following the procedures H, I and J below.
Figure imgf000035_0001
10 Scheme 2
Figure imgf000036_0001
Method 1
Step 1
In a first method according to the invention a compound of formula (II), wherein R1 and n are as defined in the first aspect of the invention and LG1 is a leaving group, is reacted with a compound of formula (III), wherein A1, A2 and A3 are as defined in the first aspect of the invention, to yield a compound of formula (VI) as illustrated in reaction A of the schemes above.
Reaction A is used to prepare compounds of formulae (Via) or (Vlb) by reaction of a compound of formulae (Ilia) or (lllb) respectively with a compound of formula (II) wherein LG1 represents a leaving group such as iodo, bromo, chloro or a sulphonate group (e.g. -OS(0)2CF3, -OS(0)2CH3 or -OS(0)2PhMe). Said reaction may be performed under standard conditions in the presence of a suitable base such as pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, or mixtures thereof, and an appropriate solvent such as pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, dimethylsulphoxide, water or mixtures thereof and, for example, at around room temperature or above, or under microwave irradiation reaction conditions.
The reaction may also be carried out in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc)2, Cul (or Cul/diamine complex) copper tris(triphenyl-phosphine)bromide, Pd(OAc)2, tris(dibenzylideneacetone) dipalladium(O) (Pd2(dba)3) or N 1CI2 and also optionally in the presence of an additive such as Ph3P, 2,2'- bis(diphenylphosphino)-1 , 1 '-binaphthyl, xantphos, Nal or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as sodium hydride, triethylamine, pyridine, N,N'-dimethylethylenediamine, sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, sodium tert-butoxide or potassium tert-butoxide (or a mixture thereof, optionally in the presence of 4A molecular sieves), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran) or a mixture thereof.
This reaction may be carried out under microwave irradiation reaction conditions.
The reaction mixture may be stirred at room temperature or heated until the starting materials have been consumed. The reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3rd Edition, New York, 1999). Step 2
The nitro group of the compound of formulae (Via) or (Vlb) is subsequently reduced to a primary amine group to yield the compound of formulae (la) or (lb) respectively according to the invention as illustrated in reaction B of the schemes above. Reaction B is carried out with a suitable reducing agent such as Fe, SnC , Raney Nickel and H2/Pt02. The reaction may be carried out in the presence of and acid such as acetic acid and in a suitable solvent such as ethyl acetate, water, methanol, ethanol and/or tetrahydrofuran. Other reducing agents or acids may be employed, as is known by the person skilled in the art. The reaction mixture is stirred at room temperature, or heated until the starting materials have been consumed. The reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3rd Edition, New York, 1999).
Method 2
In a second method according to the invention a compound of formula (II), wherein R1 and n are as defined in the first aspect of the invention and LG1 is a leaving group, is reacted with a compound of formulae (IVa) or (IVb) respectively, wherein A1 , A2 and A3 are as defined in the first aspect of the invention, to yield a compound of formulae (la) or (lb) respectively according to the invention as illustrated in reaction C of the schemes above.
Reaction C is carried out under standard amine arylation conditions such as those explained for step 1 of method 1 described above. Method 3
Step 1
In a third method according to the invention a compound of formula (II), wherein, R1 and n are as defined in the first aspect of the invention and LG1 is a leaving group, is reacted with a compound of formulae (Va) or (Vb) respectively, wherein A1 , A2 and A3 are as defined in the first aspect of the invention and LG2 represents a suitable leaving group such as such as iodo, bromo, chloro or a sulphonate group (e.g. -OS(0)2CF3, -OS(0)2CH3 or -OS(0)2PhMe), to yield a compound of formulae (Vila) or (Vllb) respectively as illustrated in reaction D of the schemes above.
Reaction D is carried out under standard amine arylation conditions such as those explained for step 1 of method 1 described above.
Step 2
The leaving group in the compound of formulae (Vila) or (Vllb) is subsequently replaced by a group -NH-PG1 wherein PG1 is an amino protecting group such as methyl carbamate, tert-butyl carbamate, 9-fluorenylmethyl carbamate, benzyl carbamate, 2-(trimethylsilyl)ethyl carbamate, trifluoroacetamide, benzylamine, allylamine, tritylamine, trichloroacetyl, trifluoroacetyl, p-toluenesulfonyl or allyl carbamate to yield the compound of formulae (Villa) or (VI I lb) respectively according to the invention as illustrated in reaction E of the schemes above.
The reaction E is carried out by causing compound of formulae (Vila) or (Vllb) respectively to react with a compound of formula PGi-NH2 wherein PG1 is as hereinabove defined. The reaction may be carried out under standard conditions in the presence of a suitable base (e.g. pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, or mixtures thereof), and appropriate solvent (e.g. pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, triethylamine, dimethylsulphoxide, water or mixtures thereof) and for example at around room temperature or above, or under microwave irradiation reaction conditions.
Optionally it may also be carried out in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc)2, Cul (or Cul/diamine complex) copper tris(triphenyl-phosphine)bromide, Pd(OAc)2, tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3) or NiCI2 and of optional additive such as Ph3P, 2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthyl, xantphos, Nal or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as sodium hydride, triethylamine, pyridine, Ν,Ν'-dimethylethylenediamine, sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, sodium tert-butoxide or potassium tert-butoxide (or a mixture thereof, optionally in the presence of 4A molecular sieves), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N- methylpyrrolidinone, tetrahydrofuran or a mixture thereof).
This reaction may be carried out under microwave irradiation reaction conditions.
The reaction mixture may be stirred at room temperature or heated until the starting materials have been consumed. The reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3rd Edition, New York, 1999).
Step 3 In a final step, the amino protecting group (PGi) of the compound of formulae (Villa) or (Vlllb) is cleaved to yield the compound of formulae (la) or (lb) respectively as illustrated in reaction F of the scheme above.
Said reaction may be carried under standard conditions known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3rd Edition, New York, 1999). For instance, the removal of a tert- butyl carbamate amine protecting group can be performed in the presence of a strong protic acid (e.g. 3M HCI or CF3COOH) or TMS-I; a 2-(trimethylsilyl)ethyl carbamate amine protecting group can be removed in the presence of a fluoride ion (e.g. Bu4NF); a 9-fluorenylmethyl carbamate amine protecting group by treatment with a mild base (e.g piperidine or morpholine); a benzyl carbamate amine protecting group by hydrogenolysis, treatment with BBr3 or Na/NH3, PdC and Et3SiH; a trifluoroacetamide amine protecting group can be removed by treatment with a base (e.g. K2CO3) or NH3; p-toluenesulfonyl protecting group can be cleaved with a strong acid or Na(Hg); allyl carbamate amine protecting group is cleaved with Pd(0) and a reducing agent (e.g. Bu3SnH or Et3SiH); benzylamine can be cleaved by hydrogenolysis (e.g. H2, Pd/C and HCI); a tritylamine can be cleaved with HCI or H2, Pd/C; an allylamine can be cleaved by treatment with polymethylhydrosiloxane (PMHS), ZnCI2 and Pd(PPh3)4 or in oxydative conditions (e. g. NMO, Os04 and Nal04); a trichloroacetyl amine protecting group can be removed with NaBH4; a trifluoroacetyl amine protecting group can be cleaved with a base (e.g. K2C03 Na2C03).
Other deprotection conditions may be employed, as is known by the person skilled in the art. An appropriate solvent may be used. The reaction mixture is stirred at room temperature, or heated until the starting materials have been consumed.
Method 4
In a fourth method according to the invention, a compound of formulae (IXa1 ), (IXa2), (IXa3), (IXa4), (IXb1 ) or (IXb2), wherein R1, A1 , A2 and A3 and n are as defined in the first aspect of the invention and LG3 is a leaving group is caused to reacted to yield a compound of formulae (la) or (lb) according to the invention as illustrated in reaction G of the schemes above.
Compounds wherein R3 represents a group -ORa
To prepare compounds of formulae (la) or (lb) wherein R3 represents a group -ORa a compound of formulae (IXa), (IXa2), (IXa3), (IXa4), (IXb1 ) or (IXb2), wherein LG3 represents a leaving group such as iodo, bromo, chloro or a sulphonate group (e.g. -OS(O)2CF3, -OS(O)2CH3 or -OS(O)2PhMe) is caused to react with a compound of formula H-R3 wherein R3 represents -ORa and Ra is as defined above. Said reaction may be performed under standard conditions in the presence of a suitable base such as pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, or mixtures thereof), and an appropriate solvent such as pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, triethylamine, dimethylsulphoxide, water or mixtures thereof and, for example, at around room temperature or above, or under microwave irradiation reaction conditions.
The reaction may also be carried out in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc)2, Cul (or Cul/diamine complex) copper tris(triphenyl-phosphine)bromide, Pd(OAc)2, tris(dibenzylideneacetone) dipalladium (0) (Pd2(dba)3) or N 1CI2 and also optionally in the presence of an additive such as Ph3P, 2,2'- bis(diphenylphosphino)-1 , 1 '-binaphthyl, xantphos, Nal or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as sodium hydride, triethylamine, pyridine, N, N'-dimethylethylenediamine, sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, sodium tert-butoxide or potassium tert-butoxide (or or a mixture thereof, optionally in the presence of 4A molecular sieves), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or a mixture thereof.
This reaction may be carried out under microwave irradiation reaction conditions
The reaction mixture may be stirred at room temperature or heated until the starting materials have been consumed. The reaction may be carried out with protecting groups present and those protecting groups may be removed after the reaction. Suitable protecting groups are known to the person skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3rd Edition, New York, 1999).
Compounds wherein R3 represents a group selected from -C-u^ alkyl, -C¾-R
Figure imgf000042_0001
To prepare compounds of formulae (la) or (lb) wherein R3 represents a group selected from -Ci-4 alkyl, -C3-6 cycloalkyl and -C3-7 heterocyclyl, a compound of formulae (IXa), (IXa2), (IXa3), (IXa4), (IXb1 ) or (IXb2), wherein LG3 represents a suitable leaving group such as iodo, bromo, chloro or a sulphonate group (e.g. -OS(0)2CF3, -OS(0)2CH3 or -OS(0)2PhMe) is caused to react with a compound of formula Q-R3 wherein Q represents a suitable group such as alkali metal group (e.g. lithium), a Grignard reagent (e.g. MgX), - B(OH)2, -B(OR)2 or -Sn(R)3, wherein each R independently represents an alkyl group, or, in the case of -B(OR)2, the respective R groups may be linked together to form a 4- to 6- membered cyclic group. The reaction may be performed, for example in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, Cu, Pd/C, PdCI2, Pd(OAc)2, Pd(Ph3P)4, Pd(Ph3P)2CI2 (i.e. palladium tetrakistriphenylphosphine), Pd2(dba)3 or NiCI2 and a ligand such as t-Bu3P, (C6Hn)3P, Ph3P, AsPh3, P(o-Tol)3, 1 ,2- bis(diphenylphosphino)ethane, 2,2'-bis(di-tert-butylphosphino)-1 , 1 '-biphenyl, xantphos or a mixture thereof, together with a suitable base such as, sodium carbonate, potassium phosphate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium fluoride, triethylamine, diisopropylethylamine, sodium tert-butoxide, or potassium tert-butoxide (or mixtures thereof) in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or mixtures thereof. The reaction may also be carried out for example at room temperature or above. Alternative reactions conditions include microwave irradiation conditions.
The initial compounds and starting materials, e.g. the compounds of formula (II), (Ilia), (lllb), (IVa), (IVb), (Va), and (Vb), are either commercially available or can be obtained following procedures described in the literature. Compounds of formula (IXa1 ), (IXa2), (IXa3), (IXa4), (IXb1 ) and (IXb2), can also be obtained following anyone of methods 1 , 2 or 3 described above.
Use of the Compounds of the Invention Compounds of the Invention have the ability to bind allosterically to mutated β-galactosidase enzyme and, thereby, stabilizing the enzyme against denaturation. Therefore Compounds of the Invention can be used/administered to treat an/or prevent conditions associated with the alteration of the activity of β-galactosidase, specifically galactosidase β-1 or GLB1 , including GM1 gangliosidoses and Morquio syndrome, type B, in a patient suffering from said condition.
Accordingly, the present invention is directed to a method of treating or preventing a condition associated with the alteration of the activity of GLB1 in a patient, comprising administering to the patient in need thereof an effective amount of a compound of any one of formulae (IA), (IIA), or (I), or a pharmaceutically acceptable salt or solvate thereof.
The present invention is also directed to a method of treating GM1 ganglisidosis or Morquio B syndrome in a patient, comprising administering to the patient in need thereof an effective amount of a compound of any one of formulae (IA), (IIA), or (I), or a pharmaceutically acceptable salt or solvate thereof.
The present invention is also directed to a method of increasing β- galactosidase activity in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of defined formulae (IA), (IIA), or (I), or a pharmaceutically acceptable salt or solvate thereof. The present invention is also directed to the use of a compound represented by any of defined formulae (IA), (IIA), or (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating and/or preventing a condition associated with the alteration of the activity of β-galactosidase, specifically galactosidase β-1 or GLB1 , including GM1 gangliosidoses and Morquio syndrome, type B, in a patient suffering from said condition. Pharmaceutical compositions
Due to their activity, the Compounds of the Invention can be used in human medicine. As described above, the Compounds of the Invention are useful for treating or preventing a condition associated with the alteration of the activity of β-galactosidase. The Compounds of the Invention can be administered to any patient suffering said condition. The term "patient" as used herein refers to any human that may experience the beneficial effects of a Compound of the Invention.
When administered to a patient, a Compound of the Invention can be administered as a component of a composition that comprises a pharmaceutically acceptable excipient or carrier.
The term "excipient" refers to a vehicle, diluent, or adjuvant that is administered with the active ingredient. Such pharmaceutical excipients can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and similar. Water or saline queous solutions and aqueous dextrose and glycerol solutions, particularly for injectable solutions, are preferably used as vehicles. Suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, 21st Edition, 2005; or "Handbook of Pharmaceutical Excipients," Rowe C.R.; Paul J.S.; Marian E.Q., sixth Edition, incorporated herein by reference.
Examples of pharmaceutical compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid compositions (solutions, suspensions or emulsions) for oral, topical or parenteral administration. In a preferred embodiment, the pharmaceutical compositions are in an oral delivery form. Pharmaceutical forms suitable for oral administration can be tablest and capsules, and can contain conventional excipients known in the art, such as binders, for example syrup, gum Arabic, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, cornstarch, calcium phosphate, sorbitol, or glycine; lubricants for the preparation of tablets, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents, such as sodium lauryl sulphate. Solid oral compositions can be prepared by conventional methods of blending, filling or preparation of tablets. Repeated blending operations can be used to distribute the active ingredient in all the compositions that use large amounts of fillers. Such operations are conventional in the art. The tablets can be prepared, for example, by dry or wet granulation and optionally can be coated by well known methods in normal pharmaceutical practice, in particular using enteric coating.
Pharmaceutical compositions can also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the appropriate unit dosage form. Suitable excipients, such as fillers, buffering agents or surfactants, can be used.
The mentioned formulations can be prepared using standard methods, such as those described or referred to in the Spanish and U.S. Pharmacopoeias and similar reference texts.
In general, the effective amount of a Compound of the Invention to be administered depends on the relative efficacy of the compound chosen, the severity of the condition or disorder being treated, and the patient's weight. The active compound can be administered one or more times a day, for example 1 , 2, 3, or 4 times daily, with typical total daily doses in the range from about 0.01 mg/kg of body weight/day to about 1000 mg/kg of body weight/day. In one embodiment, the effective dosage amount of a Compound of the Invention is about 500 mg/kg of body weight/day or less. In another embodiment, the effective dosage amount of a Compound of the Invention is about 100 mg/kg of body weight/day or less. In another embodiment, the effective dosage amount ranges from about 0.01 mg/kg of body weight/day to about 100 mg/kg of body weight/day of a Compound of the Invention; in another embodiment, from about 0.02 mg/kg of body weight/day to about 50 mg/kg of body weight/day of a Compound of the Invention; and in another embodiment, from about 0.025 mg/kg of body weight/day to about 20 mg/kg of body weight/day of a Compound of the Invention. A composition of the invention can be prepared by a method comprising admixing a Compound of the Invention with a pharmaceutically acceptable excipient or carrier. Admixing can be accomplished using methods known for admixing a compound and a pharmaceutically acceptable excipient or carrier. In one embodiment, the Compound of the Invention is present in the composition in an effective amount.
The following examples are illustrative, but not limiting, of the compounds, compositions and methods of the present invention. Suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art in view of this disclosure are within the spirit and scope of the invention.
General experimental conditions
The compound lUPAC names given herein were generated with ChemBioDraw Ultra 12.0. or 12.0.2.
Hereinafter, the term "h" means hours, "eq" means equivalents, "min" means minutes, "Pd2(dba)3" means tn's(dibenzylideneacetone)-dipalladium(0), "XantPhos" means 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; "SnC " means tin(ll) chloride; "TLC" means thin layer chromatography; and "HPLC" means high-performance liquid chromatography.
NMR spectra were recorded in a Varian Mercury 400 MHz spectrometer (at room temperature).
The HPLC measurements were performed using a HPLC Waters Alliance HT comprising a pump (Edwards RV12) with degasser, an autosampler, a diode array detector and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an eletrospray ionization source (micromass ZQ4000), Nitrogen was used as the nebulizer gas. Data acquisition was performed with MassLynx software.
HPLC method A: The reverse phase HPLC purifications were carried out on a YMC-Pack ODS-AQ (50x4.6 mm, D S. 3 μιη, 12 nm) column. Solvent A: water 0.1 % formic acid; Solvent B: acetonitrile with 0.1 % formic acid. Gradient: 5% of B to 100% of B within 3.5 min. Flux: 1 .6 mL/min at 50°C.
HPLC method B: Column: Agilent Zorbax 3.5 μητι, SB-C8 (4.6x75 mm); wavelength: 210/254 nm; flow: 1 mL/min; run time: 7 min; Time & mobile phase- gradient (time in min/B): 0/5, 3.5/90, 5/90, 5.5/5, 7/5 [B: acetonitrile; A: formic acid (0.1 % in water)]; MASS: Agilent-single quad-multimode-APCI-ESI.
HPLC method C: Column: Agilent Zorbax 3.5 μητι, SB-C8 (4.6x75 mm); wavelength: 210/254 nm; flow: 1 mL/min; run time: 7 min; Time & mobile phase- gradient (time in min/B): 0/30, 3.5/95, 5/95, 5.5/30, 7/30 [B: acetonitrile; A: formic acid (0.1 % in water)]; MASS: Agilent-single quad-multimode-APCI- ESI.
HPLC method D: Column: Waters Symmetry C-18 Column (4.6x75 mm) 3.5 pm, flow 1 mL/min, runtime: 5 min, Time & mobile phase-isocratic (time in min/B): 0/80, 5/80 [B: acetonitrile, A: formic acid (0.1 % in water)]; LC/MS/MS module Applied Biosystem-API 3200 with Shimadzu LC.
HPLC method E: Direct mass: Time & mobile phase-isocratic (time in min/B) using union: 0/80, 1/80 [B: acetonitrile, formic acid (0.1 % in water)]; LC/MS/MS module Applied Biosystems-API-2000 with Agilent LC. MW calculated is an isotopic average and the "found mass" is referring to the most abundant isotope detected in the LC-MS.
General procedures Ai, Ci,Di
Following procedures A, C and D as those described in Schemes 1 or 2 compounds of formulae (la), (lb), (Via), (VIb), (Vila) or (Vllb) may be prepared in the conditions described below:
Figure imgf000049_0001
A mixture of the appropriate arylamine (Ilia), (1Mb), (IVa), (IVb), (Va) or (Vb) (ex: 2-chloropyridin-4-amine) (2.2 eq) and sodium hydride (2.6 eq) in dry dioxane was stirred for 30 min at room temperature. Then, the appropriate isoquinoline (II) (ex: 1 ,5-dichloroisoquinoline) (1 eq) was added portion wise and the mixture was refluxed for 5h or overnight. On cooling, water (2 mL) was added and the solvent was removed under vacuum. The reaction mixture was diluted with ethyl acetate and washed with water. The combined organic layers were dried over anhydrous magnesium sulphate, filtered, and concentrated under vacuum. The crude mixture was purified by flash column chromatography (hexanes/ethyl acetate) to obtain the desired amino product (la), (lb), (Via), (VIb), (Vila) or (Vllb) (ex: 5-chloro-N-(2-chloropyridin-4-yl)isoquinolin-1 -amine). Intermediate 1
5-Chloro-N-(2-chloropyridin-4-yl)isoquinolin
Figure imgf000050_0001
HPLC-MS (method A): Rt= 3.23 min, [M+H]+ m/z 290, 292. Yield: 68%.
Intermediate 2
7-Chloro-N- 2-chloropyridin-4-yl)isoquinolin-1 -amine
Figure imgf000050_0002
HPLC-MS (method A): Rt= 3.22 min, [M+H]+ m/z 290, 292. Yield: 75%. Example 1
N2-(5-chloroisoquinolin-1 -yl)pyridine-2,6-diamine
Figure imgf000050_0003
HPLC-MS (method A): Rt= 1 .85 min, (M+H)+ m/z 271 , 273. 1 H NMR (400 MHz, CD3OD) δ 8.29 (d, J = 7.4 Hz, 1 H), 8.09 (s, 1 H), 7.82 (d, J = 7.4 Hz, 1 H), 7.56 (t, J = 8.0 Hz, 2H), 7.46 (t, J = 7.9 Hz, 2H), 6.26 (d, J = 8.7 Hz, 1 H).
Yield: 17%. Intermediate 3
/V-(2-Chloropyridin-4-yl)-7-methoxyisoquinolin-1 -amine.
Figure imgf000051_0001
HPLC-MS (method A): Rt= 2.81 min, [M+H]+ m/z 286, 288. Yield: 51 %.
General Procedures A2, C2, D2
Following procedures A, C and D as those described in Schemes 1 or 2 compounds of formulae (la), (lb), (Via), (VIb), (Vila) or (Vllb) may be prepared in the conditions described below:
Figure imgf000051_0002
Figure imgf000052_0001
A mixture of the appropriate chloride (II) (ex: 1 ,7-dichloroisoquinoline) (1 eq), the appropriate amine (Ilia), (1Mb), (IVa), (IVb), (Va) or (Vb) (ex: 3- nitroaniline)(1 .5 eq), Pd2(dba)3 (0.1 eq), XantPhos (0.2 eq) and cesium carbonate (2eq) in dioxane (5.3 mL/mmol) (pre-degasified) was heated at 140°C for 2-5h under nitrogen atmosphere. The mixture was filtered through a celite pad and concentrated under reduced pressure. Alternatively, extraction with ethyl acetate, washing with brine and drying with sodium sulphate was also performed. The residue was purified by flash column chromatography (dichloromethane/methanol or hexanes/ethyl acetate) to obtain the desired product (la), (lb), (Via), (Vlb), (Vila) or (Vllb) (ex: 7-chloro-/V-(3- nitrophenyl)isoquinolin-1 -amine).
Intermediate 4
tert-Butyl (2-((7-chloroisoquinolin-1 -yl)amino)pyrimidin-4-yl)carbamate oc
Figure imgf000052_0002
HPLC-MS (method A): Rt= 2.22 min, [M+H]+ m/z 372. Yield: 16%. Example 2
N4-(7-chloroisoquinolin-1-yl)pyrimidine-2,4-diamine
Figure imgf000053_0001
HPLC-MS (method A): Rt= 1.83 min, [M+H]+ m/z 272, 274.
1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7.91 (s, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.77 - 7.70 (m, 1 H), 7.25 - 7.18 (m, 1 H), 6.20 (s, 1 H).
Yield: 1%. Example 3
N2-(7-chloroisoquinolin-1-yl)pyridine-2,6-diamine
Figure imgf000053_0002
HPLC-MS (method A): Rt= 1.85 min, [M+H]+ m/z 271 , 273.
1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.70 (s, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 5.2 Hz, 1H), 6.13 (d, J = 7.5 Hz, 1H), 5.64 (s, 2H).
Yield: 26%.
Example 4
N2-(5,7-dichloroisoquinolin-1-yl)pyridine-2,6-diamine
Figure imgf000054_0001
HPLC-MS (method A): Rt= 2.05 min, [M+H]+ m/z 305, 307.
1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.74 (s, 1H), 8.19 (d, J
1H), 8.03 (s, 1H), 7.38 (d, J = 5.5 Hz, 3H), 6.14 (s, 1H), 5.66 (s, 2H).
Yield: 18%.
Example 5
N2-(5-(trifluoromethyl)isoquinolin-1-yl)pyridine-2,6-diamine
Figure imgf000054_0002
HPLC-MS (method A): Rt= 2.03 min, [M+H]+ m/z 305.
1H NMR (400 MHz, CD3OD) δ 8.62 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 7.4 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.46 (td, J = 7.9, 5.2 Hz, 2H), 7.35 (s, 2H), 6.27 (d, J = 8.5 Hz, 1H).
Yield: 9%.
Example 6
N2-(7-(trifluoromethoxy)isoquinolin-1-yl)pyridine-2,6-diamine
Figure imgf000055_0001
HPLC-MS (method A): Rt= 2.02 min, [M+H]+ m/z 321.
1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.99 (broad singlet, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.25 (broad singlet, 2H), 6.28-6.22 (m, 1H).
Yield: 42%.
Example 7
N2-(5-(trifluoromethoxy)isoquinolin-1-yl)pyridine-2,6-diamine
Figure imgf000055_0002
HPLC-MS (method A): Rt= 2.05 min, [M+H]+ m/z 321.
1H NMR (400 MHz, CD3OD) δ 8.35 (d, J = 7.9 Hz, 1H), 8.09 (broad singlet, 1H), 7.67 (dt, J = 16.0, 8.0 Hz, 2H), 7.47 (t, J = 7.9 Hz, 2H), 7.41 - 7.26 (broad signal, 1H), 6.27 (d, J = 8.7 Hz, 1H).
Yield: 22%.
Example 8
N2-(7-methoxyisoquinolin-1-yl)pyridine-2,6-diamine
Figure imgf000056_0001
HPLC-MS (method A): Rt= 1 .97 min, [M+H]+ m/z 267.
1 H NMR (400 MHz, CD3OD) δ 8.71 (s, 2H), 8.55 (d, J = 8.9 Hz, 1 H), 8.15 (td, J = 12.2, 4.3 Hz, 3H), 6.91 (d, J = 8.3 Hz, 1 H), 6.65 - 6.36 (m, 1 H), 4.12 (s, 3H). Yield: 10%.
Intermediate 5
tert-Butyl (6-((7-chloroisoquinolin-1 -yl)amino)-5-fluoropyridin-2-yl)carbamate oc
Figure imgf000056_0002
HPLC-MS (method A): Rt= 2.65 min, [M+H]+ m/z 389, 390.
Yield: without purification. Intermediate 6
7-Chloro-N-(5-nitropyridin-2-yl)isoquinolin-1 -amine
Figure imgf000056_0003
HPLC-MS (method A): Rt= 2.45 min, [M+H]+ m/z 301 , 303. Yield: 65%. Intermediate 7
tert-Butyl (5-((7-chloroisoquinolin-1 -yl)amino)pyndin-2-yl)carbamate.
Figure imgf000057_0001
HPLC-MS (method A): Rt= 2.43 min, [M+H]+ m/z 371 , 373.
Yield: without purification.
Example 9
N2-(7-Chloroisoquinolin-1 -yl)pyrazine-2,5-diamine
Figure imgf000057_0002
HPLC-MS (method A): Rt= 1 .67 min, [M+H]+ m/z 272, 274.
1 H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1 H), 8.12 (d, J = 5.7 Hz, 1 H), 7.91 (d, J = 8.7 Hz, 1 H), 7.75 (dd, J = 8.7, 2.0 Hz, 1 H) 7.54 (s, 1 H), 7.34 (d, J = 5.4 Hz, 1 H), 6.1 1 (d, J = 5.8 Hz, 1 H). Minor tautomery peaks were observed at δ 8.73, 8.63, 8.56, 7.71 - 7.68, 7.65, 7.46, 7.40 - 7.36, 6.70, and 6.35.
Yield: 24%.
Example 10
/V2-(7-Chloroisoquinolin-1 -yl)-4-(pyridin-3-yloxy)pyridine-2,6-diamine
Figure imgf000058_0001
HPLC-MS (method A): Rt= 2.33 min, [M+H]+ m/z 364, 365.
1H NMR (400 MHz, CD3OD) δ 8.46 - 8.39 (m, 2H), 8.33 (d, J = 8.5 Hz, 1 H),
8.15 (d, J = 8.3 Hz, 1H), 8.02 (s, 1H), 7.86 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.72
(ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.67 (ddd, J = 8.4, 2.8, 1.3 Hz, 1H), 7.52 (dd, J
8.4, 4.8 Hz, 1H), 7.31 (s, 1H), 5.78 (d, J = 2.0 Hz, 1H).
Yield: 20%.
Intermediate 8
7-Chloro-/V-(5-nitropyrimidin-2-yl)isoquinolin-1 -amine
Figure imgf000058_0002
HPLC-MS (method A): Rt= 2.47 min, [M+H]+ m/z 302, 304.
Yield: not purified.
Intermediate 9
7-Chloro-/V-(4-nitropyridin-2-yl)isoquinolin-1 -amine
Figure imgf000059_0001
HPLC-MS (method A): Rt= 2.35 min, [M+H]+ m/z 301 , 303.
Yield: 79% (85% purity).
Intermediate 10
tert-Butyl (5-((7-chloroisoquinolin-1 -yl)amino)pyrimidin-2-yl)carbamate
Figure imgf000059_0002
HPLC-MS (method A): Rt= 1 .63 min, [M+H]+ m/z 472, 474.
Yield: not purified.
Example 11
A/3-(7-Chloroisoquinolin-1-yl)pyridine-3,5-diamine
Figure imgf000059_0003
HPLC-MS (method A): Rt= 1 .78 min, [M+H]+ m/z 271 , 273. 1 H NMR (400 MHz, CD3OD) δ 8.44 (s, 1 H), 8.13 (s, 1 H), 7.96 (d, J = 5.8 Hz, 1 H), 7.79 (d, J = 8.7 Hz, 1 H), 7.67 (d, J = 2.0 Hz, 2H), 7.65 (d, J = 2.0 Hz, 1 H), 7.18 (d, J = 5.8 Hz, 1 H).
Yield: 32%.
Example 12
/V3-(7-Chloroisoquinolin-1 -yl)pyhdazine-3,6-diamine
Figure imgf000060_0001
HPLC-MS (method A): Rt= 1 .73 min, [M+H]+ m/z 272, 274.
H NMR (400 MHz, CD3OD) δ 8.51 (d, J = 1 .9 Hz, 1 H), 7.81
7.66 (dd, J = 8.6, 2.1 Hz, 1 H), 7.03 (m, 2H).
Yield: 12%.
Example 13
/V4-(7-Chloroisoquinolin-1 -yl)pyhmidine-4,6-diamine
Figure imgf000060_0002
HPLC-MS (method A): Rt= 1 .70 min, [M+H]+ m/z 272, 274. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.14 (d, J = 1.0 Hz, 1H), 8.13 (s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.71 (dd, J = 8.7, 2.0 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J = 5.1 Hz, 1H).
Yield: 33%.
Example 14
/V2-(7-Chloroisoquinolin-1-yl)pyrazine-2,5-diamine
Figure imgf000061_0001
HPLC-MS (method A): Rt= 1.65 min, [M+H]+ m/z 272, 274.
1H NMR (400 MHz, CD3OD): δ 8.47 (s, 1H), 8.45 (d, J = 1.9 Hz, 1H), 7.83 (d, J = 1.5 Hz, 1H), 7.80 (s, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.66 (dd, J = 8.7, 2.0 Hz, 1H), 7.05 (s, 1H).
Yield: 32%.
Example 15
/V2-(7-Methylisoquinolin-1-yl)pyridine-2,6-diamine
Figure imgf000061_0002
HPLC-MS (method A): Rt= 1.83 min, [M+H]+ m/z 251. 1H NMR (400 MHz, CD3OD): δ 8.09 (s, 1H), 7.90 (s, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.27-6.17 (m, 1H), 5.83 (d, J= 7.9 Hz, NH), 2.57 (s, 3H).
Yield: 9%.
Example 16
/V3-(7-Methylisoquinolin-1-yl)pyridazine-3,6-diamine
Figure imgf000062_0001
HPLC-MS (method A): Rt= 1.48 min, [M+H]+ m/z 252.
1H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 7.82 (s, 1H), 7.70 (s, 1H), 7.65 (d, J = 8.3 Hz, 1 H), 7.55 (dd, J = 8.3, 1.5 Hz, 1 H), 7.05 (s, 1 H), 7.02 - 6.98 (m, 1 H), 2.55 (s, 3H).
Yield: 18%.
Intermediate 11
tert-Butyl (5-((7-methylisoquinolin-1-yl)amino)pyridin-2-yl)carbamate
Figure imgf000062_0002
HPLC-MS (method A): Rt= 2.10 min, [M+H]+ m/z 351
Yield: not purified. Example 17
/V2-(7-Methoxyisoquinolin-1-yl)pyrazine-2,6-diamine
Figure imgf000063_0001
HPLC-MS (method A): Rt= 1.62 min, [M+H]+ m/z 268.
1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.69 (d, J = 4.3 Hz, 1H), 7.97 (d, J = 5.6 Hz, 1H), 7.90 (s, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.52 (s, 1H), 7.36 (dd, J = 8.8, 2.2 Hz, 1H), 7.26 (d, J = 5.6 Hz, 1H), 6.05 (d, J = 5.7 Hz, 1H), 3.93 (d, J = 11.4 Hz, 3H).
Yield: 27%.
Example 18
/V3-(7-Methoxyisoquinolin-1-yl)pyridazine-3,6-diamine
Figure imgf000063_0002
HPLC-MS (method A): Rt= 1.47 min, [M+H]+ m/z 268.
1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 2.2 Hz, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.34 (dd, J = 8.9, 2.5 Hz, 1H), 7.10 (s, 1H), 6.86 (d, J = 9.4 Hz, 1 H), 6.06 (s, 2H), 3.93 (s, 3H).
Yield: 14%.
Intermediate 12
7-Methoxy-/V-(5-nitropyridin-2-yl)isoquinolin-1 -amine
Figure imgf000064_0001
HPLC-MS (method A): Rt= 1 .88 min, [M+H]+ m/z 297.
Yield: not purified.
Intermediate 13
7-Methoxy-/V-(5-nitropyrimidin-2-yl)isoquinolin-1 -amine
Figure imgf000064_0002
HPLC-MS (method A): Rt= 1 .97 min, [M+H]+ m/z 298.
Yield: 47%.
Intermediate 14
tert-Butyl (5-((7-methoxyisoquinolin-1 -yl)amino)pyridin-2-yl)carbamate
Figure imgf000064_0003
HPLC-MS (method A): Rt= 2.05 min, [M+H]+ m/z 367.
Yield: not purified.
Intermediate 15
tert-Butyl (5-((5-chloroisoquinolin-1 -yl)amino)pyridin-2-yl)carbamate
Figure imgf000065_0001
HPLC-MS (method A): Rt= 2.48 min, [M+H]+ m/z 371 , 373.
Yield: not purified.
Intermediate 16
5-Chloro-/V-(5-nitropyhdin-2-yl)isoquinolin-1 -amine
Figure imgf000065_0002
HPLC-MS (method A): Rt= 2.72 min, [M+H]+ m/z 300, 302.
Yield: not purified. Example 19
/V2-(5-(Trifluoromethyl)isoquinolin-1 -yl)pyrazine-2,6-diamine
Figure imgf000065_0003
HPLC-MS (method A): Rt= 1 .85 min, [M+H]+ m/z 306.
1 H NMR (400 MHz, CD3OD): δ 8.67 (brs, 2H), 8.1 1 (brs, 2H), 7.71 (brs, 2H), 7.52 (broad signal, 2H).
Yield: 34%. Example 20
/V3-(5-Chloroisoquinolin-1-yl)pyndazine-3,6-diamine
Figure imgf000066_0001
HPLC-MS (method A): Rt= 2.00 min, [M+H]+ m/z 272, 274.
1H NMR (400 MHz, CD3OD) δ 8.41 (d, J = 8.5 Hz, 1 H), 7.90 (d, J = 5.9 Hz, 1 H),
7.83 (s, 1H), 7.81 (dd, J = 7.6, 1.0 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.39 (s, 1H),
7.02 (d, J = 9.5 Hz, 1H).
Yield: 8%.
Example 21
/V2-(6-Chloroisoquinolin-1-yl)pyridine-2,6-diamine
Figure imgf000066_0002
HPLC-MS (method A): Rt= 1.87 min, [M+H]+ m/z 271 , 273.
1H NMR (400 MHz, CD3OD) δ 8.29 (d, J =8.9 Hz, 1H), 7.94 (s, 1H), 7.79 (d, J =
1.6 Hz, 1 H), 7.54 (dd, J = 9.0, 2.1 Hz, 1 H), 7.43 (t, J = 7.9 Hz, 1 H), 7.27 (s, 1 H),
7.10 (s, 1H), 6.23 (d, J= 8.4 Hz, 1H).
Yield: 21%.
Example 22
/V3-(6-Chloroisoquinolin-1-yl)pyridazine-3,6-diamine
Figure imgf000067_0001
HPLC-MS (method A): Rt= 1 .75 min, [M+H]+ m/z 272, 274.
1 H NMR (400 MHz, CD3OD) δ 8.43 (d, J = 8.9 Hz, 1 H), 7.78 (s, 3H), 7.55 (dd, J = 9.0, 1 .9 Hz, 1 H), 7.03 (d, J = 9.2 Hz, 2H).
Yield: 9%.
Example 23
/V2-(5,6-Dichloroisoquinolin-1 -yl)pyridine-2,6-diamine
Figure imgf000067_0002
HPLC-MS (method A): Rt= 2.03 min, [M+H]+ m/z 305, 307.
1 H NMR (400 MHz, CD3OD) δ 8.29 (d, J = 9.1 Hz, 1 H), 8.10 (s, 1 H), 7.69 (d, J = 9.0 Hz, 1 H), 7.49 (s, 1 H), 7.46 (t, J = 8.0 Hz, 1 H), 7.29 (s, 1 H), 6.26 (dd, J = 8.0, 0.7 Hz, 1 H).
Yield: 1 1 %.
Example 24
/V2-(5-Methoxyisoquinolin-1 -yl)pyridine-2,6-diamine
Figure imgf000067_0003
HPLC-MS (method A): Rt= 1 .83 min, [M+H]+ m/z 267. 1 H NMR (400 MHz, CD3OD) δ 7.97 (d, J = 5.7 Hz, 1 H), 7.83 (d, J = 8.5 Hz, 1 H), 7.55 (t, J = 8.4 Hz, 2H), 7.44 (t, J = 7.9 Hz, 1 H), 7.34 - 7.24 (m, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 6.23 (d, J = 7.9 Hz, 1 H), 4.01 (s, 3H).
Yield: 13%.
Example 25
/V2-(5-Methoxyisoquinolin-1 -yl)pyrazine-2,6-diamine
Figure imgf000068_0001
HPLC-MS (method A): Rt= 1 .62 min, [M+H]+ m/z 268.
1 H NMR (400 MHz, CD3OD) δ 8.49 (s, 1 H), 7.91 (s, 2H), 7.54 (dd, J = 18.3, 10.0 Hz, 3H), 7.19 (d, J = 7.8 Hz, 1 H), 4.01 (s, 3H).
Yield: 15%.
Intermediate 17
5-Methoxy-/V-(5-nitropyrimidin-2-yl)isoquinolin-1 -amine
Figure imgf000068_0002
HPLC-MS (method A): Rt= 1 .93 min, [M+H]+ m/z 298.
Yield: not purified.
Example 26
/V2-(7-Chloroisoquinolin-1 -yl)-4-methylpyridine-2,6-diamine
Figure imgf000069_0001
HPLC-MS (method A): Rt= 2.00 min, [M+H]+ m/z 285, 287.
1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 7.96 (s, 1H), 7.79 (d, J
1H), 7.68 (dd, J = 8.8, 1.9 Hz, 1H), 7.17 (s, 2H), 6.12 (s, 1H), 2.25 (s,
Yield: 17%.
Example 27
1-((6-Aminopyndin-2-yl)amino)isoquinoline-7-carbonitrile
Figure imgf000069_0002
HPLC-MS (method B): Rt= 2.8 min, [M+H]+ m/z 262.
1H NMR (400 MHz, DMSO-d6): 59.5 (s, 1H), 9.21 (s, 1H), 8.20 (s, 1H), 7.98 (m, 2H), 7.48 (d, J =6.8 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.31 (s, 1H), 6.16 (d, J =7.6 Hz, 1H), 5.70 (s, 2H). Minor tautomer peaks were observed at δ 14.9, 8.85, 7.39 and 6.16.
Yield: 8%.
Example 28
1-((6-Aminopyrazin-2-yl)amino)isoquinoline-7-carbonitrile
Figure imgf000070_0001
HPLC-MS (method B): Rt= 4.04 min, [M+H]+ m/z 263.
1H NMR (400 MHz, DMSO-d6): 59.69 (s, 1H), 9.23 (s, 1H), 8.68 (s, 1H), 8.25 (d, J = 6.0 Hz, 1H), 8.03 (s, 1H), 7.58 (s, 1H), 7.39 (d, J = 5.6 Hz, 1H), 6.19 (s, 2H), 5.76 (s, 1H). Minor tautomer peaks were observed at 514.3, 8.89, 8.04, 7.80, 7.68, 7.49, 7.39, 6.73 and 6.42.
Yield: 3%. Example 29
2-Amino-6-((7-chloroisoquinolin-1-yl)amino)isonicotinonitrile
Figure imgf000070_0002
HPLC-MS (method D): Rt= 0.52 min, [M+H]+ m/z 296.
1H NMR (400 MHz, DMSO-d6): 59.71 (s, 1H), 8.71 (s, 1H), 8.17 (d, J = 5.6 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.77-7.73 (m, 2H), 7.39 (d, J = 5.6 Hz, 1H), 6.39 (s, 1H), 6.29 (s, 2H).
Yield: 19%.
Example 30
/V2-(5-Chloroisoquinolin-1-yl)pyrazine-2,6-diamine
Figure imgf000071_0001
HPLC-MS (method B): Rt= 3.46 min, [M+H]+ m/z 272.
1H NMR (400 MHz, DMSO-d6): 59.51 (brs, 1H), 8.58 (s, 1H), 8.56 (s, 1H), 8.18 (brs, 1 H), 7.90 (d, J = 7.2 Hz, 2H), 7.58-7.49 (m, 2H), 6.21 (brs, 2H).
Yield: 12%.
Example 31
/V2-(7-Chloroisoquinolin-1-yl)-4-methoxypyridine-2,6-diamine
Figure imgf000071_0002
HPLC-MS (method C): Rt= 4.4 min, [M+H]+ m/z 301.
1H NMR (400 MHz, DMSO-d6): 59.22 (s, 1H), 8.69 (s, 1H), 8.09 (s, 1H), 7.87- 7.67 (m, 2H), 7.25 (d, J = 8 Hz, 2H), 5.74 (s, 1 H), 5.62 (s, 2H), 3.91 (s, 3H). Yield: 11%.
Example 32
/V2-(7-Chloroisoquinolin-1-yl)-4-(4-chlorophenoxy)pyridine-2,6-diamine
Figure imgf000072_0001
HPLC-MS (method D): Rt= 0.51 min, [M+H]+ m/z 397.
1 H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1 H), 8.70 (s, 1 H), 8.04 (d, J = 5.6 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 7.73 (dd, J = 8.8, 2.0 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 2H), 7.32-7.29 (m, 2H), 7.21 (d, J = 8.8 Hz, 2H), 5.76 (s, 2H), 5.55 (s, 1 H).
Yield: 21 %.
Intermediate 18
Figure imgf000072_0002
HPLC-MS (method C): Rt = 4.74 min, [M+H]+ m/z 471 .
Yield: 95%.
General procedure E
Following procedures E as those described in Schemes 1 or 2 compounds of formulae (Villa) or (Vlllb) may be prepared in the conditions described below:
Figure imgf000073_0001
A mixture of the appropriate chloride (Vila) or (VI lb) (ex: 5-chloro-N-(2- chloropyridin-4-yl)isoquinolin-1 -amine) (1 eq), the appropriate amine NH2-PG1 (ex: tert-butyl carbamate)(1 .5 eq), Pd2(dba)3 (0.1 eq), XantPhos (0.2 eq) and cesium carbonate (2 eq) in dioxane (5.3 mL/mmol) (pre- degasified) was heated at 140°C for 2-5h under nitrogen atmosphere. The mixture was filtered through a celite pad and concentrated under reduced pressure. Alternatively, extraction with ethyl acetate, washing with brine and drying with sodium sulphate was also performed. The residue was purified by flash column chromatography (dichloromethane/methanol or hexanes/ethyl acetate) to obtain the desired product (Villa) or (VI I lb) (ex: tert-Butyl (4-((5-chloroisoquinolin-1 - yl)amino)pyridin-2-yl)carbamate).
Intermediate 19
tert-Butyl (4-((7-chloroisoquinolin-1 -yl)amino)pyridin-2-yl)carbamate
Figure imgf000074_0001
HPLC-MS (method A): Rt= 2.30 min, [M+H]+ m/z 371 , 373.
Yield: next step without purification. Intermediate 20
tert-Butyl (4-((5-chloroisoquinolin-1 -yl)amino)pyridin-2-yl)carbamate. oc
Figure imgf000074_0002
HPLC-MS (method A): Rt= 2.32 min, [M+H]+ m/z 371 , 373.
Yield: next step without purification.
Intermediate 21
tert-Butyl (4-((7-methoxyisoquinolin-1 -yl)amino)pyridin-2-yl)carbamate oc
Figure imgf000074_0003
HPLC-MS (method A): Rt= 2.15 min, [M+H]+ m/z 367.
Yield: not purified. Intermediate 22
tert-Butyl (4-((7-chloroisoquinolin-1 -yl)(methyl)amino)pyridin-2-yl)carbamate
Figure imgf000075_0001
HPLC-MS (method A): Rt
Yield: 48% (not purified)
General procedure F Following procedures F as those described in Schemes 1 or 2 compounds of formulae (Villa) or (VI I lb) may be prepared in the conditions described below:
Figure imgf000075_0002
Trifluoroacetic acid (TFA) (2 mL) was added to a solution of the appropriate carbamate (Vila) or (Vllb) (ex: tert-butyl (4-((7-chloroisoquinolin-1 - yl)amino)pyridin-2-yl)carbamate) in dichloromethane (2 mL). The solution was stirred at room temperature for 3-5h and concentrated under vacuum. The resultant residue was purified by flash column chromatography (dichloromethane/methanol) to obtain the desired amine product (la) or (lb) (ex: /V4-(7-chloroisoquinolin-1-yl)pyridine-2,4-diamine). Example 33
N4-(7-chloroisoquinolin-1-yl)pyridine-2,4-diamine
Figure imgf000076_0001
HPLC-MS (method A): Rt= 1.83 min, [M+H]+ m/z 270, 272.
1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.66 (d, J = 1.8 Hz, 1H), 8.26 (d, J = 5.7 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.62 (s, 2H), 7.59 (d, J = 5.8 Hz, 1H), 7.12 (dt, J = 5.6, 2.8 Hz, 1H).
Yield: 48% (two steps).
Example 34
N4-(5-chloroisoquinolin-1-yl)pyridine-2,4-diamine
Figure imgf000076_0002
HPLC-MS (method A): Rt= 1.88 min, [M+H]+ m/z 270, 272.
1H NMR (400 MHz, CD3OD) δ 8.22 (dt, J = 8.5, 0.9 Hz, 1H), 8.12 (d, J = 6.0 Hz, 1H), 7.75 (dd, J = 7.6, 0.9 Hz, 1H), 7.64 (d, J = 6.2 Hz, 1H), 7.54 (dd, J = 6.0, 0.9 Hz, 1H), 7.49 (dd, J = 8.5, 7.6 Hz, 1H), 7.26 (d, J = 1.9 Hz, 1H), 6.83 (dd, J = 6.2, 2.0 Hz, 1H). Yield: 15%.
Example 35
N2-(7-chloroisoquinolin-1-yl)-3-fluoropyridine-2,6-diamine
Figure imgf000077_0001
HPLC-MS (method A): Rt= 1.77 min, [M+H]+ m/z 289, 291.
1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.71 (m, 3H), 7.31 (dd, J = 10.3, 8.7 Hz, 1H), 7.04 - 6.66 (m, 1H), 6.12 (s, 1H), 5.83 (s, 2H), 5.56 (dd, J = 8.3, 1.9 Hz, 1H).
Yield: 46%.
Example 36
N2-(7-chloroisoquinolin-1-yl)pyrimidine-2,4-diamine
Figure imgf000077_0002
HPLC-MS (method A): Rt= 1.77 min, [M+H]+ m/z 272, 274.
1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.96 (s, 1H), 7.89 (d, J
1H), 7.77 (d, J = 8.8 Hz, 1H), 7.64 (dd, J = 8.7, 2.1 Hz, 1H), 7.29 (d, J
1H), 7.07 (s, 1H). Example 37
N5-(7-chloroisoquinolin-1-yl)pyridine-2,5-diamine
Figure imgf000078_0001
HPLC-MS (method A): Rt= 1.58 min, [M+H]+ m/z 271 , 273.
1H NMR (400 MHz, CD3OD) δ 8.40 (d, J = 1.9 Hz, 1H), 8.14 (s, 1H), 7.79 (dd, J
= 22.5, 5.9 Hz, 2H), 7.75 - 7.72 (m, 1H), 7.67 - 7.61 (m, 1H), 7.07 (d, J = 5.9
Hz, 1H), 6.68 (d, J = 9.0 Hz, 1H).
Yield: 10% (two steps).
Example 38
/V5-(7-Chloroisoquinolin-1-yl)pyrimidine-2,5-diamine
Figure imgf000078_0002
HPLC-MS (method A): Rt= 1.53 min, [M+H]+ m/z 271 , 273.
1H NMR (400 MHz, CD3OD) δ 8.53 (s, 2H), 8.38 (dd, J = 1.2, 0.8 Hz, 1H), 7.85
(d, J = 5.8 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.65 (dd, J = 8.7, 2.0 Hz, 1H), 7.10
(d, J = 5.9 Hz, 1H).
Yield: 24% (two steps).
Example 39
/V4-(7-Methoxyisoquinolin-1-yl)pyridine-2,4-diamine
Figure imgf000079_0001
HPLC-MS (method A): Rt= 1 .73 min, [M+H]+ m/z 266.
1 H NMR (400 MHz, CD3OD) δ 8.45 (d, J = 2.0 Hz, 1 H), 7.91 (d, J = 5.8 Hz, 1 H), 7.78 (d, J = 8.7 Hz, 1 H), 7.66 (dd, J = 8.7, 2.0 Hz, 1 H), 7.44 (s, 1 H), 7.22 - 7.13 (m, 3H), 3.51 (s, 3H).
Yield: 9% (two steps).
Example 40
/V5-(7-Methylisoquinolin-1 -yl)pyridine-2,5-diamine
Figure imgf000079_0002
HPLC-MS (method A): Rt= 1 .30 min, [M+H]+ m/z 251 .
1 H NMR (400 MHz, CD3OD) δ 8.1 1 (s, 1 H), 8.09 (d, J = 2.6 Hz, 1 H), 7.72 - 7.64 (m, 3H), 7.56 - 7.52 (m, 1 H), 7.02 (d, J = 5.9 Hz, 1 H), 6.67 (d, J = 8.9 Hz, 1 H), 2.56 (s, 3H).
Yield: 7% (two steps). Example 41
/V5-(7-Methoxyisoquinolin-1 -yl)pyridine-2,5-diamine
Figure imgf000080_0001
HPLC-MS (method A): Rt= 1.30 min, [M+H]+ m/z 267.
1H NMR (400 MHz, CD3OD) δ 8.09 - 8.03 (m, 1H), 7.70 (d, J
7.68 - 7.64 (m, 3H), 7.32 (dd, J = 9.0, 2.4 Hz, 1H), 7.01 (dd, J
1 H), 6.66 (dd, J = 8.8, 0.7 Hz, 1 H), 3.96 (s, 3H).
Yield: 35%.
Example 42
/V5-(5-Chloroisoquinolin-1-yl)pyridine-2,5-diamine
Figure imgf000080_0002
HPLC-MS (method A): Rt= 1.60 min, [M+H]+ m/z 271 , 273.
1H NMR (400 MHz, CD3OD) δ 8.26 (dt, J = 8.5, 0.9 Hz, 1 H), 8.09 (d, J = 2.6 Hz, 1H), 7.90 (d, J = 6.1 Hz, 1H), 7.78 (dt, J = 8.9, 2.4 Hz, 1H), 7.71 (dd, J = 8.8, 2.6 Hz, 1H), 7.51 (dd, J = 8.4, 7.6 Hz, 1H), 7.35 (dd, J = 6.1, 0.9 Hz, 1H), 6.67 (dd, J = 8.8, 0.7 Hz, 1H).
Yield: 33%.
Example 43
/V4-(7-Chloroisoquinolin-1-yl)-/V4-methylpyridine-2,4-diamine
Figure imgf000080_0003
HPLC-MS (method A): Rt = 1 .72 min, [M+H]+ m/z 285, 287.
1 H NMR (400 MHz, CDCI3) δ 8.38 (d, J = 5.7 Hz, 1 H), 7.76 (ddd, J = 8.6, 6.0, 4.4 Hz, 2H), 7.63 - 7.51 (m, 3H), 5.80 (dd, J = 6.3, 2.2 Hz, 1 H), 5.70 (d, J = 2.0 Hz, 1 H), 4.84 (s, 2H), 3.42 (s, 3H).
Yield: 12%.
Example 44
/V5-(7-Chloroisoquinolin-1 -yl)-/V5-methylpyridine-2,5-diamine
Figure imgf000081_0001
1 H NMR (400 MHz, DMSO-d6): 5 8.17 (d, J = 5.2 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.60-7.56 (m, 2H), 7.52 (d, J = 1.6 Hz, 1 H), 7.36 (d, J = 5.2 Hz, 1 H), 7.22 (dd, J = 8.8 Hz, 2.4 Hz, 1 H), 6.45 (d, J = 8.8 Hz, 1 H), 5.94 (s, 2H), 3.34 (s, 3H) HPLC-MS (method C): Rt = 1 .54 min, [M+H]+ m/z 285.
Yield: 34%.
General Procedure B
Following procedures B as those described in Schemes 1 or 2 compounds of formulae (la) or (lb) may be prepared in the conditions described below:
(F)n O, (Fin NH2
Figure imgf000081_0002
Figure imgf000082_0001
A mixture of the appropriate nitro intermediate (Via) or (Vlb) (ex: 7-chloro-N-(5- nitropyridin-2-yl)isoquinolin-1 -amine) and SnCl2-H20 (4 eq) in ethyl acetate (12 mL/mmol) was refluxed overnight. The obtained solution was washed with sodium bicarbonate (sat. sol.) (5x) and was extracted with ethyl acetate (3x). The combined organic layers were dried (magnesium sulphate), filtered and concentrated under vacuum. The residue was purified by flash column chromatography (dichloromethane/methanol) to yield the desired amino product (la) or (lb) (ex: /V2-(7-chloroisoquinolin-1 -yl)pyridine-2,5-diamine).
Example 45
N2-(7-chloroisoquinolin-1 -yl)pyridine-2,5-diamine
Figure imgf000082_0002
HPLC-MS (method A): Rt= 1 .75 min, (M+H)+ m/z 271 , 273.
1 H NMR (400 MHz, CD3OD) δ 8.39 (s, 1 H), 7.87 - 7.83 (m, 2H), 7.75 (d, J = 8.7
Hz, 1 H), 7.65 (dd, J = 8.7, 2.0 Hz, 2H), 7.21 (dd, J = 8.7, 2.9 Hz, 1 H), 7.08 (s,
1 H).
Yield: 91 %. Example 46
/V2-(7-Chloroisoquinolin-1 -yl)pyrimidine-2,5-diamine
Figure imgf000083_0001
HPLC-MS (method A): Rt= 1.63 min, [M+H]+ m/z 271 , 273.
1H NMR (400 MHz, CD3OD) δ: 8.56 (s, 1H), 8.17 (s, 2H), 7.71 - 7.60 (m, 3H), 6.97 (s, 1H).
Yield: 47%.
Example 47
/V2-(7-Chloroisoquinolin-1-yl)pyridine-2,4-diamine
Figure imgf000083_0002
HPLC-MS (method A): Rt= 1.93 min, [M+H]+ m/z 271 , 273.
1H NMR (400 MHz, CD3OD) δ 8.40 (d, J = 1.8 Hz, 1 H), 8.04 (d, J = 5.9 Hz, 1 H), 7.85 - 7.81 (m, 1H), 7.79 (d, J = 6.2 Hz, 1H), 7.69 (ddd, J = 8.7, 3.5, 2.0 Hz, 1H), 7.29-7.25 (m, 1H), 7.19 (s, 1H), 6.36 (dd, J = 6.2, 2.1 Hz, 1H).
Yield: 13%.
Example 48
/V2-(7-Methoxyisoquinolin-1 -yl)pyridine-2,5-diamine
Figure imgf000084_0001
HPLC-MS (method A): Rt= 1 .75 min, [M+H]+ m/z 267.
1 H NMR (400 MHz, CD3OD) δ 7.84 (dd, J = 2.9, 0.6 Hz, 1 H), 7.76 (d, J = 6.0 Hz, 1 H), 7.69 (dd, J = 13.9, 8.9 Hz, 2H), 7.42 - 7.33 (m, 2H), 7.23 (dd, J = 8.7, 2.9 Hz, 1 H), 7.10 (d, J = 5.7 Hz, 1 H), 3.98 (s, 3H).
Yield: 38%.
Example 49
/V2-(7-Methoxyisoquinolin-1 -yl)pyrimidine-2,5-diamine
Figure imgf000084_0002
HPLC-MS (method A): Rt= 1 .88 min, [M+H]+ m/z 268.
1 H NMR (400 MHz, CD3OD) δ 7.84 (s, 1 H), 7.71 (d, J = 8.9 Hz, 1 H), 7.63 (s, 1 H), 7.42 (t, J = 7.9 Hz, 1 H), 7.34 (dd, J = 8.9, 2.5 Hz, 1 H), 7.16 (s, 1 H), 6.20 (d, J = 8.1 Hz, 1 H), 3.97 (s, 3H).
Yield: 46%. Example 50
/V2-(5-Chloroisoquinolin-1 -yl)pyridine-2,5-diamine
Figure imgf000084_0003
HPLC-MS (method A): Rt= 2.67 min, [M+H]+ m/z 271 , 273. 1 H NMR (400 MHz, CD3OD) δ 8.29 (d, J = 8.4 Hz, 1 H), 8.07 (s, 1 H), 7.81 (dd, J = 7.6, 0.9 Hz, 1 H), 7.58 - 7.52 (m, 1 H), 7.46 (t, J = 7.9 Hz, 2H), 7.38 (s, 1 H), 6.25 (d, J = 8.7 Hz, 1 H).
Yield: 77%.
Example 51
/V2-(5-Methoxyisoquinolin-1 -yl)pyrimidine-2,5-diamine
Figure imgf000085_0001
HPLC-MS (method A): Rt= 1 .62 min, [M+H]+ m/z 268.
1 H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 8.00 (d, J = 8.4 Hz, 1 H), 7.79 (d, J 6.0 Hz, 1 H), 7.53 (t, J = 8.2 Hz, 1 H), 7.46 (dd, J = 7.2, 3.3 Hz, 1 H), 7.21 (d, J 7.8 Hz, 1 H), 4.01 (s, 3H).
Yield: 6%.
Intermediate 23
tert-Butyl (2-((2-amino-6-((7-chloroisoquinolin-1 -yl)amino)pyrimidin-4 yl)oxy)ethyl)(methyl)carbamate
Figure imgf000085_0002
Pd2(dba)3 (43 mg, 0.046 mmol, 0.05 eq) was added to a solution of 7- chloroisoquinolin-1 -amine (166 mg, 0.929 mmol, 1.0 eq), 4-chloro-6-(2- (methylamino)ethoxy)pyrimidin-2-amine (280 mg, 0.929 mmol, 1 .0 eq), xantphos (54 mg, 0.092 mmol, 0.1 eq) and cesium carbonate (606 mg, 1 .85 mmol, 2.0 eq) in pre-degassed 1 ,4-dioxane (10 V) and the reaction mixture was heated to 130°C for 2-3h. After consumption of starting material (TLC), the reaction mixture was cooled to room temperature and filtered over celite bed. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (2x100 mL). The combined organic extract was washed with brine solution (50 mL) followed by water (50 mL); dried over anhydrous sodium sulfate and concentrated. The crude compound was purified by flash column chromatography (Methanol/dichloromethane) to afford tert-butyl (2-((2-amino-6- ((7-chloroisoquinolin-1 -yl)amino)pyrimidin-4-yl)oxy)ethyl)(methyl)carbamate. HPLC-MS (method B): Rt= 5.6 min, [M+H]+ m/z 445.
Yield: 75%. Example 52
/V4-(7-Chloroisoquinolin-1 -yl)-6-(2-(methylamino)ethoxy)pyrimidine-2,4-diamine.
Figure imgf000086_0001
Hydrochloric acid in 1 ,4-dioxane (0.5 ml, 20% W/V) was added to a solution of tert-butyl (2-((2-amino-6-((7-chloroisoquinolin-1 -yl)amino)pyrimidin-4- yl)oxy)ethyl)(methyl)carbamate (300 mg, 0.674 mmol, 1 .0 eq) in tetrahydrofuran (10 V) at 0°C and stirred at room temperature for 2h. After consumption of starting material (TLC), the resultant precipitated was filtered and purified by semi-preparative HPLC (Column: CHEMSIL, SEMI-PREP-ODS-C18, 10 micron (20 x 250 mm); wavelength: 225 nm; flow: 15 mL/min; run time: 10 min; time & mobile phase-lsocratic (time in min/B): 0/30, 10/30 [B: acetonitrile: methanol (50:50); A: 0.1 % formic acid]) to afford compound MX-0296-01 .
HPLC-MS (method B): Rt= 2.40 min, [M+H]+ m/z 345.
1 H NMR (400 MHz, DMSO-d6): 5 9.59 (s, 1 H), 8.64 (s, 1 H), 8.18 (s, 1 H), 7.91 (s, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.41 (s, 1 H), 6.92 (s, 1 H), 6.17 (s, 2H), 4.25 (t, J = 6.9 Hz, 2H), 2.79 (t, J = 6.0, 2H), 2.33 (s, 3H). (Absence of -NH proton which is part of the aliphatic chain was observed when spectrum was recorded in DMSO-d6).
Yield: 5%.
Synthesis of Compounds of the Invention wherein R5 is C -4 alkyl
Compounds of formula (IA) wherein R5 is Ci-4 alkyl can be prepared, for example, by following general procedures 1 ) H, I, and J, and 2) K, L, and M, below.
General Procedure H
Following procedures as those described in Schemes 1 or 2, compounds of formulae (lAa) or (lAb), wherein R11 , R12, R13, R4, n, A1 , A2, and A3 are as defined above for formula (IA) and R5 is hydrogen, can be prepared. Following procedure H below, compounds of formulae (IIIAa) and (IIIAb), wherein R5 is hydrogen, can be prepared ("NPhth" is a phthalimide protected amine group):
Figure imgf000087_0001
>13 (lAb) ) 13 (IIIAb)
The appropriate amine (ex: /V3-(7-Methylisoquinolin-1 -yl)pyridazine-3,6-diamine) (1 eq.), phthalic anhydride (1 eq.) and anhydrous sodium acetate (1 .6 - 2 eq) were refluxed (120°C) in acetic acid (20 vol) for 2-3h or overnight under nitrogen atmosphere (or heated under microwave irradiation, 900 watts, 3-5 min). Reaction mixture was then cooled down and was concentrated under reduced pressure. The resultant crude was dissolved in ethyl acetate and washed with sodium hydrogencarbonate (x2). The aqueous layer was extracted with ethyl acetate (x2), and the combined organic layers were dried (magnesium sulphate), filtered and concentrated under vacuum to give the desired protected amine (ex: 2-(6-((7-methylisoquinolin-1 -yl)amino)pyridazin-3- yl)isoindoline-1 ,3-dione). Alternatively, the resultant crude was quenched with ice-cold water and the pH was adjusted to ~ 8 using ammonium hydroxide solution to afford a solid, which was filtered, washed with water and dried under reduced pressure.
Alternatively, the -NH2 group in compounds of formulae (lAa) and (lAb) wherein R5 is hydrogen, can be protected by reacting, for example, with tert-butyl carbamate to obtain a protected group -N(BOC)BOC.
Intermediate 24
2-(6-((7-Methylisoquinolin-1 -yl)amino)pyridazin-3-yl)isoindoline-1 ,3-dione
Figure imgf000088_0001
HPLC-MS (method A): Rt = 2.03 min, [M+H]+ m/z 382.
Yield: 43% (not purified). Intermediate 25
2-(6-((7-Chloroisoquinolin-1 -yl)amino)pyridin-2-yl)isoindoline-1 ,3-dione
Figure imgf000089_0001
HPLC-MS (method C): Rt = 3.08 min, [M+H]+ m/z 401 .
Yield: 73% (not purified).
Intermediate 26
2-(6-((7-Methoxyisoquinolin-1 -yl)amino)pyridin-2-yl)isoindoline-1 ,3-dione
Figure imgf000089_0002
HPLC-MS (method C): Rt = 3.04 min, [M+H]+ m/z 397.
Yield: 63% (not purified). Intermediate 27
1 -((6-(1 ,3-Dioxoisoindolin-2-yl)pyridin-2-yl)amino)isoquinoline-7-carbonitnle
Figure imgf000090_0001
HPLC-MS (method C): Rt
Yield: 40% (not purified).
Intermediate 28
2-(6-((7-Chloroisoquinolin-1 -yl)amino)pyrazin-2-yl)isoindoline-1 ,3-dione
Figure imgf000090_0002
HPLC-MS (method C): Rt = 3.72 min, [M+H]+ m/z 402.
Yield: 45% (not purified). General Procedure I
Following the general procedure I, compounds of formulae (IIIAa) and (IIIAb) can be converted to corresponding compounds (IVAa) and (IVAb), where R5 is C -4 alkyl (such as, e.g., methyl):
Figure imgf000091_0001
lodomethane (1.5 eq.) was added to a solution of the appropriate amine (1 eq) (ex: 2-(6-((7-methylisoquinolin-1 -yl)amino)pyridazin-3-yl)isoindoline-1 ,3-dione) and cesium carbonate (1 .5 eq) in dimethylformamide at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature during 72 h. The mixture was concentrated under reduced pressure. The resultant crude was dissolved in ethyl acetate and washed with water. The organic layer was dried (magnesium sulphate), filtered and concentrated under vacuum to obtain the desired amine methylated compounds (ex: 2-(6-(methyl(7- methylisoquinolin-1 -yl)amino)pyridazin-3-yl)isoindoline-1 ,3-dione).
Corresponding compounds where the -NH2 group has been protected by -N(BOC)BOC can be reacted similarly to obtain compounds where R5 is a -Ci-4 alkyl group, such as a methyl group (see Intermediate 34 below).
Intermediate 29
2-(6-(methyl(7-methylisoquinolin-1 -yl)amino)pyridazin-3-yl)isoindoline-1 ,3-dione
Figure imgf000091_0002
HPLC-MS (method A): Rt = 1 .95 min, [M+H]+ m/z 414.
Yield: 75% (not purified). Intermediate 30
2-(6-((7-Chloroisoquinolin-1 -yl)(methyl)amino)pyridin-2-yl)isoindoline-1 ,3-dione
Figure imgf000092_0001
HPLC-MS (method C): Rt = 4.26 min, [M+H]+ m/z 415.
Yield: 83% (not purified).
Intermediate 31
2-(6-((7-Methoxyisoquinolin-1 -yl)(methyl)amino)pyridin-2-yl)isoindoline-1 ,3- dione
Figure imgf000092_0002
HPLC-MS (method C): Rt = 3.88 min, [M+H]+ m/z 41 1 . Yield: 36% (not purified).
Intermediate 32
1 -((6-(1 ,3-Dioxoisoindolin-2-yl)pyridin-2-yl)(methyl)amino)isoquinoline-7- carbonitrile
Figure imgf000093_0001
HPLC-MS (method C): Rt = 3.88 min, [M+H]+ m/z 41 1 .
Yield: 33% (not purified).
Intermediate 33
2-(6-((7-Chloroisoquinolin-1 -yl)(methyl)amino)pyrazin-2-yl)isoindoline-1 ,3-dione
Figure imgf000093_0002
HPLC-MS (method C): Rt = 4.15 min, [M+H]+ m/z 416.
Yield: not purified Intermediate 34
Figure imgf000094_0001
HPLC-MS (method C): Rt = 4.85 min, [M+H]+ m/z 485.
Yield: 91 %
General Procedure J
Compounds of formulae (IVAa) and (IVAb) can be de-protected as described below to obtain compounds of formulae (lAa) and (lAb), respectively, wherein R5 is C1-4 alkyl:
Figure imgf000094_0002
Figure imgf000095_0001
A mixture of the appropriate protected amine (1 eq) (ex: 2-(6-(methyl(7- methylisoquinolin-1 -yl)amino)pyridazin-3-yl)isoindoline-1 ,3-dione) and hydrazine monohydrate (2 eq) in ethanol was stirred at room temperature for 2 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The resultant crude was dissolved in ethyl acetate and washed with water. The organic layer was dried (magnesium sulphate), filtered and concentrated under vacuum. The resultant residue was purified by flash column chromatography (dichloromethane/methanol) to obtain the desired free amine(ex: /V3-methyl-/V3-(7-methylisoquinolin-1 -yl)pyridazine-3,6-diamine).
Example 53
/V3-Methyl-/V3-(7-methylisoquinolin-1 -yl)pyridazine-3,6-diamine
Figure imgf000095_0002
HPLC-MS (method A): Rt = 1 .75 min, [M+H]+ m/z 266.
1 H NMR (400 MHz, CD3OD) 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1 H), 7.71 (d, J = 1.2 Hz, 2H), 7.59 (d, J = 9.6 Hz, 1 H), 7.31 (s, 1 H), 7.29 (d, J = 9.6 Hz, 1 H), 7.06 (d, J = 6.6 Hz, 1 H), 4.00 (s, 3H), 2.54 (s, 3H).
Yield: 12%. Example 54
/V2-(7-Chloroisoquinolin-1 -yl)-/V2-methylpyridine-2,6-diamine
Figure imgf000096_0001
1 H NMR (400 MHz, DMSO-d6): δ 8.36 (d, J = 5.6 Hz, 1 H) , 8.01 (d, J = 8.8 Hz, 1 H), 7.72 (dd, J = 8.8, 2.0 Hz, 1 H), 7.66 (d, J = 6.0 Hz, 1 H), 7.61 (s, 1 H), 7.16 (dd, J = 8.0, 7.6 Hz, 1 H) , 5.95 (d, J = 8.4 Hz, 1 H), 5.70 (s, 2H), 5.60 (d, J = 8.0 Hz, 1 H), 3.46 (s, 3H).
HPLC-MS (method B): Rt = 3.36 min, [M+H]+ m/z 285.
Yield: 15%. (PTLC purification was required further to FCC).
Example 55
/V2-(7-Methoxyisoquinolin-1 -yl)-/V2-methylpyridine-2,6-diamine
Figure imgf000096_0002
1 H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J = 5.2 Hz, 1 H), 7.89 (d, J = 8.8 Hz, 1 H), 7.58 (d, J = 6.0 Hz, 1 H), 7.37 (dd, J = 9.2, 2.4 Hz, 1 H), 7.09 (dd, J = 8.8, 7.6 Hz, 1 H), 6.99 (d, J = 2.0 Hz, 1 H), 5.89 (d, J = 7.6 Hz, 1 H), 5.68 (brs, 2H), 5.46 (d, J = 7.6 Hz, 1 H), 3.64 (s, 3H), 3.46 (s, 3H).
HPLC-MS (method B): Rt = 3.12 min, [M+H]+ m/z 281 .
Yield: 48%. Example 56
1-((6-Aminopyridin-2-yl)(methyl)amino)isoquinoline-7-carbonitnle
Figure imgf000097_0001
1H NMR (400 MHz, DMSO-d6): 58.44 (d, J = 5.6 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.94 (dd, J = 8.4, 2.0 Hz, 1H), 7.65 (d, J = 5.6 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.02 (d, J = 7.6 Hz, 1H), 5.82 (d, J = 8.0 Hz, 1H), 5.72 (brs, 2H), 3.5 (s, 3H).
HPLC-MS (method B): Rt = 3.12 min, [M+H]+ m/z 276.
Yield: 24%.
Example 57
/V2-(7-Chloroisoquinolin-1-yl)-/V2-methylpyrazine-2,6-diamine
Figure imgf000097_0002
1H NMR (400 MHz, DMSO-d6): 58.42 (d, J = 6.0 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.80-7.77 (m, 2H), 7.71 (d, J= 1.6 Hz, 1H), 7.32 (s, 1H), 6.96 (s, 1H), 6.15 (brs, 2H), 3.46 (s, 3H).
HPLC-MS (method B): Rt = 3.93 min, [M+H]+ m/z 286.
Yield: 10%. General Procedure K
Following procedures A, C and D described in Schemes 1 or 2 above, compounds of formulae (lAa), (lAb), (VIIAa), and (VIIAb), wherein R11 , R12 R13, R4, R5, n, A1 , A2, and A3 are as defined above for formula (IA), can be prepared similarly in the conditions described below:
Figure imgf000098_0001
A mixture of the appropriate chloride (ex: 1 ,7-dichloroisoquinoline) (1 eq), the appropriate 6-chloro-/V-methylpyridazin-3-amine (1 eq), Pd2(dba)3 (0.05 eq), XantPhos (0.1 eq) and cesium carbonate (1 .5 eq) in dioxane (5.3 mL/mmol) (pre- degasified) was heated at 130°C for 2-5h under nitrogen atmosphere. The mixture was filtered through a celite pad and concentrated under reduced pressure. Alternatively, extraction with ethyl acetate, washing with brine and drying with sodium sulphate was also performed. The residue was purified by flash column chromatography (dichloromethane/methanol or hexanes/ethyl acetate) to obtain the desired product (ex: 7-chloro-/V-(3-nitrophenyl)isoquinolin- 1 -amine). Intermediate 35
7-Chloro-/V-(6-chloropyridazin-3-yl)-/V-methylisoquinolin-1 -amine
Figure imgf000099_0001
HPLC-MS (method C): Rt = 3.69 min, [M+H]+ m/z 305.
Yield: 53%.
Intermediate 36
/V-(6-chloropyridazin-3-yl)-7-methoxy-/V-methylisoquinolin-1 -amine
Figure imgf000099_0002
HPLC-MS (method C): Rt = 3.35 min, [M+H]+ m/z 301 .
Yield: 39%.
Intermediate 37
1 -((6-Chloropyridazin-3-yl)(methyl)amino)isoquinoline-7-carbonitrile
Figure imgf000099_0003
HPLC-MS (method C): Rt = 3.12 min, [M+H]+ m/z 296.
Yield: 37%.
Intermediate 38
7-Chloro-/V-(2-chloropyridin-4-yl)-/V-methylisoquinolin-1 -
Figure imgf000100_0001
Sodium Hydride (8 mg, 0.314 mmol, 1.1 eq.) was added to a flame-dried round- bottom flask under nitrogen atmosphere. Anhydrous THF (2 ml_) was added. The slurry was cooled to 0 °C and 7-chloro-/V-(2-chloropyridin-4-yl)isoquinolin-1 - amine (83 mg, 0.286 mmol, 1 eq.). After stirring at 0°C for 15 minutes methyl iodide (20 μΙ_, 0.314 mmol, 1.1 eq.) was added end the reaction was allowed to warm to room temperature during 2h. The reaction was diluted with ethyl acetate and washed with water (x1 ). The aqueous layer was extracted with ethyl acetate (x2), and the combined organics were washed with brine, dried with magnesium sulphate, filtered and concentrated in vacuum. Purification by flash chromatography on silica gel (hexane/ethyl acetate) afforded 84 mg (96%) of desired compound.
HPLC-MS (method A): Rt = 2.92 min, [M+H]+ m/z 304, 306.
Yield: 96%.
General Procedure L
Following a procedure similar to procedure E as described in Schemes 1 or 2 above, compounds of formulae (VIIIAa) or (VIIIAb) can be prepared in the conditions described below:
Figure imgf000101_0001
Pd2(dba)3 (0.05 eq) was added to a solution of the appropriate chloro derivative (1 .0 eq) (ex: 7-chloro-/V-(6-chloropyridazin-3-yl)-/V-methylisoquinolin-1 -amine), 4-methoxybenzyl amine (3.0 eq), BINAP (0.1 eq) and sodium tert-butoxide (1.5 eq) in dioxane (20 ml), and the reaction mixture was heated to 100°C for 2-3 hrs. The mixture was cooled and diluted with water (50 ml) and extracted with ethyl acetate (2 χ 100 ml). The combined organic extract was washed with water (50 ml) followed by brine solution (50 ml); dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane/methanol or hexanes/ethyl acetate) to obtain the desired compound (ex: N3-(7-chloroisoquinolin-1 -yl)-N6- (4-methoxybenzyl)-N3-methylpyridazine-3,6-diamine).
Intermediate 39
/V3-(7-Chloroisoquinolin-1 -yl)-/V6-(4-methoxybenzyl)-/V3-methylpyridazine-3,6- diamine
Figure imgf000102_0001
HPLC-MS (method C): Rt = 2.80 min, [M+H]+ m/z 406.
Yield: 33%.
Intermediate 40
/V3-(4-Methoxybenzyl)-/\/6-(7-methoxyisoquinolin-1 -yl)-/\/6-methylpyridazine-3,6- diamine
Figure imgf000102_0002
HPLC-MS (method C): Rt = 2.77 min, [M+H]+ m/z 402.
Yield: 99%. Intermediate 41
1 -((6-((4-Methoxybenzyl)amino)pyridazin-3-yl)(methyl)amino)isoquinoline-7- carbonitrile
Figure imgf000103_0001
HPLC-MS (method C): Rt = 2.60 min, [M+H]+ m/z 397.
Yield: 99% (not purified).
General Procedure M
Following procedures similar to those described in Schemes 1 or 2 above, compounds of formulae (lAa) and (lAb) can be prepared in the conditions described below:
Figure imgf000103_0002
Figure imgf000103_0003
Trifluoroacetic acid (5 ml) was added to a solution of the appropriate protected amine (1 eq) (ex: ^-(Z-Chloroisoquinolin-l -y -A^^-methoxybenzy -A/3- methylpyridazine-3,6-diamine) at RT and the reaction mixture was stirred at 60°C for 5-6 hrs. Trifluoroacetic acid was evaporated under reduced pressure, the resultant crude was poured in to ice-cold water and the mixture was basified using saturated sodium hydrogen carbonate solution (pH ~ 9). The solution was extracted with ethyl acetate (3 X 30 ml) and the organic was washed with water, brine solution (50 ml); dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane/methanol or hexanes/ethyl acetate) to obtain the desired compounds (ex: N3-(7-chloroisoquinolin-1 -yl)-N3-methylpyridazine- 3,6-diamine).
Example 58
/V3-(7-Chloroisoquinolin-1 -yl)-/V3-methylpyridazine-3,6-diamine
Figure imgf000104_0001
1 H NMR (400 MHz, DMSO-d6): δ 8.28 (d, J = 5.6 Hz, 1 H), 8.01 (d, J = 8.8 Hz, 1 H), 7.71 (dd, J = 8.8, 1 .6 Hz, 1 H), 7.60 (d, J = 5.6 Hz, 1 H), 7.56 (s, 1 H), 7.04 (d, J = 9.2 Hz, 1 H), 6.78 (d, J = 9.6 Hz, 1 H), 6.06 (brs, 2H), 3.45 (s, 3H).
HPLC-MS (method B): Rt = 3.19 min, [M+H]+ m/z 286.
Yield: 12%. Example 59
/V3-(7-Methoxyisoquinolin-1 -yl)-/V3-methylpyridazine-3,6-diamine
Figure imgf000105_0001
1 H NMR (400 MHz, DMSO-d6): ): δ 8.14 (d, J = 5.6 Hz, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.55 (d, J = 5.6 Hz, 1 H), 7.36 (m, 1 H), 6.98 (d, J = 2.0 Hz, 1 H), 6.84 (d, J = 9.2 Hz, 1 H), 6.74 (d, J = 9.2 Hz, 1 H), 6.02 (brs, 2H), 3.68 (s, 3H), 3.45 (s, 3H). Signals due to possible minor tautomer were observed at 12.0, 8.00, 7.84, 7.44 and 7.36.
HPLC-MS (method B): Rt = 3.15 min, [M+H]+ m/z 282.
Yield: 3%.
Example 60
1 -((6-Aminopyridazin-3-yl)(methyl)amino)isoquinoline-7-carbonitrile
Figure imgf000105_0002
1 H NMR (400 MHz, DMSO-d6): ): δ 8.38 (d, J = 5.2 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 8.0 (s, 1 H), 7.95 (d, J = 8.8 Hz, 1 H), 7.63 (d, J = 5.2 Hz, 1 H), 7.20 (d, J = 9.6 Hz, 1 H), 6.84 (d, J = 9.2 Hz, 1 H), 6.21 (brs, 2H), 3.55 (s, 3H).
HPLC-MS (method C): Rt = 1 .1 1 min, [M+H]+ m/z 277.
Yield: 6%.
Synthesis of other intermediates (starting materials)
Intermediate 42
tert-Butyl (5-nitropyridin-2-yl)carbamate
Figure imgf000106_0001
5-Nitropyridin-2-amine (1 eq), Boc20 (1 .2 eq), DMAP (0.2 eq) was added to a flask under nitrogen atmosphere. Dichloromethane was added at room temperature and the mixture was stirred overnight. Ethyl acetate was added to the crude, the precipitated was filtered and washed with ethyl acetate to obtain the desired tert-butyl (5-nitropyridin-2-yl)carbamate.
HPLC-MS (method A): Rt= 2.88 min, [M+H]+ m/z: 240.
Yield: 80%.
Intermediate 43
tert-Butyl (5-aminopyridin-2-yl)carbamate
Figure imgf000106_0002
tert-Butyl (5-nitropyridin-2-yl)carbamate (1 eq), Pd/C (10% w/w) and ethyl acetate was added to a flask under H2 atmosphere. The mixture was stirred at room temperature overnight. The mixture was filtered through a celite pad and the filtrate concentrated under reduced pressure to obtain tert-butyl (5- aminopyridin-2-yl)carbamate.
HPLC-MS (method A): Rt= 1 .50 min, [M+H]+ m/z: 210.
Yield: quantitative yield.
Intermediate 44
2,6-Difluoro-4-(pyridin-3-yloxy)pyridine
Figure imgf000106_0003
Pyridin-3-οΙ (1.5 eq) and potassium carbonate (1 .5 eq) were added to a solution of 2,4,6-trifluoropyridine (1 eq) in dimethylformamide at -50°C. The reaction mixture was slowly warmed to room temperature. The mixture was stirred at room temperature for 4h. The mixture was diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate (x2), and the combined organics were dried (magnesium sulphate), filtered and concentrated in vacuo to give the desired compound as a brown oil.
HPLC-MS (method A): Rt= 2.35 min, [M+H]+ m/z: 209.
Yield: 53%.
Intermediate 45
4-(Pyridin-3-yloxy)pyridine-2,6-diamine
Figure imgf000107_0001
A mixture of 2,6-Difluoro-4-(pyridin-3-yloxy)pyridine in NH4OH was heated to 120°C in a pressure vessel for 5 days. Cooled to room temperature and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate (x2), and the combined organics were dried (magnesium sulphate), filtered and concentrated in vacuo to give the desired compound.
HPLC-MS (method A): Rt= 1 ,07 min, [M+H]+ m/z: 203.
Yield: 36%.
Intermediate 46
tert-Butyl (5-nitropyrimidin-2-yl)carbamate
Figure imgf000107_0002
5-Nitropyrimidin-2-amine (1 eq), Boc20 (1 .2 eq), 4-dimethylaminopyridine (0.2eq) were added to a flask under nitrogen atmosphere and dichloromethane at room temperature. The mixture was stirred at room temperature overnight. Ethyl acetate was added and a precipitated formed was filtered and washed with ethyl acetate to obtain the desired tert-butyl (5-nitropyridin-2-yl)carbamate. (Crude contains approximately 20% of tert-butyl (5-nitropyrimidin-2- yl)dicarbamate mixture. Was used in the next step without purification).
HPLC-MS (method A): Rt= 2.83 min, [M+H]+ m/z: 241.
Yield: 78%.
Intermediate 47
tert-Butyl (5-aminopyrimidin-2-yl)carbamate
Figure imgf000108_0001
tert-butyl (5-nitropyrimidin-2-yl)carbamate (1 eq), Pd/C (10% w/w) and ethyl acetate were mixed and stirred at room temperature overnight under H2 atmosphere. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to obtain tert-butyl (5- aminopyrimidin-2-yl)carbamate (Crude contains approximately 20% of tert-butyl (5-aminopyrimidin-2-yl)dicarbamate. Was used in the next step without purification).
HPLC-MS (method A): Rt= 1 ,63 min, [M+H]+ m/z: 21 1.
Yield: 98%.
Intermediate 48
4-Chloro-6-(2-(methylamino)ethoxy)pyrimidin-2 -amine
Figure imgf000109_0001
Sodium hydride (134 mg, 3.353 mmol, 1.1 eq) was added portion wise to a solution of tert-butyl (2-hydroxyethyl)methylcarbamate (534 mg, 3.048 mmol, 1 .0 eq) and compound 4,6-dichloropyrimidin-2-amine (500 mg, 3.048 mmol, 1 .0 eq) in tetrahydrofuran (20 mL/mmol) and the reaction mixture was heated under microwave radiation (600 W) for 20 min. After consumption of the starting materials (TLC), the reaction mixture was let to cool to room temperature and quenched with water (50 mL) and extracted with ethyl acetate (2x100 mL). The combined organic extracts were washed with brine solution (50 mL) followed by water (50 mL); dried over anhydrous sodium sulfate and concentrated. The crude compound was purified by flash column chromatography (Si02; ethyl acetate/hexane) to afford 4-Chloro-6-(2-(methylamino)ethoxy)pyrimidin-2- amine. HPLC-MS (method E): Rt= 4.7 min, [M+H]+ m/z: 303.
Yield: 43%.
Intermediate 49
Dimethyl 4-bromopyridine-2,6-dicarboxylate
Figure imgf000109_0002
Phosphorous pentabromide (42 g) was added to chelidemic acid (5.0 g, 0.025 mol) and heated 80°C for 3 hours. After consumption of starting materials (TLC), the reaction mixture was cooled to room temperature, diluted with chloroform (400 mL) and filtered. The filtrate was cooled to -10°C and methanol (75 mL) was added drop wise and the mixture was stirred at -10°C. After 1 h, the reaction mixture was brought to room temperature and concentrated under vacuum. The resulting residue was diluted with ice-cold water (300 mL) to afford a precipitate. The solid precipitate was filtered, washed with water and dried under vacuum to afford dimethyl 4-bromopyridine-2,6-dicarboxylate., which was taken to the next step without further purification. Crude yield: 5.2 g.
HPLC-MS (method C): Rt= 2.72 min, [M+H]+ m/z: 274.
Yield: not purified.
Intermediate 50
4-Bromopyridine-2,6-dicarboxamide
Figure imgf000110_0001
Ammonia gas was purged into a solution of Dimethyl 4-bromopyridine-2,6- dicarboxylate (5.2 g, 0.019 mol) in methanol (Note: 150 mL hot methanol was required for dissolution) for 2h at room temperature. After consumption of starting materials (TLC), the reaction mixture was concentrated under vacuum. The resulting residue was washed with ethyl acetate (10 mL), filtered and dried under vacuum to get the crude product 4-bromopyridine-2,6-dicarboxamide. as white solid, which was taken to the next step without further purification. 4.1 g.
HPLC-MS (method C): Rt= 1 .09 min, [M+H]+ m/z: 244.
Yield: Without purification. Intermediate 51
4-Bromopyridine-2,6-diamine
Figure imgf000111_0001
Bromine (0.2 ml) was added drop wise to a KOH solution (5M, 20 ml_) at 0°C and reaction mixture was stirred at 0°C. After 1 h, 4-Bromopyridine-2,6- dicarboxamide (4.1 g, 0.017 mol) was added slowly to the reaction mixture at 0°C and stirred for 30 min. Further, the reaction mixture was heated 90°C for 2h. After consumption of starting materials (TLC), the reaction mixture was extracted with ethyl acetate (5x100 ml_). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The crude was washed with hexane, filtered and dried under vacuum to afford the desired 4- Bromopyridine-2,6-diamine, which was taken to the next step without further purification (1 .86 g.)
HPLC-MS (method C): Rt= 0.8 min, [M+H]+ m/z: 190.
Yield: not purified.
Intermediate 52
2,6-Diaminoisonicotinonitrile
Figure imgf000111_0002
Copper(l) cyanide (478 mg, 5.30 mmol) was added to 4-Bromopyridine-2,6- diamine (500 mg, 2.65 mmol) in dimethylformamide (15 ml_) and the mixture was heated at 200°C under nitrogen for 4h. After noticing 30% formation of the required product by LC-MS, reaction mixture was cooled to room temperature, quenched with ice-cold water and extracted with ethyl acetate (2x100 ml_). The combined organic extracts were washed with brine solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The obtained residue was purified by semi-preparative HPLC (Column: CHEMSIL, SEMI- PREP-ODS-C18, 10 micron (20 x 250 mm); wavelength: 210 nm; flow: 15 mL/min; run time: 15 min; time & mobile phase-gradient (time in min/B): 0/23, 9.5/23, 9.6/90, 14/90, 14.1/23, 15/23 [B: acetonitrile: methanol (50:50); A: 10 mM Ammonium acetate]) to afford compound 2,6-diaminoisonicotinonitrile (6.0 mg).
HPLC-MS (method D): Rt= 0.69 min, [M+H]+ m/z: 135.
Yield: 17%.
Intermediate 53
Dimethyl 4-hydroxypyridine-2,6-dicarboxylate
Figure imgf000112_0001
Concentrate sulfuric acid (1 drop) was added to a solution of Chelidemic acid (250 mg, 1 .24 mmol) in MeOH (10 ml_) and refluxed for 16h. After consumption of starting material (TLC), the reaction mixture was cooled to room temperature and concentrated. Water (50 ml_) was added to the reaction crude and pH was adjusted to ~7 by using saturated sodium hydrogen carbonate solution. The white solid obtained was filtered; washed with water and dried under vacuum to get the 190 mg of dimethyl 4-hydroxypyridine-2,6-dicarboxylate. as white solid.
HPLC-MS (method B): Rt= 1 .26 min, [M+H]+ m/z: 212.
Yield: 72%. Intermediate 54
Dimethyl 4-methoxypyridine-2,6-dicarboxylate
Figure imgf000113_0001
lodomethane (1 .31 g, 2.0 eq) was added to a stirred suspension of dimethyl 4- hydroxypyridine-2,6-dicarboxylate (0.98 g, 1 eq) and sodium hydride (0.28 g, 1 .5 eq) in DMF (150 ml) at 0°C and reaction medium was stirred for 12h at room temperature. After consumption of starting materials (TLC), reaction mixture was diluted with water (10 mL) and extracted in ethyl acetate (2 χ 20ml). The combined organic extracts were washed with brine solution (10 mL) followed by water (10 mL) and the resulting organic layer was dried over anhydrous sodium sulfate and concentrated. The crude was purified by flash column chromatography (dichloromethane/Acetone) to afford desired compound dimethyl 4-methoxypyridine-2,6-dicarboxylate.
HPLC-MS (method B): Rt= 2.2 min, [M+H]+ m/z: 226.
Yield: 60%.
Intermediate 55
4-Methoxypyridine-2,6-dicarboxamide
Figure imgf000113_0002
Ammonia was purged in to a cooled solution of dimethyl 4-methoxypyridine-2,6- dicarboxylate (0.6 g, 2.66 mmol) in MeOH (60 mL) for 2h at 10°C. After consumption of starting material as (TLC), the white precipitate formed was filtered off and completely dried under vacuum to afford desired compound 4- methoxypyridine-2,6-dicarboxamide.
HPLC-MS (method B): Rt= 2.86 min, [M+H]+ m/z: 196.
Yield: 98%.
Intermediate 56
4-Methoxypyridine-2,6-diamine
Figure imgf000114_0001
Bromine (0.27 ml, 2 eq) was added to a solution of KOH (5M, 27.7 ml) at 0°C and the mixture was stirred for 30 min. To reaction mixture, compound 4- Methoxypyridine-2,6-dicarboxamide (500 mg) in 1 ,4-dioxane (5 mL) was added drop wise at 0°C and stirred at 0°C. After 1 h, the reaction temperature was gradually raised to room temperature and reaction mixture was heated to 80°C for 1 h. After consumption of starting material as observed by TLC, reaction mixture was cooled to room temperature; diluted with water (20 mL) and extracted in dichloromethane (10x50 mL). The combined organic extract was dried over anhydrous sodium sulfate and concentrated to afford the desired 4- methoxypyridine-2,6-diamine.
HPLC-MS (method B): Rt= 1 .7 min, [M+H]+ m/z: 140.
Yield: 42%.
Intermediate 57
Dimethyl 4-chloropyridine-2,6-dicarboxylate
Figure imgf000115_0001
Phosphoryl chloride (1 ml) was added to Chelidemic acid (4-methoxypyridine- 2,6-diamine, 500 mg, 2.48 mmol) taken in round bottom flask and the reaction mixture was heated at 90°C for 3h. After consumption of starting material (TLC), the reactiuon mixture was cooled to room temperature and diluted with chloroform (20 ml_). Reaction mixture was further cooled to -10°C and methanol (10 ml_) was added dropwise and stirred at the same temperature. After 1 h, the reaction mixture was brought to room temperature; diluted with water (30 ml_) and extracted. The organic layer was separated; dried over anhydrous sodium sulfate and concentrated to afford a crude compound, which was taken to the next step without further purification.
HPLC-MS (method B): Rt= 3.4 min, [M+H]+ m/z: 230.
Yield: Without purification.
Intermediate 58
4-Chloropyridine-2,6-dicarboxamide
Figure imgf000115_0002
Ammonia gas was purged to a solution of compound dimethyl 4-chloropyridine- 2,6-dicarboxylate (900 mg, 3.93 mmol) in hot methanol (10 ml_) 2h at room temperature. After consumption of starting materials as (TLC), the reaction mixture was concentrated and the resulting residue was washed with ethyl acetate (10 ml_); filtered and dried under vacuum to get the product 4- chloropyridine-2,6-dicarboxamide as white solid. HPLC-MS (method B): Rt= 1 .45 min, [M+H]+ m/z: 200.
Yield: 64%.
Intermediate 59
4-(4-Chlorophenoxy)pyridine-2,6-dicarboxamide
Figure imgf000116_0001
Potassium carbonate (53 mg, 0.37 mmol) was added to a solution of 4- chloropyridine-2,6-dicarboxamide (50 mg, 0.25 mmol) and 4-chlorophenol (32 mg, 0.25 mmol) in dimethylformamide (2 mL) and the reaction mixture was stirred under N2 at 120°C for 4h. After consumption of starting materials (TLC), the reaction mixture was let to cool to room temperature and quenched with ice water. The solid obtained was filtered, washed with water and dried under vacuum to afford the desired compound 4-(4-Chlorophenoxy)pyridine-2,6- dicarboxamide.
HPLC-MS (method B): Rt= 3.8 min, [M+H]+ m/z: 292.
Yield: 51 %. Intermediate 60
4-(4-Chlorophenoxy)pyridine-2,6-diamine
Figure imgf000116_0002
Bromine (273 mg, 1 .72 mmol) was added drop wise to solution of KOH (462 mg, 8.42 mmol) in water (2 ml_) at 0 °C and reaction medium was stirred at 0°C. After 1 h, a suspension of 4-(4-chlorophenoxy)pyridine-2,6-dicarboxamide (200 mg, 0.687 mmol) in 1 ,4-dioxan (2 ml_) was added slowly to the reaction mixture at 0°C. Further, the reaction mixture was heated to 90°C for 1 h. After consumption of starting materials (TLC), the reaction mixture was extracted in ethyl acetate (2x25ml_). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The crude was washed with hexane, filtered and dried under vacuum to afford desired 4-(4- Chlorophenoxy)pyridine-2,6-diamine.
HPLC-MS (method B): Rt= 3.08 min, [M+H]+ m/z: 236.
Yield: 81 %. Intermediate 61
Figure imgf000117_0001
di-tert-Butyl dicarbonate (3.0 g, 14.38 mmol, 4 eq) was added to a solution of 5- nitropyridin-2-amine (500 mg, 3.57 mmol, 1 eq), Λ/,/V-diisopropyl ethylenediamine (1 .35 g, 10.71 mmol, 3 eq) and 4-dimethylaminopyridine (42 mg, 0.357 mmol, 0.1 eq) in dichloromethane (15 ml) at 0°C and the reaction mixture was stirred at room temperature for 12 hrs. Mixture was diluted with water (30 ml) and extracted with dichloromethane (2 X 30 ml). The combined organic extract was washed with water (50 ml) followed by brine solution (50 ml); dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexanes/ethyl acetate) to obtain the desired compound.
HPLC-MS (method C): Rt = 4.49 min, [M+H]+ m/z 140. Yield: 83%.
Intermediate 62
Figure imgf000118_0001
Palladium (80 mg, 10% on C, 25% w/w) was added to a pre-degassed solution of intermediate 61 (300 mg, 0.884 mmol, 1 .0 eq) in EtOH and ethyl acetate (1 : 1 , 10 ml) and the reaction mixture was stirred under hydrogen (atmosphere pressure) at room temperature for 12 hrs. Mixture was filtered off through celite and concentrated under reduced pressure.
HPLC-MS (method C): Rt = 3.20 min, [M+H]+ m/z 310.
Yield: 91 %. Example 61
2-Amino-6-((7-chloroisoquinolin-1 -yl)amino)pyridin-4-ol
Figure imgf000118_0002
The title compound was prepared as follows: a) Intermediate 63
fe/f-Butyl (6-bromo-4-hydroxypyridin-2-yl)carbamate
Figure imgf000118_0003
A mixture of 2,6-dibromo-4-fluoropyridine (1 eq), tert-butylcarbamate (4 eq), Pd2(dba)3 (0.1 eq), XantPhos (0.2 eq) and cesium carbonate (2 eq) in dioxane (5.3 mL/mmol) (pre- degasified) was heated at 90°C for 5h under nitrogen atmosphere. The mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane/methanol/0.1 %NH3) to obtain the desired product.
HPLC-MS (method A): Rt = 2.72 min, [M+H]+ m/z 289, 291 .
Yield: 15% b) Intermediate 64
tert-Butyl (6-((7-chloroisoquinolin-1 -yl)amino)-4-hydroxypyridin-2-yl)carbamate
Figure imgf000119_0001
Intermediate 64 was prepared from intermediate 63 using general procedures A2, C2, and D2.
HPLC-MS (method A): Rt = 2.37 min, [M+H]+ m/z 387.
Yield: not purified. c) 2-Amino-6-((7-chloroisoquinolin-1 -yl)amino)pyridin-4-ol
The title compound was prepared from Intermediate 64 using General procedure F HPLC-MS (method A): Rt = 1 .90 min, [M+H]+ m/z 287. 1 H NMR (400 MHz, CD3OD) δ 8.64 (s, 1 H), 8.14 (d, J = 6.0 Hz, 1 H), 7.92 (d, J =
8.8 Hz, 1 H), 7.80 (dd, J = 8.7, 2.0 Hz, 1 H), 7.43 (d, J = 6.0 Hz, 1 H), 6.12 (d, J =
1 .9 Hz, 1 H), 5.67 (d, J = 2.0 Hz, 1 H).
Yield: 8% (two steps).
Biological Assays
Compounds according to the present invention are capable of binding allosterically to mutated β-galactosidase enzyme thereby stabilizing the enzyme against denaturation and enhancing its catalytic activity. Material and methods
Enhancement of β-galactosidase activity measured in transfected cells with WT or mutant proteins P.T420K, P.R457Q, P.Y83C and P.R201 H
Vector construction
The coding region of human wild-type β-galactosidase cDNA was amplified by PCR in two fragments that were ligated and cloned in a pUC18 vector. Mutations p.T420K, p.R457Q, p.Y83C and p.R201 H were generated by site- directed mutagenesis using the QuickChangeTM Site-Directed Mutagenesis XL kit (Stratagene, La Jolla, CA) according to the manufacturer's instructions. The constructs were resequenced to ensure that no spurious mutation had been introduced. For protein expression, the wild-type and mutated cDNAs were subcloned into the pcDNA3.1 expression vector.
Cell culture and transfection
COS-7 cells were cultured in 100 mm diameter tissue culture dishes with DMEM (Sigma-Aldrich, St. Louis, MO), 10% fetal bovine serum (Life Technologies S.A., Carlsbad, CA), and antibiotics. For transfection with wild- type and mutant β-galactosidase cDNAs, 8x104 cells per well were plated in 12- well microplates. Twenty-four hours later, 1 .6 g of the corresponding plasmid mixed with 2.5 μΙ of LipofectamineTM 2000 Reagent (Life Technologies S.A., Carlsbad, CA) was added to each well. As a negative control, a pcDNA vector carrying antisense β-galactosidase cDNA was transfected. After 6 hours of incubation at 37°C, transfection medium was removed, and the cells were exposed to fresh medium adding the compounds at the desired concentration. After 48 hours of incubation, the cells were washed with PBS and incubated with or without the compounds for another 24 hours. At the end of this period, the medium was removed, and cells were washed and exposed for 4 hours to complete medium. Then, cells were collected and centrifuged at 13000 rpm for 5 minutes. Cellular pellets were washed twice with PBS and stored at -80°C until the enzymatic analysis was performed. Enzyme activity β-galactosidase activity in cell lysates was measured by using 4-ΜΙΙ-β- galactopyranoside substrate (Sigma-Aldrich, St. Louis, MO). Lysates were resuspended in 200 μΙ of 0.9% NaCI containing 0.01 % triton X-100 lysis buffer to promote membrane disruption. The cell suspension was sonicated and centrifuged at 13000 rpm 2 min to remove insoluble materials. Then, lysates were mixed with 4-MU^-galactopyranoside in 100 mM citrate buffer (pH=4) 100 mM NaCI for 30 min at 37°C. The reaction was terminated by adding 200 mM glycin-NaOH buffer (pH=10.7). The liberated 4-MU was measured with a fluorescence reader (excitation 340 nm, emission 460 nm, Modulus Microplate Multimode Reader, Turner Biosystems). Protein quantification was determined using BCA protein assay kit (Pierce BCA Protein Assay Kit, Thermo Fisher Scientific Inc., Waltham, MA).
Measurements were interpolated in a 4-MU standard curve and normalized by protein quantity. Enzyme activities were expressed in treated cells as X-fold increase in comparison with non-treated cells (X=1 represents no enhancement).
In COS-7 cells transiently transfected with human GLB1 mutants p.T420K, p.R457Q, p.Y83C and p.R201 H, compounds of the invention, tested at 12.5- 100 μΜ, significantly enhanced the enzymatic activity with a value equal or greater than 20%, when compared with the residual activity of non-treated cells. When compared with activity of cells transfected with wilde-type GLB1 , such enhancement of activity is reported in literature as a meaningful increase on enzymatic activity. Mutants p.T420K and p.R457Q are responsible for adult type III GM1 -gangliosidosis, and mutant p.Y83C causes Morquio B disease. Mutation p.R201 H has been found in patients with juvenile (type II) and adult (type III) GM1 -gangliosidosis and Morquio B disease.
The capacity of the compounds of the invention to produce an increase in enzyme activity in COS-7 cells bearing T420K human GLB1 at concentrations between 6 and 50 μΜ is denoted as follows:
- Increase in comparison with non-treated of >2.5 fold is shown as A - Increase in comparison with non-treated of >1 .7-2.5 fold is shown as B
- Increase in comparison with non-treated of 1 .2-1 .7 fold is shown as C
- D means that no increase compared with non-treated cells was detected in this method
ND means "not determined"
Example Activity in T420K
1 A
2 A
3 A
4 B
5 D
6 B
7 B
8 A
9 B
10 D
1 1 D
12 A Example Activity in T420K
13 C
14 C
15 A
16 A
17 B
18 A
19 D
20 D
21 B
22 D
23 C
24 A
25 A
26 B
27 B
28 C
29 C
30 D
31 D
32 D
33 C
34 B
35 C
36 C
37 A
38 C
39 C
40 C
41 C
42 B Example Activity in T420K
43 B
44 D
45 A
46 A
47 C
48 D
49 D
50 A
51 A
52 A
53 ND
54 C
55 ND
56 ND
57 ND
58 ND
59 ND
60 ND
61 ND
All publications cited in this specification are incorporated herein by reference. While the invention has been described with reference to particular embodiments, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims

1 . A compound of formula (IA):
Figure imgf000125_0001
or a salt or solvate thereof, wherein: each A1 is independently selected from the group consisting of nitrogen and C(R2A); each of A2 and A3 is independently selected from the group consisting of nitrogen, C(R3A) and C(NH2); provided that exactly one of A2 and A3 is C(NH2) and wherein no less than one and no more than two of A1, A2 and A3 are nitrogen; R11, R12, and R13 are each independently selected from the group consisting of hydrogen, halogen, -CN, -ORbA, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, with the proviso that at least one R11, R12, and R13 is other than hydrogen;
R2A is selected from the group consisting of hydrogen, halogen, -CN, Ci-4 alkyl, and halo(Ci-4)alkyl; each one of R3A is independently selected from the group consisting of hydrogen, halogen, -CN, -ORaA, -Ci-4 alkyl, -C3-i0 cycloalkyl, and 5- to 10- membered heterocyclyl, said alkyl, cycloalkyl and heterocyclyl groups are optionally substituted with 1 , 2 or 3 groups each independently selected from the group consisting of halogen, hydroxy, -Ci-4 alkyl optionally substituted with 1 , 2 or 3 halogen atoms, -N(RbA)2, and Ci-4 alkoxy optionally substituted with 1 , 2 or 3 independently selected halogen atoms; each R4 is independent selected from the group consisting of halogen, Ci-4 alkyl, Ci-4 alkoxy, CN and hydroxy;
R5 is hydrogen or Ci-4 alkyl; n has a value selected from 0, 1 or 2; each RaA is independently selected from the group consisting of hydrogen, -Ci-4 alkyl, -C3-10 cycloalkyl, -Ci-4 alkyl-(C3-io)cycloalkyl, -C6-10 aryl, -Ci-4 alkyl-(C6- io)aryl, 5- to 10-membered heteroaryl, -Ci-4 alkyl-(5- to 10-membered heteroaryl), 5- to 10-membered heterocyclyl, -Ci-4 alkyl-(5- to 10-membered heterocyclyl), wherein any of which, when other than hydrogen, is optionally being substituted with 1 , 2 or 3 groups each independently selected from the group consisting of halogen, -CN, -ORbA, -SRbA, -N(RbA)2, -Ci-4alkyl optionally substituted with 1 , 2, or 3 independently selected halogen atoms, optionally substituted C6-io aryl, optionally substituted 5- to 10-membered heteroaryl, and optionally substitututed 5- to 10-membered heterocyclyl; and each RbA is independently selected from the group consisting of hydrogen, -Ci-4 alkyl, -(C3-io)cycloalkyl, 5- to 10-membered heterocyclyl; wherein said alkyl, cycloalkyl or heterocyclyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms.
2. The compound of claim 1 , having the formula (MA):
Figure imgf000126_0001
(DA)
or a salt or solvate thereof, wherein:
R4, R5, R11, R12, and R13 are as defined in claim 1 ,
n is 0 or 1 , and
Het is selected from the group consisting of
Figure imgf000127_0001
wherein R2A and R3A are each independently as defined in claim 1 .
3. The compound of claim 1 or 2, wherein both R2A and R3A are hydrogen. 4. The compound of claim 1 or 2, wherein R2A is hydrogen and R3A is as defined in claim 1.
5. The compound of claim 4, wherein R3A is -ORaA wherein RaA is -Ci-4 alkyl optionally substituted with 1 , 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -SRbA, -N(RbA)2, and optionally substituted C-6-10 aryl, wherein RbA is each independently hydrogen or Ci-4 alkyl.
The compound of any one of claims 1 -5, wherein n is 0, R11 and R12 are both hydrogen and R13 is selected from the group consisting of halogen, - CN, -ORbA, and -Ci-4 alkyl, wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 independently selected halogen atoms, and wherein RbA is hydrogen or alkyl optionally substituted with 1 , 2, or 3 independently selected halogen atoms.
The compound of any one of claims 1 -6, wherein R5 is hydrogen. The compound of any one of claims 1 -6, wherein R5 is Ci-4 alkyl.
A compound of formula (I),
Figure imgf000128_0001
(I)
wherein: · each of A1 is independently selected from the group consisting of nitrogen and C(R2);
• each of A2 and A3 is independently selected from the group consisting of nitrogen, C(R3) and C(NH2);
• wherein exactly one of A2 and A3 is C(NH2) and wherein no less than one and not more than two of A1, A2 and A3 are nitrogen; • each R1 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORb, and -Ci-4 alkyl wherein said -Ci-4 alkyl group is optionally substituted by 1 , 2 or 3 halogen atoms, with the proviso that at least one R1 is not hydrogen;
• R2 is selected from the group consisting of hydrogen, fluorine, -CN, methyl and trifluoromethyl;
• each one of R3 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -Ci-4 alkyl, -C3-i 0 cycloalkyl, and 5- to 10- membered-C2-i o heterocyclyl, said alkyl, cycloalkyl and heterocyclyl groups being optionally substituted with 1 , 2 or 3 groups independently selected from the group consisting of halogen, hydroxy, -Ci-4 alkyl optionally substituted with 1 , 2 or 3 halogen atoms, -N(Rb)2 and methoxy, optionally substituted with 1 , 2 or 3 halogen atoms;
• n has a value selected from 0, 1 or 2;
• each Ra independently is selected from the group consisting of hydrogen, -Ci-4 alkyl, -C3-i o cycloalkyl, -Ci-4 alkyl-C3-i o cycloalkyl, -C-6-10 aryl, -Ci-4 alkyl-C6-i o aryl, 5- to 10-membered-d-io heteroaryl, -Ci-4 alkyl- 5- to 10-membered-C-M o heteroaryl, 5- to 10-membered-C2-io heterocyclyl, -Ci-4 alkyl-5- to 10-membered-C2-io heterocyclyl; said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups optionally being substituted with 1 , 2 or 3 groups independently selected from halogen, hydroxy, -CN, -ORb, -SRb, -N(Rb)2, -C1 -4alkyl optionally substituted with 1 , 2, or 3 halogen atoms, optionally substituted C-6-10 aryl, optionally substituted 5- to 10-membered-Ci-io heteroaryl and 5- to 10-membered-C2-io heterocyclyl;
• each Rb independently represent, on each occasion when used herein hydrogen, -Ci-4 alkyl, -C3-io cycloalkyl, 5- to 10-membered-C2-io heterocyclyl; said alkyl, cycloalkyl or heterocyclyl groups optionally being substituted by 1 , 2 or 3 independently fluorine atoms,
or a solvate or a salt thereof.
10. The compound of any one of claims 1 -9, wherein n has a value of zero.
1 1 . The compound of claim 1 , 9, or 10, wherein one of A2 is C(NH2).
12. The compound of claim 1 , 9, or 10, wherein A3 is C(NH2).
13. The compound according to any one of claims 1 and 9-12, wherein one only of A1, A2 and A3 is nitrogen. 14. The compound of any one of claims 1 and 9-12, wherein two of A1 , A2 and A3 are nitrogen.
15. The compound of any one of claims 9-14, one or two of R1 are hydrogen.
16. The compound of claim 15, wherein the substituents R1 at positions 5 and 6 of the isoquinoline ring are hydrogen and the substituent R1 at position 7 of the isoquinoline ring is selected from the group consisting of chlorine, methyl, trifluoromethyl and -ORb, wherein Rb is selected from the group consisting of methyl and trifluoromethyl.
17. The compound of claim 15, wherein the substituents R1 at positions 6 and 7 of the isoquinoline ring are hydrogen and the substituent R1 at position 5 of the isoquinoline ring is selected from the group consisting of chlorine and -ORb wherein Rb is selected from the group consisting of methyl and trifluoromethyl.
18. The compound of claim 1 selected from the group consisting of:
N2-(5-chloroisoquinolin-1 -yl)pyridine-2,6-diamine,
N4-(7-Chloroisoquinolin-1 -yl)pyrimidine-2,4-diamine,
N -(7-Chloroisoquinolin-1 -yl)pyridine-2,6-diamine,
N -(5,7-Dichloroisoquinolin-1 -yl)pyridine-2,6-diamine,
N -(7-(trifluoromethoxy)isoquinolin-1 -yl)pyridine-2,6-diamine,
N -(5-(trifluoromethoxy)isoquinolin-1 -yl)pyridine-2,6-diamine,
N -(7-chloroisoquinolin-1 -yl)pyrazine-2,5-diamine,
N4-(7-Chloroisoquinolin-1 -yl)pyridine-2,4-diamine,
N4-(5-Chloroisoquinolin-1 -yl)pyridine-2,4-diamine,
N -(7-Chloroisoquinolin-1 -yl)-3-fluoropyridine-2,6-diamine,
N -(7-Chloroisoquinolin-1 -yl)pyrimidine-2,4-diamine,
N5-(7-Chloroisoquinolin-1 -yl)pyridine-2,5-diamine, and N2-(7-Chloroisoquinolin-1 -yl)pyridine-2,5-diamine,
or a salt or a solvate thereof.
19. The compound of claim 1 selected from the group consisting of
/V3-(7-chloroisoquinolin-1 -yl)pyridazine-3,6-diamine,
/V4-(7-chloroisoquinolin-1 -yl)pyrimidine-4,6-diamine,
/V2-(7-chloroisoquinolin-1 -yl)pyrazine-2,5-diamine,
/V2-(7-methylisoquinolin-1 -yl)pyridine-2,6-diamine,
/V3-(7-methylisoquinolin-1 -yl)pyridazine-3,6-diamine,
/V2-(7-methoxyisoquinolin-1 -yl)pyrazine-2,6-diamine,
/V3-(7-methoxyisoquinolin-1 -yl)pyridazine-3,6-diamine,
/V2-(6-chloroisoquinolin-1 -yl)pyridine-2,6-diamine,
/V2-(5,6-dichloroisoquinolin-1 -yl)pyridine-2,6-diamine,
/V2-(5-methoxyisoquinolin-1 -yl)pyridine-2,6-diamine,
/V2-(5-methoxyisoquinolin-1 -yl)pyrazine-2,6-diamine,
/V2-(7-chloroisoquinolin-1 -yl)-4-methylpyridine-2,6-diamine,
1 -((6-aminopyridin-2-yl)amino)isoquinoline-7-carbonitrile,
1 - ((6-aminopyrazin-2-yl)amino)isoquinoline-7-carbonitrile,
2- amino-6-((7-chloroisoquinolin-1 -yl)amino)isonicotinonitrile,
/V5-(7-chloroisoquinolin-1 -yl)pyrimidine-2,5-diamine,
/V4-(7-methoxyisoquinolin-1 -yl)pyridine-2,4-diamine,
/V5-(7-methylisoquinolin-1 -yl)pyridine-2,5-diamine,
/V5-(7-methoxyisoquinolin-1 -yl)pyridine-2,5-diamine,
/V5-(5-chloroisoquinolin-1 -yl)pyridine-2,5-diamine,
/V4-(7-chloroisoquinolin-1 -y -A^-methylpyridine^^-diamine,
/V5-(7-chloroisoquinolin-1 -yl)-/V5-methylpyridine-2,5-diamine,
/V2-(7-chloroisoquinolin-1 -yl)pyrimidine-2,5-diamine,
/V2-(7-chloroisoquinolin-1 -yl)pyridine-2,4-diamine,
/V2-(5-chloroisoquinolin-1 -yl)pyridine-2,5-diamine,
/V2-(5-methoxyisoquinolin-1 -yl)pyrimidine-2,5-diamine,
/V4-(7-chloroisoquinolin-1 -yl)-6-(2-(methylamino)ethoxy)pyrimidine-2,4- diamine; /V3-methyl-/V3-(7-m ethyl iso
/V2-(7-chloroisoquinolin-1 -yl)-/V2-methylpyndine-2,6-diamine,
/V2-(7-methoxyisoquinolin-1 -yl)-/V2-methylpyndine-2,6-diamine,
1 -((6-aminopyridin-2-yl)(methyl)amino)isoquinoline-7-carbonitnle,
/V2-(7-chloroisoquinolin-1 -yl)-/V2-methylpyrazine-2,6-diamine,
/V3-(7-chloroisoquinolin-1 -yl)-/V3-methylpyndazine-3,6-diamine,
/V3-(7-methoxyisoquinolin-1 -yl)-/V3-methylpyndazine-3,6-diamine,
1 - ((6-aminopyridazin-3-yl)(methyl)amino)isoquinoline-7-carbonitnle, and
2- amino-6-((7-chloroisoquinolin-1 -yl)amino)pyridin-4-ol,
or a salt or solvate thereof.
A pharmaceutical composition, comprising a compound of any one of claims 1 -19, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. 21 . A compound as defined in anyone of claims 1 -19 for use in the prevention or treatment of a condition associated with the alteration of the activity of GLB1.
22. A compound for use according to claim 21 , wherein the condition associated with the alteration of the activity of GLB1 is selected from the group consisting of GM1 gangliosidoses and Morquio syndrome, type B.
23. A method of treating or preventing a condition associated with the alteration of the activity of GLB1 in a patient, comprising administering to the patient in need thereof an effective amount of a compound as defined in any one of claims 1 -19, or a pharmaceutically acceptable salt or solvate thereof.
24. A method of treating GM1 ganglisidosis or Morquio B syndrome in a patient, comprising administering to the patient in need thereof an effective amount of a compound as defined in any one of claims 1 -19, or a pharmaceutically acceptable salt or solvate thereof. 25. A method of increasing β-galactosidase activity in a patient in need thereof, comprising administering to the patient an effective amount of a compound as defined in any one of claims 1 -19, or a pharmaceutically acceptable salt or solvate thereof.
26. Use of compound as defined in anyone of claims 1 -19 for the manufacture of a medicament for the prevention or treatment of a condition associated with the alteration of the activity of GLB1.
27. Use according to claim 21 , wherein the condition associated with the alteration of the activity of GLB1 is selected from the group consisting of GM1 gangliosidoses and Morquio syndrome, type B. 28. Pharmaceutical composition comprising a compound as defined in anyone of claims 1 -19 for use in prevention or treatment of a condition associated with the alteration of the activity of GLB1 .
29. Pharmaceutical composition for use according to claim 28 wherein the condition associated with the alteration of the activity of GLB1 is selected from the group consisting of GM1 gangliosidoses and Morquio syndrome, type B.
PCT/IB2016/050413 2015-01-28 2016-01-28 Heteroarylaminoisoquinolines, methods for their preparation and therapeutic uses thereof WO2016120808A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15382019 2015-01-28
EP15382019.6 2015-01-28

Publications (1)

Publication Number Publication Date
WO2016120808A1 true WO2016120808A1 (en) 2016-08-04

Family

ID=52462258

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/050413 WO2016120808A1 (en) 2015-01-28 2016-01-28 Heteroarylaminoisoquinolines, methods for their preparation and therapeutic uses thereof

Country Status (1)

Country Link
WO (1) WO2016120808A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017091661A1 (en) * 2015-11-25 2017-06-01 Strovel Jeffrey William Bicyclic bet bromodomain inhibitors and uses thereof
WO2018122746A1 (en) * 2016-12-28 2018-07-05 Minoryx Therapeutics S.L. Isoquinoline compounds, methods for their preparation, and therapeutic uses thereof in conditions associated with the alteration of the activity of beta galactosidase
US10266536B2 (en) 2013-03-14 2019-04-23 Convergene Llc Methods and compositions for inhibition of bromodomain-containing proteins
US20190256492A1 (en) * 2018-02-19 2019-08-22 Washington University Alpha-synuclein ligands
US11174242B2 (en) 2016-12-29 2021-11-16 Minoryx Therapeutics S.L. Heteroaryl compounds and their use
WO2022049253A1 (en) * 2020-09-07 2022-03-10 Bayer Aktiengesellschaft Substituted n-heteroaryl-n-pyridinylacetamides as p2x4 modulators

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1433776A1 (en) 2001-09-07 2004-06-30 Seikagaku Corporation Carba-sugar amine derivatives and treatments for disorder of glycolipid metabolism containing the same as the active ingredient
WO2006100586A1 (en) 2005-03-24 2006-09-28 Technische Universität Graz Glycosidase-inhibiting iminosugars
WO2008034575A1 (en) 2006-09-19 2008-03-27 Technische Universität Graz Iminosugar glycoconjugates
WO2009049421A1 (en) 2007-10-18 2009-04-23 The Hospital For Sick Children Compositions and methods for enhancing enzyme activity in gaucher, gm1-gangliosidosis/morquio b disease, and parkinson's disease
WO2010046517A1 (en) 2008-10-22 2010-04-29 Consejo Superior De Investigaciones Científicas (Csic) Compounds promoting the activity of mutant glycosidases
WO2015014900A1 (en) * 2013-07-31 2015-02-05 Minoryx Therapeutics S.L. Di(hetero)arylamides and sulfonamides, methods for their preparation and therapeutic uses thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1433776A1 (en) 2001-09-07 2004-06-30 Seikagaku Corporation Carba-sugar amine derivatives and treatments for disorder of glycolipid metabolism containing the same as the active ingredient
WO2006100586A1 (en) 2005-03-24 2006-09-28 Technische Universität Graz Glycosidase-inhibiting iminosugars
WO2008034575A1 (en) 2006-09-19 2008-03-27 Technische Universität Graz Iminosugar glycoconjugates
WO2009049421A1 (en) 2007-10-18 2009-04-23 The Hospital For Sick Children Compositions and methods for enhancing enzyme activity in gaucher, gm1-gangliosidosis/morquio b disease, and parkinson's disease
WO2010046517A1 (en) 2008-10-22 2010-04-29 Consejo Superior De Investigaciones Científicas (Csic) Compounds promoting the activity of mutant glycosidases
WO2015014900A1 (en) * 2013-07-31 2015-02-05 Minoryx Therapeutics S.L. Di(hetero)arylamides and sulfonamides, methods for their preparation and therapeutic uses thereof

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CACIOTTI A. ET AL., BIOCHIM BIOPHYS ACTA, vol. 1812, no. 7, July 2011 (2011-07-01), pages 782 - 890
E.W. MARTIN: "Remington's Pharmaceutical Sciences", 2005
OGAWA S. ET AL., BIOORG. MED. CHEM., vol. 10, no. 6, 2002, pages 1967 - 1972
ROWE C.R.; PAUL J.S; MARIAN E.Q.: "Handbook of Pharmaceutical Excipients"
SUZUKI ET AL., CELL. MOL. LIFE SCI., vol. 65, 2008, pages 351 - 353
T. W. GREENE: "Protective Groups in Organic Synthesis", 1999
WUTS, P. G. M.; GREENE, T. W.: "Greene's Protective Groups in Organic Synthesis", 2007, J. WILEY & SONS

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10717739B2 (en) 2013-03-14 2020-07-21 Convergene Llc Methods and compositions for inhibition of bromodomain-containing proteins
US10266536B2 (en) 2013-03-14 2019-04-23 Convergene Llc Methods and compositions for inhibition of bromodomain-containing proteins
EP4050005A1 (en) * 2015-11-25 2022-08-31 Convergene Llc Bicyclic bet bromodomain inhibitors and uses thereof
AU2016361441B2 (en) * 2015-11-25 2021-08-12 Convergene Llc Bicyclic BET bromodomain inhibitors and uses thereof
WO2017091661A1 (en) * 2015-11-25 2017-06-01 Strovel Jeffrey William Bicyclic bet bromodomain inhibitors and uses thereof
US10508106B2 (en) 2015-11-25 2019-12-17 Convergene Llc Bicyclic BET bromodomain inhibitors and uses thereof
US11028079B2 (en) 2015-11-25 2021-06-08 Convergene, Llc Small molecule BET bromodomain inhibitors and uses thereof
CN110494432A (en) * 2016-12-28 2019-11-22 米尼奥尔克斯治疗有限公司 Isoquinoline compound, preparation method and its is changing the therapeutical uses in relevant illness to betagalactosidase activity
JP2020514284A (en) * 2016-12-28 2020-05-21 ミノリックス セラピューティクス エセ．エレ． Isoquinoline compounds, methods of their preparation, and their therapeutic use in conditions associated with altered activity of beta-galactosidase
AU2017388300B2 (en) * 2016-12-28 2022-03-31 Minoryx Therapeutics S.L. Isoquinoline compounds, methods for their preparation, and therapeutic uses thereof in conditions associated with the alteration of the activity of beta galactosidase
CN110494432B (en) * 2016-12-28 2022-08-12 米尼奥尔克斯治疗有限公司 Isoquinoline compounds, methods of preparation thereof and therapeutic use thereof in disorders associated with altered beta-galactosidase activity
WO2018122746A1 (en) * 2016-12-28 2018-07-05 Minoryx Therapeutics S.L. Isoquinoline compounds, methods for their preparation, and therapeutic uses thereof in conditions associated with the alteration of the activity of beta galactosidase
US11440898B2 (en) 2016-12-28 2022-09-13 Minoryx Therapeutics S.L. Isoquinoline compounds, methods for their preparation, and therapeutic uses thereof in conditions associated with the alteration of the activity of beta galactosidase
JP7144863B2 (en) 2016-12-28 2022-09-30 ミノリックス セラピューティクス エセ．エレ． Isoquinoline compounds, methods for their preparation, and their therapeutic use in conditions associated with altered activity of beta-galactosidase
US11174242B2 (en) 2016-12-29 2021-11-16 Minoryx Therapeutics S.L. Heteroaryl compounds and their use
US11739072B2 (en) 2016-12-29 2023-08-29 Minoryx Therapeutics S.L. Heteroaryl compounds and their use
US20190256492A1 (en) * 2018-02-19 2019-08-22 Washington University Alpha-synuclein ligands
WO2022049253A1 (en) * 2020-09-07 2022-03-10 Bayer Aktiengesellschaft Substituted n-heteroaryl-n-pyridinylacetamides as p2x4 modulators

Similar Documents

Publication Publication Date Title
WO2016120808A1 (en) Heteroarylaminoisoquinolines, methods for their preparation and therapeutic uses thereof
EP3253762B1 (en) 9h-pyrrolo-dipyridine derivatives
ES2206691T3 (en) DERIVATIVES OF 6-PHENYL PIRIDIL-2-AMINA USEFUL AS INHIBITORS OF US.
CA3142902A1 (en) 2,3-dihydroquinazolin compounds as nav1.8 inhibitors
CA2890886C (en) Indole carboxamide derivatives as p2x7 receptor antagonists
DK3019482T3 (en) TRISUBSTITUTED BENZOETRIAZOLD DERIVATIVES AS DIHYDROORO-TATOXYGENASE INHIBITORS
KR20150087271A (en) Pyrimidine-2,4-diamine derivatives for treatment of cancer
CN110382500B (en) Urea compounds for dual IDO and TDO inhibitors
EP3027590A1 (en) Di(hetero)arylamides and sulfonamides, methods for their preparation and therapeutic uses thereof
CA3083061A1 (en) 1,2,4-oxadiazole derivatives as histone deacetylase 6 inhibitors
US11021486B2 (en) Coumarin-like cyclic compound as MEK inhibitor and use thereof
AU2017388466B2 (en) Heteroaryl compounds and their use
WO2015166398A1 (en) 3h-imidazo[4,5-b]pyridine derivatives as dihydroorotate dehydrogenase inhibitors
JP7144863B2 (en) Isoquinoline compounds, methods for their preparation, and their therapeutic use in conditions associated with altered activity of beta-galactosidase
CN111808080B (en) Substituted pyridine or pyrimidine compound, preparation method and medical application thereof
WO2021105906A1 (en) Aryl and heteroaryl compounds, and therapeutic uses thereof in conditions associated with the alteration of the activity of galactocerebrosidase
JP2023503465A (en) Heteroaryl compounds and their therapeutic use in conditions associated with altered beta-glucocerebrosidase activity

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16704939

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16704939

Country of ref document: EP

Kind code of ref document: A1