WO2015150555A1 - Macrocylic pyrimidine derivatives - Google Patents

Macrocylic pyrimidine derivatives Download PDF

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Publication number
WO2015150555A1
WO2015150555A1 PCT/EP2015/057399 EP2015057399W WO2015150555A1 WO 2015150555 A1 WO2015150555 A1 WO 2015150555A1 EP 2015057399 W EP2015057399 W EP 2015057399W WO 2015150555 A1 WO2015150555 A1 WO 2015150555A1
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Prior art keywords
alkyl
int
independently
haloci
hydroxyl
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PCT/EP2015/057399
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French (fr)
Inventor
Gaston Stanislas Marcella Diels
Bruno Schoentjes
Matthias Luc Aimé VERSELE
Didier Jean-Claude Berthelot
Marc Willems
Marcel Viellevoye
Werner Constant Johan Embrechts
Berthold Wroblowski
Lieven Meerpoel
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Janssen Pharmaceutica Nv
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Publication date
Priority to UAA201611005A priority Critical patent/UA118219C2/en
Priority to MYPI2016001777A priority patent/MY185491A/en
Priority to JP2016560825A priority patent/JP6529513B2/en
Priority to CA2942636A priority patent/CA2942636C/en
Priority to US15/300,956 priority patent/US10017509B2/en
Priority to NZ725399A priority patent/NZ725399A/en
Priority to KR1020167028764A priority patent/KR102390276B1/en
Application filed by Janssen Pharmaceutica Nv filed Critical Janssen Pharmaceutica Nv
Priority to AU2015239098A priority patent/AU2015239098B2/en
Priority to MX2016012992A priority patent/MX369798B/en
Priority to EP15713522.9A priority patent/EP3126364B1/en
Priority to CN202111600011.XA priority patent/CN114213415A/en
Priority to BR112016021982-1A priority patent/BR112016021982B1/en
Priority to EA201692003A priority patent/EA031246B1/en
Priority to SG11201608240RA priority patent/SG11201608240RA/en
Priority to ES15713522.9T priority patent/ES2667723T3/en
Priority to CN201580018080.6A priority patent/CN106164075B/en
Publication of WO2015150555A1 publication Critical patent/WO2015150555A1/en
Priority to IL248005A priority patent/IL248005B/en
Priority to PH12016501963A priority patent/PH12016501963B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • the present invention relates to substituted macrocylic pyrimidine derivatives having EF2K inhibitory activity and optionally also Vps34 inhibitory activity.
  • the invention further relates to processes for preparing such compounds, pharmaceutical
  • compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
  • Eukaryotic elongation factor 2 (EF2) is essential for protein elongation: its affinity for the ribosome, and hence protein elongation rate, is controlled by its phosphorylation state.
  • EF2K or eEF2K elongation factor 2 kinase
  • This regulation is critical under various forms of cellular stress, such as nutrient limitation and hypoxia, or conditions of increased energy expenditure, such as muscle exercise.
  • local subcellular regulation of EF2 phosphorylation by EF2K at nerve growth cones or at the synapse ensures preferential translation of certain nerve growth factors and neurotransmitters.
  • Dysregulation of EF2 (Thr56) phosphorylation has been associated with several devastating pathologies, including cancer and depression. Tumour cells often experience various forms of stress (hypoxia, nutrient deprivation), and therefore activate eEF2K activity to balance protein elongation rates with the high demand for de novo protein synthesis. Indeed, EF2 is highly phosphoryated in tumour tissue compared to normal tissue as an adaptive response to nutrient limitation (Leprivier et al., Cell 2013, 153(5): 1064-1079). Deregulation of this control through inhibition of eEF2K is thought to fatally increase energy expenditure in tumour cells, and represent an anti- tumour strategy through induction of metabolic crisis (Hait et al, Clin Cancer Res.
  • BDNF brain-derived neurotrophic factor
  • NMD A N-Methyl-D-aspartic acid
  • EF2K inhibition has been proposed as a fast-acting antidepressant therapy
  • EF2K is activated by direct phosphorylation by AMPK, whereas EF2K is regulated through inhibitory phosphorylation by growth and cell cycle kinases, such as S6K and CDK2.
  • EF2K is a Ca2+/calmodulin-dependent kinase; this regulation may be key for the synaptic regulation of EF2K.
  • EF2K is an atypical kinase: the primary sequence of its catalytic domain is only remotely related to that of canonical kinases, such as serine/threonine kinases, tyrosine kinases, or lipid kinases.
  • Compounds with EF2K inhibitory activity may prevent the stress-induced phosphorylation of eEF2 in cells and in xenografted tumours in mice.
  • many cell types utilize autophagy as a recycling mechanism to cope with low nutrient availability, hypoxia and other forms of cellular stress.
  • Autophagy is a catabolic process, in which cytosolic content, including proteins, protein aggregates and entire organelles are engulfed in vesicles (autophagosomes) which fuse to lysosomes to enable degradation of macromolecules to recuperate building blocks (amino acids, fatty acids, nucleotides) and energy (Hait et al, Clin Cancer Res. 2006, 12: 1961-1965).
  • the double membrane of autophagosomes critically consists of phosphatidylinositol- (3)-phosphate [PI(3)P], the product of the class III PI3K, Vps34 (also called PIK3C3).
  • Vps34 and the adaptor protein, Beclinl, are both essential for autophagy in mammalian cells (Amaravadi et al., Clin Cancer Res. 2011, 17:654-666). Autophagy is upregulated in tumors, and inhibition of autophagy using the lysosomotropic agent, chloroquine (which inhibits the fusion of lysosomes to autophagosomes), or R Ai approaches can impair tumorigenesis.
  • Vps34 may inhibit autophagy in cancer cells under stress. Moreover it was found that cancer cells, partially deficient in autophagy through knockdown of Beclin, are especially sensitive to Vps34 inhibition, suggesting that autophagy-deficient tumors (e.g. because of mono-allelic deletion of beclinl, as frequently found in breast, ovarian and prostate cancer, or other genetic lesions (Maiuri et al, Cell Death Differ. 2009, 16(l):87-93) may be most susceptible to Vps34 inhibition.
  • WO 2009/112439 describes 4-aryl-2-anilino-pyrimidines as PLK kinase inhibitors.
  • the compounds of the present invention have EF2 inhibitory activity and optionally also have Vps34 inhibitory activity.
  • the compounds according to the invention and the pharmaceutical compositions comprising such compounds may be useful for treating or preventing, in particular treating, diseases such as cancer, depression, and memory and learning disorders.
  • the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment of a haematological malignancy or solid tumour.
  • said solid tumour is selected from the group consisting of glioblastoma, meduUoblastoma, prostate cancer, breast cancer, ovarian cancer and colorectal cancer, and the like.
  • This invention concerns compounds of Formula (I)
  • X a , X b and X c each independently represent CH or N; -Xi- represents -(CHRi 2 ) s -NRi-X e -Ci_ 4 alkanediyl-(S0 2 )p3- or
  • Ci_ 4 alkanediyl moieties optionally substituted with hydroxyl or hydroxyCi_ 4 alkyl;
  • b ring may contain extra bonds to form a bridj ring system selected from 2,5-diazabicyclo[2.2.2]octanyl, 3,8- diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,9- diazabicyclo[3.3.1 ]nonyl;
  • X d i represents CH or N
  • X d2 represents CH 2 or NH
  • X d i and X d2 represents nitrogen
  • Ri represents hydrogen, Ci_ 4 alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, cyanoCi_ 4 alkyl,
  • each R 3 independently represents hydrogen; oxo; hydroxyl; carboxyl; -NR 3a R 3 b;
  • Ci_ 4 alkyl may optionally be substituted with phenyl; Ci_ 4 alkyl optionally substituted with cyano, carboxyl, Ci_ 4 alkyloxy,
  • R 3a and R 3 b are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 or 2 further heteroatoms selected from N, O or S0 2 , said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_ 4 alkyl, halo, hydroxyl, or haloCi_ 4 alkyl;
  • R 4 represents hydrogen, Ci_ 4 alkyl or Ci_ 4 alkyloxyCi_ 4 alkyl
  • each R 5a independently represents hydrogen or Ci_ 4 alkyl
  • R5 a substituents attached to the same carbon atom are taken together to form C 2 _ 5 alkanediyl or -(CH 2 ) p -0-(CH 2 ) p -;
  • R 5a' represents hydrogen or Ci_ 4 alkyl;
  • each R 5b independently represents hydrogen; Ci_ 4 alkyl; Ci_ 4 alkyl substituted with NR 5b iR 5b2 ; C 1-4 alkyloxyC 1-4 alkyl; hydroxyCi_ 4 alkyl; hydroxyl; C3_ 6 cycloalkyl; or phenyl optionally substituted with Ci_ 4 alkyl, halo, hydroxyl or Ci_ 4 alkyloxy; or two Rs b substituents attached to the same carbon atom are taken together to form C 2 _ 5 alkanediyl or -(CH 2 ) p -0-(CH 2 ) p -;
  • each R ⁇ 5 independently represents hydrogen, halo, hydroxyl, carboxyl, cyano, Ci_ 4 alkyl,
  • each R 6a and R 6b independently represent hydrogen or Ci_ 4 alkyl
  • each R 7 and Rg independently represent hydrogen, Ci_ 4 alkyl, haloCi_ 4 alkyl, or
  • R 7 and Rg are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 further heteroatom selected from N, O or S0 2 , said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_ 4 alkyl, halo, hydroxyl, or haloCi_ 4 alkyl;
  • Rg represents Ci_ 4 alkyl, haloCi_ 4 alkyl, or C 3 _ 6 cycloalkyl
  • each Rio independently represents a 4 to 7 membered saturated monocyclic
  • heterocyclic ring containing up to 2 heteroatoms selected from N, O or S0 2 , said heterocyclic ring being optionally substituted with 1 to 4 substituents each
  • Ci_ 4 alkyl independently selected from Ci_ 4 alkyl, halo, hydroxyl or haloCi_ 4 alkyl;
  • each Rii independently represents C 3 _ 6 cycloalkyl, phenyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N, O or S0 2 , said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_ 4 alkyl, halo, hydroxyl, or haloCi_ 4 alkyl;
  • each Ri 2 independently represents hydrogen or Ci_ 4 alkyl
  • Q represents a 4 to 7 membered saturated monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N, O or S0 2 , said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_ 4 alkyl, halo, hydroxyl or haloCi_ 4 alkyl;
  • n an integer of value 1 or 2;
  • n an integer of value 1 or 2 ;
  • p represents an integer of value 1 or 2;
  • pi represents an integer of value 1 or 2;
  • each p2 independently represents an integer of value 0, 1 or 2;
  • r represents an integer of value 0, 1 or 2;
  • each p3 independently represents an integer of value 0 or 1 ;
  • each s independently represents an integer of value 0, 1 or 2;
  • the present invention also concerns methods for the preparation of compounds of the present invention and pharmaceutical compositions comprising them.
  • the com ounds of the present invention were found to hav e EF2K inhibitory activ ity and optionally also have Vps34 inhibitory activ ity. Therefore the compounds of the present invention may be useful in the treatment or prev ention, in particular in the treatment, of diseases such as cancer, depression, neuroplasticity (synaptic
  • the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment of a haematological malignancy or solid tumour.
  • said solid tumour is selected from the group consisting of glioblastoma, meduUoblastoma, prostate cancer, breast cancer, ovarian cancer and colorectal cancer, and the like.
  • the compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof may be suitable in the treatment or prev ention, in particular in the treatment, of cancer.
  • the present invention also concerns the use of compounds of Formula (I) and pharmaceutically acceptable addition salts, and solv ates thereof, for the manufacture of a medicament for the treatment or prevention, in particular treatment, of diseases such as cancer, depression, neuroplasticity (synaptic plasticity and non-synaptic plasticity), and memory and learning disorders.
  • diseases such as cancer, depression, neuroplasticity (synaptic plasticity and non-synaptic plasticity), and memory and learning disorders.
  • Stable compound is meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • radical or group is defined as “optionally substituted” in the present invention, it is meant that said radical or group is unsubstituted or is substituted.
  • substituted with 1 to 4 substituents it is meant, to indicate that from 1 to 4 hydrogens, in particular from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using "substituted” are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • Ci_ 4 alkyl group contains from 1 to 4 carbon atoms
  • a C 3 _ 6 cycloalkyl group contains from 3 to 6 carbon atoms
  • a Ci_ 4 alkyloxy group contains from 1 to 4 carbon atoms, and so on.
  • halo as a group or part of a group is generic for fluoro, chloro, bromo, iodo unless otherwise is indicated or is clear from the context.
  • Ci_ 4 alkyl refers to a hydrocarbyl radical of Formula C n H2 n+ i wherein n is a number ranging from 1 to 4.
  • Ci_ 4 alkyl groups comprise from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms.
  • Ci_ 4 alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain.
  • Ci_ 4 alkyl includes all linear, or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes methyl, ethyl, n-propyl, /-propyl, 2-methyl-ethyl, butyl and its isomers (e.g. n-butyl, /sobutyl and tert-butyl), and the like.
  • Ci_ 4 alkyloxy refers to a radical having the
  • Ci_ 4 alkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy and /er/-butyloxy.
  • C 3 _ 6 cycloalkyl alone or in combination, refers to a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms.
  • suitable C 3 _ 6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • 'hydroxyCi_ 4 alkyl' as used herein as a group or part of a group refers to a Ci_ 4 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a hydroxyl group.
  • the term 'hydroxyCi_ 4 alkyl' therefore includes
  • hydroxyCi_ 4 alkyl monohydroxyCi_ 4 alkyl and also polyhydroxyCi_ 4 alkyl.
  • 'hydroxyCi_ 4 alkyl' is limited to monohydroxyCi_ 4 alkyl.
  • the term 'hydroxyCi_ 4 alkyloxy' as used herein as a group or part of a group refers to a hydroxyCi_ 4 alkyl-0- group wherein "hydroxyCi_ 4 alkyl" is as defined before.
  • hydroxyCi_ 4 alkyloxyCi_ 4 alkyl' as used herein as a group or part of a group refers to a hydroxyCi_ 4 alkyl-0-Ci_ 4 alkyl- group wherein "hydroxyCi_ 4 alkyl" and "Ci_ 4 alkyl" are as defined before.
  • Ci_ 4 alkyloxyhydroxyCi_ 4 alkyl' refers to a Ci_ 4 alkyl-0-hydroxyCi_ 4 alkyl- group wherein "hydroxyCi_ 4 alkyl" and "Ci_ 4 alkyl" are as defined before.
  • 'hydroxyCi_ 4 alkyloxyhydroxyCi_ 4 alkyl' as used herein as a group or part of a group refers to a hydroxyCi_ 4 alkyl-0-hydroxyCi_ 4 alkyl- group wherein
  • hydroxyCi_ 4 alkyl is as defined before.
  • 'haloCi_ 4 alkyl' as used herein as a group or part of a group refers to a
  • Ci_ 4 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen.
  • the term 'haloCi_ 4 alkyl' therefore includes monohaloCi_ 4 alkyl and also polyhaloCi_ 4 alkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi_ 4 alkyl may have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and the like.
  • cyanoCi_ 4 alkyl refers to a Ci_ 4 alkyl group as defined herein which is substituted with one cyano group.
  • Ci_ 4 alkoxyCi_ 4 alkyl' refers to a Ci_ 4 alkyl-0-Ci_ 4 alkyl group wherein Ci_ 4 alkyl is as defined herein.
  • Examples of such groups include methoxyethyl, ethoxyethyl, propoxymethyl, butoxypropyl, and the like.
  • 'haloCi_ 4 alkyloxy' refers to a -O- Ci_ 4 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen.
  • the term 'haloCi_ 4 alkyloxy' therefore include monohaloCi_ 4 alkyloxy and also polyhaloCi_ 4 alkyloxy. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi_ 4 alkyloxy may have one, two, three or more halogens. Examples of such groups include -fluoroethyloxy, 2- fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like.
  • haloC i _ 4 al ky lox yC i _ 4 al k y I ' as used herein as a group or part of a group means C ' i . 4 alkyl substituted with one haloCi_ 4 alkyloxy.
  • haloC i _ 4 alkyloxyC i 4 alky ⁇ therefore refers to a haloCY 4 alkyloxy-Ci_ 4 alkyl- group wherein "haloCi_ 4 alkyloxy" and "Ci_ 4 alkyl" are as defined above. Examples of such groups include 1 -fluoroethyloxymethyl, 2-fluoroethyloxymethyl, 2-(2,2,2- tri fi uoroetho y )-eth y 1 and the like.
  • C 2 _ 4 alkenyl as used herein as a group or part of a group refers to a linear or branched hydrocarbon group containing from 2 to 4 carbon atoms and containing a carbon carbon double bond such as, but not limited to, ethenyl, propenyl, butenyl, and the like.
  • C 2 - 4 alkynyl as used herein as a group or part of a group refers to a linear or branched hydrocarbon group having from 2 to 4 carbon atoms and containing a carbon carbon triple bond.
  • Examples of 4 to 7 membered saturated monocyclic heterocyclic rings containing up to 2 heteroatoms selected from N, O or S0 2 include, but are not limited to, morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and the like.
  • 4 to 7 membered monocyclic heterocyclic rings containing up to 3 heteroatoms selected from N, O or S0 2 include both aromatic and non- aromatic ring systems. This includes unsaturated, partially saturated and saturated heterocyclic ring systems. Examples include, but are not limited to, pyridinyl, pyrimidinyl, morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and the like.
  • Ci_ 4 alkanediyl as a group or part of a group defines bivalent straight or branched chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene or methanediyl, ethan-l,2-diyl, ethan-l,l-diyl or ethylidene, propan-l,3-diyl, propan-l,2-diyl, butan-l,4-diyl, and the like.
  • C 2 - 5 alkanediyl as a group or part of a group defines bivalent straight or branched chained saturated hydrocarbon radicals having from 2 to 5 carbon atoms such as, for example, ethan-l,2-diyl, ethan-l,l-diyl or ethylidene, propan-l,3-diyl, propan- 1,2-diyl, butan-l,4-diyl, pentan-l,5-diyl, pentan-l,l-diyl, 2-methylbutan-l,4-diyl, and the like.
  • C 2 - 4 alkenediyl as a group or part of a group defines straight or branched chain bivalent hydrocarbon radicals having from 2 to 4 carbon atoms and having a double bond such as 1 2-ethenedi l 1 3- ro enedi -butenediyl, and the like.
  • R 3 substituents may replace any hydrogen atom bound to a carbon or nitrogen atom in ring b, including atoms of the bridge, including NH and CH groups in the definition of X d2 , and including CH groups in the definition of X d i.
  • two R 3 substituents may be present on the same or different atoms.
  • X d2 represents NH
  • the R 3 substituent may be present on said nitrogen atom whenever possible.
  • X d2 represents NR 3 .
  • the R 3 substituent may be present on said carbon atom.
  • X d i may represent CR 3 and X d2 may represent CHR 3 or C(R 3 ) 2 .
  • R 3 substituent may be present on any of the carbon atom represented by
  • ring b can be attached to variable 'a' via replacement of a hydrogen atom on any carbon or nitrogen atom in ring b, including carbon and nitrogen atoms in the definition of X d2 .
  • the linker with the 'a substituent' is present on X d2 or is present on a carbon atom in the alpha position of X d2 .
  • the linker with the 'a substituent' is present on X d2 .
  • the b ring is linked to the remainder of the molecule as follows
  • Xi being -(CHRi 2 ) s -NRi-X e -Ci_ 4 alkanediyl-(S0 2 ) P 3- or -(CH 2 ) s -0-X e -Ci_ 4 alkanediyl-(S0 2 )p3- is attached to the remainder of the molecule as follows:
  • Ci_ 4 alkanediyl is optionally substituted according to the scope.
  • subject refers to an animal, preferably a mammal (e.g. cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, observation or experiment.
  • a mammal e.g. cat, dog, primate or human
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • treatment is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.
  • substituents may replace any hydrogen atom bound to a carbon or nitrogen atom of the ring system.
  • the invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.
  • Enantiomers are stereoisomers that are non-superimposable mirror images of each other.
  • a 1 : 1 mixture of a pair of enantiomers is a racematc or racemic mixture.
  • Atropisomers are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. For the compounds of the present invention this may be caused by the linker ( X(-a-b-c-) of the macrocycle. All atropisomeric forms of the compounds of Formula (I ) are intended to be included within the scope of the present invention.
  • Diastereomers are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Therefore, the invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.
  • the absolute configuration is specified according to the Cahn-Ingold-Prelog system.
  • the configuration at an asymmetric atom is specified by either R or S.
  • Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers.
  • a compound of Formula (I) is for instance specified as (R)
  • a compound of Formula (I) is for instance specified as E
  • Z Z isomer
  • a compound of Formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
  • salts of the compounds of Formula (I) and solvates thereof are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable addition salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of Formula (I) and solvates thereof, are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds of Formula (I) and solvates thereof containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers,
  • the salt form can be converted by treatment with acid into the free acid form.
  • solvate comprises the hydrates and solvent addition forms which the compounds of Formula (I) are able to form, as well as pharmaceutically acceptable addition salts thereof. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • the compounds of the invention as prepared in the processes described below may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures.
  • a manner of separating the enantiomeric forms of the compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, involves liquid chromatography using a chiral stationary phase. Said pure
  • stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • an element in particular when mentioned in relation to a compound of Formula (I), comprises all isotopes and isotopic mixtures of this element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • Radiolabeled compounds of Formula (I) comprises all isotopes and isotopic mixtures of this element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • (I) may comprise a radioactive isotope selected from the group of H, H, C, F, I, 123 I, 125 I, I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the radioactive isotope is selected from the group of H, H, C, F, I, 123 I, 125 I, I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the radioactive isotope is selected from the group of H, H, C, F, I, 123 I, 125 I, I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the radioactive isotope is selected from the group of H, H, C, F, I, 123 I, 125 I, I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the radioactive isotope is selected from the group of H, H, C, F, I, 123 I, 125 I, I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the radioactive isotope from the group of H, H, C and F. More preferably, the radioactive isotope
  • deuterated compounds are intended to be included within the scope of the present invention.
  • a compound means 1 compound or more than 1 compound.
  • the present invention concerns novel compounds of Formula (I), tautomers and stereoisomeric forms thereof, wherein
  • X a , X b and X c each independently represent CH or N;
  • -Xi- represents -(CHRi 2 ) s -NRi-X e -Ci_4alkanediyl-(S0 2 )p3- or -(CH 2 ) s -0-X e -Ci_ 4 alkanediyl-(S0 2 ) P 3-; wherein each of said Ci_ 4 alkanediyl moieties are optionally substituted with hydroxyl or hydroxyCi_ 4 alkyl;
  • Xdi represents CH or N
  • Xd 2 represents CH 2 or NH
  • a ring represents phenyl or pyridyl;
  • R 2 is hydrogen
  • Ci_ 4 alkanediyl or C 2 _ 4 alkenediyl each of said Ci_ 4 alkanediyl and C 2 _ 4 alkenediyl optionally being substituted with 1 to 4 hydroxyl substituents;
  • Ci_ 4 alkanediyl or C 2 _ 4 alkenediyl each of said Ci_ 4 alkanediyl and C 2 _ 4 alkenediyl optionally being substituted with 1 to 4 hydroxyl substituents;
  • R4 represents hydrogen, Ci_ 4 alkyl or Ci_ 4 alkyloxyCi_ 4 alkyl
  • each R 5a independently represents hydrogen or Ci_ 4 alkyl
  • each R 5b independently represents hydrogen; Ci_ 4 alkyl; Ci_ 4 alkyloxyCi_ 4 alkyl;
  • Ci_ 4 alkyl hydroxyCi_ 4 alkyl; hydroxyl; C 3 _ 6 cycloalkyl; or phenyl optionally substituted with Ci_ 4 alkyl, halo, hydroxyl or Ci_ 4 alkyloxy;
  • each Re independently represents hydrogen, halo, hydroxyl, carboxyl, cyano, Ci_ 4 alkyl,
  • each R 6a and R 6b independently represent hydrogen or Ci_ 4 alkyl; each R 7 and Rg independently represent hydrogen, Ci_ 4 alkyl, haloCi_ 4 alkyl, or C 3 _ 6 cycloalkyl; or
  • R 7 and Rg are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 further heteroatom selected from N, O or S0 2 , said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_ 4 alkyl, halo, hydroxyl, or haloCi_ 4 alkyl;
  • Rg represents Ci_ 4 alkyl, haloCi_ 4 alkyl, or C 3 _ 6 cycloalkyl
  • each Rio independently represents a 4 to 7 membered saturated monocyclic
  • heterocyclic ring containing up to 2 heteroatoms selected from N or O, said
  • heterocyclic ring being optionally substituted with 1 to 4 substituents each
  • Ci_ 4 alkyl independently selected from Ci_ 4 alkyl, halo, hydroxyl or haloCi_ 4 alkyl;
  • each Rii independently represents C 3 _ 6 cycloalkyl, phenyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 to 4 substituents each
  • Ci_ 4 alkyl independently selected from Ci_ 4 alkyl, halo, hydroxyl, or haloCi_ 4 alkyl;
  • each Ri 2 independently represents hydrogen or Ci_ 4 alkyl; in particular Ri 2 represents hydrogen;
  • n an integer of value 1 or 2;
  • n an integer of value 1 or 2 ;
  • pi represents an integer of value 1 or 2;
  • each p2 independently represents an integer of value 0, 1 or 2;
  • r represents an integer of value 0, 1 or 2;
  • each p3 independently represents an integer of value 0 or 1 ;
  • each s independently represents an integer of value 0, 1 or 2;
  • the present invention concerns novel compounds of Formula (I), tautomers and stereoisomeric forms thereof, wherein
  • X a , X b and X c each independently represent CH or N;
  • -Xi- represents -(CHRi 2 ) s -NRi-X e -Ci_4alkanediyl-(S0 2 )p3- or -(CH 2 ) s -0-X e -Ci_ 4 alkanediyl-(S0 2 )p 3 -; wherein each of said Ci_ 4 alkanediyl moieties are optionally substituted with hydroxyl or hydroxyCi_ 4 alkyl;
  • X d i represents CH or N; X d2 represents NH;
  • R 2 is hydrogen
  • Ci_ 4 alkanediyl or C 2 _ 4 alkenediyl each of said Ci_ 4 alkanediyl and C 2 _ 4 alkenediyl optionally being substituted with 1 to 4 hydroxyl substituents;
  • each R 3 independently represents hydrogen; oxo; hydroxyl; carboxyl; -NR 3a R3b; -
  • Ci_ 4 alkyloxyCi_ 4 alkyl optionally substituted with cyano, carboxyl, Ci_ 4 alkyloxy,
  • each R 3a and R 3b independently represent hydrogen
  • R4 represents hydrogen, Ci_ 4 alkyl or Ci_ 4 alkyloxyCi_ 4 alkyl
  • each R 5a independently represents hydrogen; each R 5b independently represents hydrogen; Ci_ 4 alkyl; Ci_ 4 alkyloxyCi_ 4 alkyl;
  • Ci_ 4 alkyl hydroxyCi_ 4 alkyl; hydroxyl; C 3 _ 6 cycloalkyl; or phenyl optionally substituted with Ci_ 4 alkyl, halo, hydroxyl or Ci_ 4 alkyloxy;
  • each Re independently represents hydrogen, halo, hydroxyl, carboxyl, cyano, Ci_ 4 alkyl, Ci_ 4 alkyloxyCi_ 4 alkyl, hydroxyCi_ 4 alkyl, haloCi_ 4 alkyl, C 2 - 4 alkenyl, C 2 _ 4 alkynyl, - NRe a s b , or
  • each R 6a and R 6b independently represent hydrogen or Ci_ 4 alkyl
  • each R 7 and Rg independently represent hydrogen;
  • R 7 and Rg are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 further heteroatom selected from N, O or S0 2 , said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_ 4 alkyl, halo, hydroxyl, or haloCi_ 4 alkyl;
  • R represents Ci_ 4 alkyl or haloCi_ 4 alkyl
  • each Rio independently represents a 4 to 7 membered saturated monocyclic
  • heterocyclic ring containing up to 2 heteroatoms selected from N or O, said
  • heterocyclic ring being optionally substituted with 1 to 4 substituents each
  • Ci_ 4 alkyl independently selected from Ci_ 4 alkyl, halo, hydroxyl or haloCi_ 4 alkyl;
  • each R 11 independently represents C 3 _ 6 cycloalkyl, phenyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 to 4 substituents each
  • Ci_ 4 alkyl independently selected from Ci_ 4 alkyl, halo, hydroxyl, or haloCi_ 4 alkyl;
  • each Ri 2 independently represents hydrogen
  • n an integer of value 1 or 2;
  • n an integer of value 1 or 2 ;
  • pi represents an integer of value 1 or 2;
  • each p2 independently represents an integer of value 0, 1 or 2;
  • r represents an integer of value 1 ;
  • each p3 independently represents an integer of value 0 or 1 ;
  • each s independently represents an integer of value 0, 1 or 2;
  • the present invention concerns novel compounds of Formula (I), tautomers and stereoisomeric forms thereof, wherein
  • X a is CH or N
  • X b and X c represent CH; -Xi- represents -(CHRi 2 ) s -NRi-X e -Ci_4alkanediyl-(S0 2 )p3- or -(CH 2 ) s -0-X e -Ci_ 4 alkanediyl-(S0 2 ) P 3-; wherein each of said Ci_ 4 alkanediyl moieties are optionally substituted with hydroxyl;
  • X d i represents CH or N
  • X d2 represents CH 2 or NH
  • X d i and X d2 represents nitrogen
  • each R 2 independently represents hydrogen
  • Ci_ 4 alkanediyl optionally being substituted with 1 hydroxyl substituent
  • each R3 independently represents hydrogen; oxo; hydroxyl;
  • R3a and R3b represent hydrogen
  • R3e and R3f represent C i_ 4 alkyl
  • R4 represents hydrogen, Ci_ 4 alkyl or Ci_ 4 alkyloxyCi_ 4 alkyl
  • R 5a represents hydrogen
  • each R 5 b independently represents hydrogen; Ci_ 4 alkyl; Ci_ 4 alkyloxyCi_ 4 alkyl;
  • hydroxyCi_ 4 alkyl or phenyl; each Re independently represents hydrogen, halo, hydroxyl, carboxyl, cyano, Ci_ 4 alkyl,
  • each R ⁇ 5 a and R6b independently represent hydrogen or Ci_ 4 alkyl
  • R 7 and Rg represent hydrogen
  • Rg represents Ci_ 4 alkyl
  • each Rio independently represents a 4 to 7 membered saturated monocyclic
  • heterocyclic ring containing up to 2 heteroatoms selected from N or O, said
  • heterocyclic ring being optionally substituted with 1 Ci_ 4 alkyl substituent
  • each Rii independently represents C 3 _ 6 cycloalkyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 oxygen atoms;
  • each Ri 2 independently represents hydrogen
  • n an integer of value 1 ;
  • n an integer of value 1 or 2 ;
  • pi represents an integer of value 1 ;
  • each p2 independently represents an integer of value 1 or 2;
  • r represents an integer of value 0 or 1 ;
  • each p3 independently represents an integer of value 0;
  • each s independently represents an integer of value 0 or 1 ;
  • Another embodiment of the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein one or more of the following restrictions apply:
  • X a is CH or N;
  • X b and X c represent CH;
  • -Xi- represents -(CHRi 2 ) s -NRi-X e -Ci_4alkanediyl-(S0 2 )p3- or -(CH 2 ) s -0- X e -Ci_ 4 alkanediyl-(S0 2 ) P 3-; wherein each of said Ci_ 4 alkanediyl moieties are optionally substituted with hydroxyl;
  • each R 2 independently represents hydrogen
  • Ci_ 4 alkanediyl optionally being substituted with 1 hydroxyl substituent
  • Ci_ 4 alkyloxyCi_ 4 alkyl optionally substituted with cyano, Ci_ 4 alkyloxy, -NR 3e R 3f , or Rio;
  • R 3a and R 3 b represent hydrogen
  • R 3e and R 3f represent Ci. 4 alkyl
  • R4 represents hydrogen, Ci_ 4 alkyl or Ci_ 4 alkyloxyCi_ 4 alkyl
  • R 5a represents hydrogen
  • each R 5b independently represents hydrogen; Ci_ 4 alkyl; Ci_ 4 alkyloxyCi_
  • each R6 a and R f ,i independently represent hydrogen or Ci_ 4 alkyl
  • R 7 and R 8 represent hydrogen
  • each Rio independently represents a 4 to 7 membered saturated monocyclic heterocyclic ring containing up to 2 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 Ci_ 4 alkyl substituent;
  • each Rn independently represents C 3 _ 6 cycloalkyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 oxygen atoms;
  • each Ri 2 independently represents hydrogen
  • n an integer of value 1;
  • each p2 independently represents an integer of value 1 or 2;
  • each p3 independently represents an integer of value 0;
  • each s independently represents an integer of value 0 or 1.
  • Another embodiment of the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein one or more of the following restrictions apply:
  • Xd 2 or is present on a carbon atom in the alpha position of Xd 2 ;
  • c represents CH 2 or a bond; in particular c represents CH 2 ; in particular c represents a bond;
  • the present invention concerns novel compounds of Formula (I), tautomers and stereoisomeric forms thereof, wherein
  • X a is CH or N
  • X b and X c represent CH;
  • X d i represents CH or N
  • X d2 represents CH 2 or NH; provided that at least one of X d i and X d2 represents nitrogen;
  • each R 2 independently represents hydrogen
  • Ci_ 4 alkanediyl optionally being substituted with 1 hydroxyl substituent
  • each R 3 independently represents hydrogen; oxo; hydroxyl
  • Ci_ 4 alkyloxymethyl optionally substituted with cyano, methyloxy, -NR 3e R3f, or R 10 ;
  • R3 a and R3b represent hydrogen
  • R3e and R3f represent methyl
  • R 4 represents hydrogen, methyl, isopropyl or methoxyethyl
  • R 5a represents hydrogen
  • each R 5b independently represents hydrogen; methyl; methyloxymethyl
  • each R6 a and R 6b independently represent hydrogen or methyl
  • R 7 and Rg represent hydrogen
  • R represents methyl
  • each Rio independently represents a 6 membered saturated monocyclic heterocyclic ring containing 2 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 methyl substituent;
  • each Rn independently represents C 3 _ 6 cyclopropyl, or a 5 to 6 membered monocyclic heterocyclic ring containing 1 oxygen atom;
  • each Ri 2 independently represents hydrogen
  • n an integer of value 1 ;
  • n an integer of value 1 or 2 ;
  • pi represents an integer of value 1; each p2 independently represents an integer of value 1 or 2;
  • r represents an integer of value 0 or 1 ;
  • each p3 independently represents an integer of value 0;
  • each s independently represents an integer of value 0 or 1 ;
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein b represents
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein b represents
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • -Xi- represents -(CHRi 2 )-NRi-X e -Ci_ 4 alkanediyl- wherein Ci_ 4 alkanediyl is optionally substituted with hydroxyl or hydroxyCi_ 4 alkyl; or -Xi- represents -NRi-X e -C 2 _ 4 alkanediyl- wherein C 2 - 4 alkanediyl is optionally substituted with hydroxyl or hydroxyC i_ 4 alkyl;
  • n 1;
  • R 6 is other than Ci_ 4 alkyl
  • R 3 is other than hydroxyC i_ 4 alkyloxyCi_ 4 alkyl; and b represents
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • -Xi- represents -(CHRi 2 )-NRi-X e -Ci_ 4 alkanediyl- wherein Ci_ 4 alkanediyl is optionally substituted with hydroxyl or hydroxyCi_ 4 alkyl; or -Xi- represents -NRi-X e -C 2 _ 4 alkanediyl- wherein C 2 - 4 alkanediyl is optionally substituted with hydroxyl or hydroxyC i_ 4 alkyl;
  • n 1;
  • R 6 is other than Ci_ 4 alkyl
  • R 3 is other than hydroxyC i_ 4 alkyloxyCi_ 4 alkyl
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • -Xi- represents -(CHRi 2 )-NRi-X e -Ci_ 4 alkanediyl- wherein Ci_ 4 alkanediyl is optionally substituted with hydroxyl or hydroxyCi_ 4 alkyl; or -Xi- represents
  • c is CH 2 ;
  • R 6 is other than Ci_ 4 alkyl
  • R 3 is other than hydroxyC i_ 4 alkyloxyCi_ 4 alkyl; and b represents
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein b represents
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein r is l , and b represents
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ring b does not contain extra bonds to form a bridged ring system.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein r is 1 and X d2 is NH.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X a , X
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein r is 1 , Xji is
  • the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein XJI is CH, and X d2 is NH; and c represents 0-.
  • the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein when b
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein when b
  • c is other than -O- or -N .3 ⁇ 4 -.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein c represents a bond or -[C(R 5a )2] m - when X dl represents CH or N; or c may also represent -O- or -NR 5a' - when X dl represents CH.
  • the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein r is 1 or 2; in particular wherein r is 1 .
  • the present invention relates to those com ounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X d l represents CH and X d2 represents NH.
  • the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein s is 1.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein p3 is 0.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein s is 0. In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein s is 0 or 1 .
  • the present invention relates to those compounds of Formula (I) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein s is 0 and p3 is O.
  • the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein s is 1 , p3 is 0 and R i 2 is H.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein m is 1 .
  • the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein p2 is 1 .
  • the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X a is CH.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X a , X(, and X c represent CH.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ring A is phenyl.
  • the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ring A is pyridyl.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ri represents Ci_ 4 alkyl, C 2 _ 4 alkenyl, C 2 - 4 alkynyl, or Ci_ 4 alkyloxyCi_ 4 alkyl; in particular Ri represents Ci_ 4 alkyl, C 2 _ 4 alkenyl, or Ci_ 4 alkyloxyCi_ 4 alkyl.
  • Ri is taken together with one R 2 or Ri 2 .
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein when Ri and R 2 are taken together, they form C 3 _ 4 alkanediyl or C 3 _ 4 alkenediyl, each of said
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • Ri represents hydrogen, Ci_ 4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, cyanoCi_ 4 alkyl,
  • R 2 is hydrogen
  • Ri and one R 2 are taken together to form C 3 _ 4 alkanediyl or C 3 _ 4 alkenediyl, each of said C 3 _ 4 alkanediyl and C 3 _ 4 alkenediyl optionally being substituted with 1 to 4 hydroxyl substituents.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ri is other than hydrogen.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 2 represents hydrogen.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 2 represents hydrogen; or R and R 2 are taken together.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ri and one R 2 are taken together to form Ci_ 4 alkanediyl optionally being substituted with 1 hydroxyl substituent; and wherein the other R 2 variables are hydrogen.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein each R w independently represents a 6 membered saturated monocyclic heterocyclic ring containing up to 2 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 Ci_ 4 alkyl substituent.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein each Rm independently represents morpholinyl or piperazinyl optionally substituted with 1 Ci_ 4 alkyl substituent.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein each Rm independently represents 4-morpholinyl, 1 -piperazinyl or 4-methyl-l -piperazinyl.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein each Rn independently represents C 3 _ 6 cycloalkyl, or a 4 to 7 membered monocyclic heterocyclic ring containing one oxygen atom.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein each Rn independently represents C 3 _ 6 cycloalkyl, or a 4 to 7 membered monocyclic heterocyclic ring containing one oxygen atom.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein each Rn independently represents C 3 _ 6 cycloalkyl, tetrahydropyranyl or tetrahydrofuranyl.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein CHR 2 is CH 2 .
  • the present invention relates to those com ounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 12 is H
  • the present inv ention relates to those com ounds of Formula (I) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein c represents CH 2 .
  • the present inv ention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, w herein c represents -[C(R 5a ) 2 ] m -.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein a represents
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein in the "b substituent', the linker with the 'a substituent' is present on X d2 or is present on a carbon atom in the alpha position of X d2 .
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein in the "b substituent', the linker with the 'a substituent' is present on X d2 .
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein in the "b substituent', the linker with the 'a substituent' is present on X d2 ; and wherein pi is 1.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -X ⁇ - represents -(CHRi 2 )-NRi-X e -Ci_ 4 alkanediyl- wherein Ci_ 4 alkanediyl is optionally substituted with hydro xyl or hydro xyCi_ 4 alkyl; or -Xi- represents
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -X ⁇ - represents -(CHRi 2 )-NRi-X e -Ci_ 4 alkanediyl-; or -Xi- represents
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3 is I I.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R () is H.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • -Xi- represents -CH 2 -NRi-CH 2 -Ci_ 4 alkanediyl-, -NRi- CH 2 -C 2 _ 4 alkanediyl-, or -Xi- represents one of the following groups wherein -(CH 2 ) 2 - is attached to 'variable a':
  • Ri represents Ci_ 4 alkyl, C 2 - 4 alkenyl, or Ci_ 4 alkyloxyCi_ 4 alkyl;
  • each R 3 independently represents hydrogen; Ci_ 4 alkyloxyCi_ 4 alkyl optionally substituted with cyano; or hydroxyCi_ 4 alkyloxyCi_ 4 alkyl; in particular R 3 is hydrogen; c is CH 2 .
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • X a , X b and X c are CH;
  • -Xi- represents -CH 2 -NRi-CH 2 -Ci_ 4 alkanediyl-, -NRi-CH 2 -C 2 _ 4 alkanediyl-, or -Xi- represents one of the following groups wherein -(CH 2 ) 2 - is attached to 'variable a':
  • Ri represents Ci_ 4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, Ci_ 4 alkyloxyCi_ 4 alkyl; in particular Ri represents Ci_ 4 alkyl, C 2 _ 4 alkenyl, or Ci_ 4 alkyloxyCi_ 4 alkyl;
  • R 3 represents hydrogen; Ci_ 4 alkyloxyCi_ 4 alkyl optionally substituted with cyano; or hydroxyCi_ 4 alkyloxyCi_ 4 alkyl; in particular R 3 is hydrogen;
  • R 6 represents H.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • -Xi- represents -CH 2 -NRi-CH 2 -Ci_ 4 alkanediyl-, -NRi-CH 2 -C 2 _ 4 alkanediyl-, or -Xi- represents one of the following groups wherein -(CH 2 ) 2 - is attached to 'variable a':
  • Ri represents Ci_ 4 alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, Ci_ 4 alkyloxyCi_ 4 alkyl; in particular Ri represents Ci_ 4 alkyl, C 2 - 4 alkenyl, or Ci_ 4 alkyloxyCi_ 4 alkyl;
  • Another embodiment of the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein one or more of the following restrictions apply:
  • -Xi- represents -CH 2 -NRi-CH 2 -Ci_ 4 alkanediyl-, -NRi-CH 2 -C 2 - 4 alkanediyl-, or -Xi- represents one of the following groups wherein -(CH 2 ) 2 - is attached to 'variable a' :
  • Ri represents Ci_ 4 alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, Ci_ 4 alkyloxyCi_ 4 alkyl; in particular Ri represents Ci_ 4 alkyl, C 2 - 4 alkenyl, or Ci_ 4 alkyloxyCi_ 4 alkyl;
  • R 3 represents hydrogen; Ci_ 4 alkyloxyCi_ 4 alkyl optionally substituted with cyano; or hydroxyCi_ 4 alkyloxyCi_ 4 alkyl; in particular R 3 is hydrogen;
  • R 6 represents H
  • (x) c is CH 2 .
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -X ⁇ - represents -CH 2 -NRi-CH 2 -Ci_ 4 alkanediyl- or -NRi-CH 2 -Ci_ 4 alkanediyl-.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -X ⁇ - represents one of the following groups wherein -(CH 2 ) 2 - is attached to 'variable a' :
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -Xi- represents one of the following groups wherein Ci_ 4 alkanediyl is attached to 'variable a' :
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein if R i is taken together with R 2 , then
  • Ci_ 4 alkanediyl is attached to 'variable a' :
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein if R i is taken together with one R 2 , the bond towards the second R 2 substituent is oriented as shown hereunder:
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • X a , X b and X c are CH;
  • ring A represents phenyl
  • R 6 is hydrogen
  • n 1;
  • c represents -[C(R 5a ) 2 ] m -;
  • n 1;
  • R 5a is hydrog
  • R 4 represents hydrogen
  • R 5 b represents hydrogen
  • -Xi- represents -CH 2 -NRi-(CH 2 ) 2 -;
  • Ri represents Ci_ 4 alkyl, C 2 _ 4 alkenyl, Ci_ 4 alkyloxyCi_ 4 alkyl, or Ci_ 4 alkyl substituted with Rii;
  • Rii is C3_6cycloalkyl; or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 or 2 substituents each independently selected from Ci_ 4 alkyl, halo, hydroxyl, or haloCi_ 4 alkyl; in particular Rn is cyclopropyl or tetrahydrofuranyl.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • -Xi- represents -CH 2 -NRi-(CH 2 ) 2 -;
  • -Xi- represents e.g. -CH 2 -NRi-(CH 2 ) 2 -; the -(CH 2 ) 2 - group is attached to 'variable a' .
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the linker with the 'a substituent' is present on X d2 or is present on a carbon atom in the alpha position of X d2 ;
  • -Xi- represents one of the following groups wherein -(CH 2 ) 2 - is attached to 'variable a' :
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • X d i and X d2 are N; the linker with the 'a substituent' is present on X d2 or is present on a carbon atom in the alpha position of X d2 ;
  • -Xi- represents one of the following groups wherein -(CH 2 ) 2 - is attached to 'variable a' :
  • R 3 is hydrogen
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein if Ri is taken together with one R 2 , the bond towards the second R 2 substituent is oriented as shown hereunder:
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R is always taken together with one R 2 .
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ri is always taken together with one R 2 , and the bond towards the second R 2 substitucnt is oriented as shown hereunder:
  • Ci_ 4 alkyloxyCi_ 4 alkyl optionally substituted with cyano, carboxyl, Ci_ 4 alkyloxy,
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • c represents a bond, -[C(R 5a ) 2 ] m -, -O- or -NR 5a' -.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • c represents a bond, -[C(R 5a ) 2 ] m -, -O- or -NR 5a' -.
  • the present invention relates to those com ounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein two R 5b substituents attached to the same carbon atom are taken together to form
  • the present invention relates to those com ounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • a represents and wherein two R 5 b substituents attached to the same carbon atom are taken together to form C 2 _ 5 alkanediyl or -(CH 2 ) p -0-(CH 2 ) p -, in particular C 2 _ 5 alkanediyl.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • -Xi- represents -NRi-X e -Ci_ 4 alkanediyl- wherein said Ci_ 4 alkanediyl moiety is optionally substituted with hydroxyl or hydroxyC i_ 4 alkyl;
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • -Xi- represents -NRi-X e -Ci_ 4 alkanediyl- wherein said Ci_ 4 alkanediyl moiety is optionally substituted with hydroxyl or hydroxyC i_ 4 alkyl;
  • Ri is taken together with R 2 to form Ci_ 4 alkanediyl substituted with 1 hydroxyl substituent.
  • the present invention relates to those com ounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -X ⁇ -
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -X ⁇ - represents one of the following groups wherein -(CH 2 ) 2 - is attached to 'variable a':
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • a r is 1; wherein the two R 5 b substituents attached to the same carbon atom are taken together to form C 2 _ 5 alkanediyl;
  • c represents -CH 2 -
  • -Xi- represents -NRi-X e -Ci_ 4 alkanediyl- wherein said Ci_ 4 alkanediyl moiety is optionally substituted with hydroxyl or hydroxyC i_ 4 alkyl;
  • Ri is taken together with R 2 to form Ci_ 4 alkanediyl substituted with 1 hydroxyl substituent.
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • c represents -CH 2 -
  • -Xi- represents -NRi-X e -Ci_ 4 alkanediyl- wherein said Ci_ 4 alkanediyl moiety is optionally substituted with hydroxyl or hydroxyC i_ 4 alkyl;
  • Ri is taken together with R 2 to form Ci_ 4 alkanediyl or C 2 _ 4 alkenediyl, each of said
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • a r is 1; wherein the two R 5 b substituents attached to the same carbon atom are taken together to form C 2 _ 5 alkanediyl;
  • the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • -Xi- represents one of the following groups wherein -(CH 2 ) 2 - is attached to 'variable
  • the present invention relates to a subgroup of Formula ( I ) as defined in the general reaction schemes.
  • the compound of Formula (I) is selected from the group consisting of compounds 43, 96, 37, 88, 45, 62, 38, 91, 42, 1, 102 and 105,
  • the compound of Formula (I) is selected from the group consisting of compounds 70, 56, 71, 59, 48, 61, 89, 15, 112, 134, 3, 5, 83, 25, 86, 137 and 54, tautomers and stereoisomeric forms thereof,
  • the compound of Formula (I) is selected from the group consisting of compounds 88, 91, 45, 35, 37, 42, 38, 40 and 43,
  • the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds,
  • references to Formula (I) also include all other sub-groups and examples thereof as defined herein.
  • compounds of the present invention may also be prepared by analogous reaction protocols as described in the general schemes below, combined with standard synthetic processes commonly used by those skilled in the art of organic chemistry. Additionally, compounds of the present invention may also be prepared by analogous reaction protocols as described in the general schemes below combined with methods described in WO2009112439. Starting materials may also be prepared by methods as described in the literature for example by the procedures described in WO 2011008788, WO 2004105765, WO 2005058318, WO 2005058913, WO2006061415, WO2006061417, WO2009016132, WO2008155421 and WO 2007003525; or Burger et al, Medicinal Chemistry Letters (2011), 2(1), 34-38.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • reaction work-up refers to the series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, extraction).
  • microwave heating may be used instead of conventional heating to shorten the overall reaction time.
  • an intermediate of Formula (III) can be replaced by an intermediate of Formula (LXVI).
  • an intermediate of Formula (V-a) can typically be replaced by an intermediate of Formula -NHRi-X e -Ci_ 4 alkanediyl-(S0 2 ) P 3-NHR 4 -.
  • a base such as for example DIPEA.
  • the rings in the position of ring b may also contain extra bonds to form a bridged ring according to the scope.
  • Ci_ 4 alkanediyl moiety in the intermediates and the final compounds such as for example the Ci_ 4 alkanediyl moiety in Formula (V-a), (VI), (VII) and (I-a) of scheme 1 , is optionally substituted as defined in the scope.
  • 'halo' is defined as Br, CI or F
  • 'PG' is defined as a protecting group such as for example fert-butoxycarbonyl, methoxycarbonyl or ethoxycarbonyl
  • 'ra' is defined as 1 or 2. All other variables in Scheme 1 are defined according to the scope of the present invention.
  • reaction conditions 1: The reduction of the nitro group in an intermediate of Formula (II) was performed a) under hydrogenation conditions: H 2 -gas atmosphere in the presence of a catalyst such as for example Raney Ni, Pd/C (for example 5 wt % or 10 wt %) or Pt/C (for example 5 wt %) in a suitable solvent such as for example methanol (MeOH), ethanol (EtOH) or tetrahydrofuran (THF); or
  • a catalyst such as for example Raney Ni, Pd/C (for example 5 wt % or 10 wt %) or Pt/C (for example 5 wt %) in a suitable solvent such as for example methanol (MeOH), ethanol (EtOH) or tetrahydrofuran (THF); or
  • a suitable base such as for example Na 2 C0 3
  • a suitable solvent such as for example N,N-dimethylacetamide (DMA) or 1 -methyl-2-pyrrolidinone (NMP) or mixture of solvents such as for example DMA/DMSO ("DMSO" means dimethyl sulfoxide);
  • a coupling agent such as for example diethyl cyanophosphonate, ( 1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), l-[bis(dimethylamino)methylene]-l H-benzotriazol- 1-ium 3-oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH- [l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et 3 N) or N,N- diisopropylethylamine (DIPEA), in a suitable solvent such as for example DMF.
  • a base such as for example triethylamine (Et 3 N) or N,N- di
  • the compounds of Formula (I) may also be converted into each other via art-known reactions or functional group transformations.
  • a compound of Formula (I), in particular a compound of Formula (I-a), wherein R 6 represents aminocarbonyl can be converted to a compound wherein R 6 represents carboxyl, by reaction with a suitable acid such as for example HCl. During this reaction, ring-opening of the macrocycle may occur. In this case, it is necessary to react the outcome of the reaction with a coupling agent such as for example diethyl cyanophosphonate, in the presence of a base such as for example triethylamine in a suitable solvent such as for example DMF, to close the macrocylic ring.
  • a coupling agent such as for example diethyl cyanophosphonate
  • 'halo' is defined as Br, CI or F;
  • 'PC is defined as a protecting group such as for example tert-butoxycarbonyl, methoxycarbonyl or ethoxycarbonyl;
  • 'ra' is defined as 1 or 2; and all other variables are defined according to the scope of the present invention.
  • a base such as for example NaH, Et 3 N or DIPEA, in a suitable solvent such as for example DMF
  • 2 in the presence of a base such as for example K 2 CO 3 , Et 3 N or DIPEA, in a suitable solvent such as CH 3 CN, DCM or N,N-dimethylacetamide (DMA);
  • Y is defined as O (in case the intermediate of Formula (X-a) was used in step 1) or Y is defined as NRi (in case the intermediate of Formula (X-b) was used in step 1);
  • 'PG' and 'halo' are as defined before in the general reaction schemes;
  • 'ra' is defined as 1 or 2; and all other variables are defined according to the scope of the present invention.
  • Y is defined as O: in a suitable solvent such as for example 2-methyl-2-propanol or NMP, in the presence of a base such as for example potassium tert-butoxide;
  • a suitable solvent such as for example 2-methyl-2-propanol or NMP
  • a base such as for example potassium tert-butoxide
  • lb (Y is defined as NRi): optionally in the presence of a suitable base, such as for example Na 2 C0 3 , optionally in the presence of a suitable solvent such as for example N,N-dimethylacetamide (DMA) or l-methyl-2-pyrrolidinone (NMP) or mixture of solvents such as for example DMA/DMSO ("DMSO” means dimethyl sulfoxide); 2: in the presence of an oxidizing agent such as for example Mn0 2 , in the presence of a suitable solvent such as for example DCM;
  • a suitable base such as for example Na 2 C0 3
  • a suitable solvent such as for example N,N-dimethylacetamide (DMA) or l-methyl-2-pyrrolidinone (NMP) or mixture of solvents such as for example DMA/DMSO
  • DMA N,N-dimethylacetamide
  • NMP l-methyl-2-pyrrolidinone
  • DMSO means dimethyl sulfoxide
  • a coupling agent such as for example diethyl cyanophosphonate, ( 1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), 1 - [bis(dimethy lamino)methylene] - 1 H-benzotriazol- 1 -ium 3 -oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH-
  • a coupling agent such as for example diethyl cyanophosphonate, ( 1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), 1 - [bis(dimethy lamino)methylene] - 1 H-benzotriazol- 1 -ium 3 -oxide hexafluorophosphat
  • HATU hexafluorophosphate
  • a base such as for example triethylamine (Et 3 N) or diisopropylethylamine (DIPEA)
  • DIPEA diisopropylethylamine
  • 'Ms' means mesyl (methanesulfonyl); 'rb' represents an integer of value 1 or 2 in case [C(R 5 b)2]rb is attached to the ring via X d2 and Xd 2 represents N, or 'rb' represents an integer of value 0, 1 or 2 in case [C(R 5 b) 2 ]rb is attached to ring via a carbon atom; all other variables are defined according to the scope of the present invention.
  • the following reaction conditions apply:
  • a coupling agent such as for example diethyl cyanophosphonate, (1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), 1 - [bis(dimethy lamino)methylene] - 1 H-benzotriazol- 1 -ium 3 -oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH- [l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et 3 N) or diisopropylethylamine (DIPEA), in a suitable solvent such as for example DMF.
  • a coupling agent such as for example diethyl cyanophosphonate, (1 H-benz
  • a suitable solvent such as for example 2-methyl-2-propanol or NMP, optionally in the presence of a base such as for example K 2 CO 3 ;
  • a deprotecting agent such as for example tetrabutyl ammonium fluoride (TBAF) in THF; or alternatively in the presence of an acid such as for example HCl in H 2 0; or alternatively in the presence of CH 3 COOH optionally in the presence of water;
  • TBAF tetrabutyl ammonium fluoride
  • a suitable solvent such as for example 2-methyl-2-propanol or NMP, optionally in the presence of a base such as for example K 2 CO 3 ;
  • 'PC is as defined before; 'ra' is defined as 1 or 2; and all other variables are defined according to the scope of the present invention.
  • a coupling agent such as for example diethyl cyanophosphonate, (1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), 1 - [bis(dimethy lamino)methylene] - 1 H-benzotriazol- 1 -ium 3 -oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH- [l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et 3 N) or diisopropylethylamine (DIPEA), in a suitable solvent such as for example DMF.
  • a base such as for example triethylamine (Et 3 N) or diisoprop
  • a compound of Formula (I-d) is reacted with an intermediate of Formula Ri-Br, to result in a compound of Formula (I-d-2).
  • This reaction typically is performed in the presence of a suitable base such as for example DIPEA, in the presence of a suitable solvent such as for example DMF.
  • Analogous functionalization reactions can be performed by replacing RiBr, for example, with alkylsulfonyl chlorides, acid chlorides or sulfamides. Other functional groups can also be introduced via reductive amination. All these reactions can be performed under standard reaction conditions well-known by the skilled person.
  • a coupling agent such as for example diethyl cyanophosphonate, ( 1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), 1 - [bis(dimethy lamino)methylene] - 1 H-benzotriazol- 1 -ium 3 -oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH- [l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et 3 N) or N,N- diisopropylethylamine (DIPEA), in a suitable solvent such as for example DMF.
  • a coupling agent such as for example diethyl cyanophosphonate
  • 'PC is as defined before; 'LC means leaving group such as for exampli chloro or mesylate; and all other variables are defined according to the scope of the present invention.
  • LG 3 introduction of a leaving group (LG) using sulfonyl chlorides such as for example methanesulfonyl chloride (MsCl) or p-toluenesulfonyl chloride (TsCl) in the presence of a suitable base such as for example DIPEA, in the presence of a suitable solvent such as for example DCM;
  • sulfonyl chlorides such as for example methanesulfonyl chloride (MsCl) or p-toluenesulfonyl chloride (TsCl)
  • a suitable base such as for example DIPEA
  • DIPEA p-toluenesulfonyl chloride
  • reaction with an intermediate of Formula V-al optionally in the presence of a suitable base, such as for example Na 2 C0 3 , optionally in the presence of a suitable solvent such as for example DMA or NMP, or in a mixture of solvents such as for example DMA/DMSO ("DMSO" means dimethyl sulfoxide);
  • a suitable base such as for example Na 2 C0 3
  • a suitable solvent such as for example DMA or NMP
  • DMSO means dimethyl sulfoxide
  • 3 firstly reaction with an intermediate of Formula (LXIV-a) in the presence of a suitable base, such as for example Et 3 N, in the presence of a suitable solvent such example CH 3 CN; and subsequently addition of (LXIV-b) to the mixture:
  • a suitable base such as for example K 2 CO 3
  • a suitable solvent such as for example DMF
  • compounds of Formula (I) wherein R 3 represents hydroxyCi_ 4 alkyl may be further functionalized to compounds of Formula (I) wherein R 3 represents optionally substituted Ci_ 4 alkyloxyCi_ 4 alkyl, according to methods well-known by the person skilled in the art. It may be necessary to protect reactive functional groups to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice. For example 2-(trimethylsilyl)ethoxymethyl can be used to protect the amino group between the pyrimidinyl ring and ring A.
  • R 3 represents Ci_ 4 alkyloxyCi_ 4 alkyl substituted with an hydroxy group
  • said hydroxy group may be functionalized to a leaving group (via reaction with for example methanesulfonyl chloride) after which it may be reacted with a
  • An intermediate of Formula (LXVI) can be reacted with an intermediate of Formula (IV-a) in the presence of a suitable acid such as for example p-toluenesulfonic acid monohydrate in a suitable solvent such as, for example, 1,4-dioxane, or a mixture of suitable solvents such as, for example, a mixture of 1,4-dioxane and 2-propanol;
  • a suitable acid such as for example p-toluenesulfonic acid monohydrate
  • a suitable solvent such as, for example, 1,4-dioxane, or a mixture of suitable solvents such as, for example, a mixture of 1,4-dioxane and 2-propanol
  • An intermediate of Formula (LXVII) can be reacted with an intermediate of Formula -NHRi-X e -Ci_ 4 alkanediyl-(S0 2 )p3-NHR 4 - optionally in the presence of a suitable base, such as for example Na 2 C0 3 , optionally in the presence of a suitable solvent such as for example N,N-dimethylacetamide (DMA) or l-methyl-2-pyrrolidinone (NMP) or mixture of solvents such as for example DMA/DMSO ("DMSO" means dimethyl sulfoxide);
  • a suitable base such as for example Na 2 C0 3
  • a suitable solvent such as for example N,N-dimethylacetamide (DMA) or l-methyl-2-pyrrolidinone (NMP) or mixture of solvents such as for example DMA/DMSO ("DMSO” means dimethyl sulfoxide);
  • a coupling agent such as for example diethyl cyanophosphonate, ( 1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), 1 - [bis(dimethy lamino)methylene] - 1 H-benzotriazol- 1 -ium 3 -oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH- [l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et 3 N) or N,N- diisopropylethylamine (DIPEA), in a suitable solvent such as for example DMF.
  • a coupling agent such as for example diethyl cyanophosphonate
  • the Boc group is directly attached to the nitrogen atom in an intermediate of Formula (LXVIII) (this is when r is 0 in the scope), the nitrogen atom can be deprotected, for example under acidic conditions (e.g. HCl in dioxane). Subsequently, the obtained intermediate may be reacted with RG-[C(Rs b )2]ra-Boc wherein RG is a reactive group such as, for example, bromo.
  • a suitable base such as for example CS 2 CO 3 in a suitable solvent such as for example DMF; and subsequently in the presence of a deprotecting group such as for example thiophenol;
  • TBAF tetrabutylammonium fluoride
  • a coupling agent such as for example diethyl cyanophosphonate, ( 1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), l-[bis(dimethylamino)methylene]-l H-benzotriazol- 1-ium 3-oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH- [l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et 3 N) or N,N- diisopropylethylamine (DIPEA), in a suitable solvent such as for example DMF.
  • a base such as for example triethylamine (Et 3 N) or N,N- di
  • Ci_ 4 alkanediyl or C 2 - 4 alkenediyl may be converted to other compounds of Formula (I) by the following reactions:
  • - hydroxyl to azide ion in a suitable solvent such as THF, in the presence of a ligand such as triphenylphosphine (PPh 3 ), an azide source such as diphenylphosphoryl. azide (DPPA) and in the presence of an ligand such as triphenylphosphine (PPh 3 ), an azide source such as diphenylphosphoryl. azide (DPPA) and in the presence of an ligand such as triphenylphosphine (PPh 3 ), an azide source such as diphenylphosphoryl. azide (DPPA) and in the presence of an ligand such as triphenylphosphine (PPh 3 ), an azide source such as diphenylphosphoryl. azide (DPPA) and in the presence of an ligand such as triphenylphosphine (PPh 3 ), an azide source such as diphenylphosphoryl. azide (DPPA) and in the presence of an ligand such as triphen
  • azodicarboxylate such as for example diisopropyl azodicarboxylatc (DIAD); azide to NH 2 : via reduction reaction in the presence of H 2 -gas atmosphere and a catalyst such as for example Pt/C or Pd/C (for example 5 wt % or 10 wt %) in a suitable solvent such as for example MeOH or THF;
  • a catalyst such as for example Pt/C or Pd/C (for example 5 wt % or 10 wt %) in a suitable solvent such as for example MeOH or THF;
  • hydroxyl to oxo Swern oxidation to a ketone using oxalyl chloride, dimethyl sulfoxide (D SO) and an organic base such as for example Eh ;
  • hydroxyl to fluoro in a suitable solvent such as THF in the presence of a suitable base (promotor) such as for example 1,8- diazabicyclo[5.4.0]undecene-7 (DBU) in the presence of a fluorinating reagent such as (diethylamino)difluorosulfonium tetrafluoroborate (XtalFluor-E®).
  • a suitable base such as for example 1,8- diazabicyclo[5.4.0]undecene-7 (DBU)
  • DBU 1,8- diazabicyclo[5.4.0]undecene-7
  • a fluorinating reagent such as (diethylamino)difluorosulfonium tetrafluoroborate (XtalFluor-E®).
  • reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and
  • stereoisomers can be isolated chromatographically using a chiral stationary phase such as, for example, Chiralpak® AD (amylose 3,5 dimethyl- phenyl carbamate) or Chiralpak® AS, both purchased from Daicel Chemical Industries, Ltd, in Japan, or by Supercritical Fluid Chromatography (SFC).
  • a chiral stationary phase such as, for example, Chiralpak® AD (amylose 3,5 dimethyl- phenyl carbamate) or Chiralpak® AS, both purchased from Daicel Chemical Industries, Ltd, in Japan, or by Supercritical Fluid Chromatography (SFC).
  • the chirally pure forms of the compounds of Formula (I) form a preferred group of compounds. It is therefore that the chirally pure forms of the intermediates and their salt forms are particularly useful in the preparation of chirally pure compounds of Formula (I). Also enantiomeric mixtures of the intermediates are useful in the preparation of compounds of Formula (I) with the corresponding configuration.
  • the compounds of the present invention have EF2 inhibitory activity and optionally may also have Vps34 inhibitory activity.
  • the compounds according to the invention and the pharmaceutical compositions comprising such compounds may be useful for treating or preventing, in particular treating, diseases such as cancer, depression, neuropiasticity (synaptic
  • plasticity and non-synaptic plasticity are plasticity and non-synaptic plasticity), and memory and learning disorders.
  • the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or the prevention, in particular in the treatment, of a haematological malignancy or solid tumour.
  • said solid tumour is selected from the group consisting of glioblastoma, medulloblastoma, prostate cancer, breast cancer, ovarian cancer and colorectal cancer.
  • the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or the prevention, in particular in the treatment, of brain tumours, in particular glioblastoma and medulloblastoma.
  • the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or the prevention, in particular in the treatment, of prostate cancer, breast cancer, ovarian cancer and colorectal cancer.
  • cancers which may be treated (or inhibited) include, but are not limited to, a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g.
  • colorectal carcinomas such as colon adenocarcinoma and colon adenoma
  • kidney for example adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, squamous lung cancer), oesophagus, head and neck, gall bladder, ovary, pancreas (e.g. exocrine pancreatic carcinoma), stomach, gastrointestinal (also known as gastric) cancer (e.g.
  • gastrointestinal stromal tumours cervix, endometrium, thyroid, prostate, or skin (for example squamous cell carcinoma or dermatofibrosarcoma protuberans); pituitary cancer, a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (e.g.
  • T-cell lymphoma diffuse large B-cell lymphoma
  • Hodgkin's lymphoma Hodgkin's lymphoma
  • non-Hodgkin's lymphoma hairy cell lymphoma
  • Burkett's lymphoma a hematopoietic tumour of myeloid lineage, for example leukemias, acute and chronic myelogenous leukemias, chronic myelomonocytic leukemia (CMML), myeloproliferative disorder, myeloproliferative syndrome, myelodysplasia syndrome, or promyelocytic leukemia; multiple myeloma; thyroid follicular cancer; hepatocellular cancer, a tumour of mesenchymal origin (e.g.
  • Ewing's sarcoma for example fibrosarcoma or rhabdomyosarcoma; a tumour of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma (such as glioblastoma multiforme) or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.
  • astrocytoma neuroblastoma
  • glioma such as glioblastoma multiforme
  • schwannoma schwannoma
  • melanoma seminoma
  • osteosarcoma xeroderma pigmentosum
  • keratoctanthoma thyroid follicular cancer
  • Kaposi's sarcoma Kaposi'sarcoma.
  • squamous lung cancer breast cancer, colorectal cancer, glioblastoma, astrocytomas, prostate cancer, small cell lung cancer, melanoma, head and neck cancer, thyroid cancer, uterine cancer, gastric cancer, hepatocellular cancer, cervix cancer, multiple myeloma, bladder cancer, endometrial cancer, urothelial cancer, colon cancer, rhabdomyosarcoma, pituitary gland cancer.
  • the compounds according to the invention and the pharmaceutical compositions comprising such compounds may also be useful for treating or preventing, in particular treating, diseases such as malaria, rheumatoid arthritis, lupus and HIV.
  • the compounds of the invention and compositions thereof can also be used in the treatment of hematopoetic diseases of abnormal cell proliferation whether pre- malignant or stable such as myeloproliferative diseases.
  • Myeloproliferative diseases (“MPD”s) are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplasia syndrome.
  • Myeloproliferative diseases include polycythemia vera, essential thrombocythemia and primary myelofibrosis. A further haemato logical disorder is hypereosinophilic syndrome. T-cell lymphoproliferative diseases include those derived from natural Killer cells.
  • the disease or condition comprising abnormal cell growth in one embodiment is a cancer.
  • the compounds of the present invention also have therapeutic applications in sensitising tumour cells for radiotherapy and chemotherapy.
  • the compounds of the present invention can be used as "radiosensitizer” and/or “chemosensitizer” or can be given in combination with another “radiosensitizer” and/or “chemosensitizer”.
  • radiosensitizer is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of the cells to ionizing radiation and/or to promote the treatment of diseases which are treatable with ionizing radiation.
  • chemosensitizer is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and/or promote the treatment of diseases which are treatable with chemotherapeutics.
  • hypoxic cell radiosensitizers e.g., 2- nitroimidazole compounds, and benzotriazine dioxide compounds
  • non-hypoxic cell radiosensitizers e.g., halogenated pyrimidines
  • various other potential mechanisms of action have been hypothesized for
  • radiosensitizers in the treatment of disease.
  • radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5- iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives of the same.
  • Photodynamic therapy (PDT) of cancers employs visible light as the radiation activator of the sensitizing agent.
  • photodynamic radiosensitizers include the following, but are not limited to: hematoporphyrin derivatives, Photo frin,
  • benzoporphyrin derivatives tin etioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same.
  • Radiosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds which promote the incorporation of radiosensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; chemotherapeutic agents which act on the tumour with or without additional radiation; or other therapeutically effective compounds for treating cancer or other diseases.
  • Chemosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds which promote the incorporation of chemosensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; chemotherapeutic agents which act on the tumour or other therapeutically effective compounds for treating cancer or other disease.
  • Calcium antagonists for example verapamil, are found useful in combination with antineoplastic agents to establish chemosensitivity in tumor cells resistant to accepted chemotherapeutic agents and to potentiate the efficacy of such compounds in drug-sensitive malignancies.
  • the invention relates to compounds of Formula (I ) and pharmaceutically acceptable addition salts, and solvates thereof, for use as a medicament.
  • the invention also relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for use in the inhibition of EF2 and optionally also for use in the inhibition of Vps34.
  • the compounds of the present invention can be "anti-cancer agents", which term also encompasses “anti-tumor cell growth agents” and “anti-neoplastic agents”.
  • the invention also relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for use in the treatment of diseases mentioned above.
  • the invention also relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the treatment or prevention, in particular for the t reatment, of said diseases.
  • the invention also relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the treatment or prevention, in particular in the treatment, of EF2 mediated diseases or conditions.
  • the invention also relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the treatment or prevention, in particular in the treatment, of EF2K. and optional ly Vps34 mediated diseases or conditions.
  • the invention also relates to the use of compounds of Formula ( 1 ) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament.
  • the invention also relates to the use of compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament for the inhibition of EF2 and optionally also for the inhibition of Vps34.
  • the invention also relates to the use of compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament for the treatment or prevention, in particular for the treatment, of any one of the disease conditions mentioned hereinbefore.
  • the invention also relates to the use of compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned hereinbefore.
  • the compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, can be administered to mammals, preferably humans for the treatment or prevention of any one of the diseases ment ioned hereinbefore.
  • the compounds of the present invention may also be used in the optimisation of industrial protein production.
  • Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of a compound of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, to warm-blooded animals, including humans.
  • An effectiv e therapeutic daily amount would be from about 0.005 mg/kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg body weight, more in particular from 0.01 mg/kg to 25 mg/kg body weight, preferably from about 0.01 mg/kg to about 1 5 mg/kg, more preferably from about 0.01 mg kg to about 10 mg/kg, even more preferably from about
  • the amount of a compound according to the present inv ention, also referred to here as the activ e ingredient, which is required to achieve a therapeutically effect will of course, vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
  • a method of treatment may also include administering the activ e ingredient on a regimen of between one and four intakes per day.
  • the compounds according to the invention are preferably formulated prior to
  • suitable pharmaceutical formulations are prepared by know n procedures using well known and readily av ailable ingredients.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula ( I ), a pharmaceutically acceptable addition salt, or a solvate thereof, and one or more additional therapeutic agents, as wel l as administration of the compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, and each additional therapeutic agents in its own separate pharmaceutical dosage formulation.
  • a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solv ate thereof, and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.
  • the active ingredient While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof.
  • the carrier or diluent must be ' " acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
  • the compounds according to the invention in particular the compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup or combination thereof may be formulated into v arious pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemical ly administering drugs.
  • compositions of this invention an effective amount of the particular compound as the activ e ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ea.se in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • Injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • Injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mi ture of saline and glucose solution.
  • injectable solutions containing a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof may be formulated in an oil for prolonged action. Appropriate oils for this purpose are.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • Acid or base addition salts of compounds of Formula (I) due to their increased water solubility over the corresponding base or acid form, are more suitable in the preparation of aqueous compositions.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quant ity of active ingredient calculated to produce the desired therapeutic effect in association with the required
  • unit dosage forms are tablets (including scored or coated tablets ), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • ⁇ -, ⁇ - or ⁇ -cyclodextrins or their derivatives in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl- ⁇ -cyclodextrin or su 1 fobuty I - ⁇ -cyclodextri n .
  • co-solvents such as alcohols may improve the solubility and/or the stability of the compounds according to the invent ion in pharmaceutical compositions.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0. 1 to 70 % by weight, even more preferably from 0. 1 to 50 % by weight of the compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, and from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
  • a combination of a compound of the present invention with another anticancer agent is envisaged, especially for use as a medicine, more specifically for use in the treatment of cancer or related diseases.
  • the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents, more particularly, with other anti-cancer agents or adjuvants in cancer therapy.
  • anti-cancer agents or adjuvants include but are not limited to:
  • platinum coordination compounds for example cisplatin optionally combined with amifostine, carboplatin or oxaliplatin;
  • taxane compounds for example paclitaxel, paclitaxel protein bound particles (AbraxaneTM) or docetaxel;
  • topoisomerase I inhibitors such as camptothecin compounds for example irinotecan, SN-38, topotecan, topotecan hcl;
  • - topoisomerase II inhibitors such as anti-tumour epipodophyllotoxins or
  • podophyllotoxin derivatives for example etoposide, etoposide phosphate or teniposide;
  • anti-tumour vinca alkaloids for example vinblastine, vincristine or vinorelbine;
  • anti-tumour nucleoside derivatives for example 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hcl, capecitabine, cladribine, fludarabine, nelarabine; alkylating agents such as nitrogen mustard or nitrosourea for example cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan (melphalan), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide optionally in combination with mesna, pipobroman, procarbazine, streptozocin, temozolomide, uracil;
  • alkylating agents such as nitrogen mustard or nitrosourea for example cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan (melphalan), lomustine, altretamine, busulfan, dacar
  • anti-tumour anthracycline derivatives for example daunorubicin, doxorubicin optionally in combination with dexrazoxane, doxil, idarubicin, mitoxantrone, epirubicin, epirubicin hcl, valrubicin;
  • IGF-1 receptor molecules that target the IGF-1 receptor for example picropodophilin
  • glucocorticoids for example prednisone
  • inhibitors of estrogen synthesis for example tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole;
  • aromatase inhibitors such as exemestane, anastrozole, letrazole, testolactone and vorozole;
  • retinoids such as retinoids, vitamin D or retinoic acid and retinoic acid metabolism blocking agents (RAMBA) for example accutane
  • RAMBA retinoic acid metabolism blocking agents
  • DNA methyl transferase inhibitors for example azacytidine or decitabine
  • antifolates for example premetrexed disodium
  • antibiotics for example antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, mithramycin;
  • antimetabolites for example clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine;
  • Bcl-2 inhibitors for example YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 or decanoic acid;
  • tubuline -binding agents for example combrestatin, colchicines or nocodazole; kinase inhibitors (e.g. EGFR (epithelial growth factor receptor) inhibitors, MTKI (multi target kinase inhibitors), mTOR inhibitors) for example flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib ditosylate, sorafenib, sunitinib, sunitinib maleate, temsirolimus;
  • kinase inhibitors e.g. EGFR (epithelial growth factor receptor) inhibitors, MTKI (multi target kinase inhibitors), mTOR inhibitors
  • EGFR epidermal growth factor receptor
  • MTKI multi target kinase inhibitors
  • mTOR inhibitors for example flavoperidol, imatinib me
  • farnesyltransferase inhibitors for example tipifarnib
  • HDAC histone deacetylase
  • telomestatin a trimer of a pregnene inhibitor
  • telomestatin a trimer of a pregnene inhibitor
  • Matrix metalloproteinase inhibitors for example batimastat, marimastat, prinostat or metastat;
  • Recombinant interleukins for example aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon alfa 2b; - MAPK inhibitors;
  • Retinoids for example alitretinoin, bexarotene, tretinoin;
  • Steroids for example dromostanolone propionate, megestrol acetate, nandrolone
  • Gonadotropin releasing hormone agonists or antagonists for example abarelix, goserelin acetate, histrelin acetate, leuprolide acetate;
  • - MEK inhibitors for example PD98059, AZD6244, CI- 1040;
  • colony-stimulating factor analogs for example filgrastim, pegfilgrastim, sargramostim; erythropoietin or analogues thereof (e.g. darbepoetin alfa);
  • CYP17 a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitor
  • CYP17 a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitor
  • CYP17 a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitor
  • CYP17 a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitor
  • mTOR inhibitors such as rapamycins and rapalogs, and mTOR kinase inhibitors
  • PI3K inhibitors and dual mTOR/PI3K inhibitors
  • - B-raf inhibitors e.g. vemurafenib
  • the present invention further relates to a product containing as first active ingredient a com ound according to the invention and as further active ingredient one or more anticancer agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.
  • the one or more other medicinal agents and the compound according to the present invention may be administered simultaneously (e.g. in separate or unitary
  • compositions or sequentially in either order.
  • the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved.
  • the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated and the particular host being treated.
  • the optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.
  • the weight ratio of the compound according to the present invention and the one or more other anticancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of
  • a particular weight ratio for the present compound of Formula ( I ) and another anticancer agent may range from 1 / 10 to 10/1 , more in particular from 1 /5 to 5 1 , even more in particular from 1/3 to 3/ 1 .
  • the platinum coordination compound is advantageously administered in a dosage of 1
  • the taxane compound is advantageously administered in a dosage of 50 to 400 mg per
  • mg/m square meter of body surface area, for example 75 to 250 mg/m , particularly for paclitaxel in a dosage of about 1 75 to 250 mg/m. and for docetaxel in about 75 to 1 50 mg/m per course of treatment.
  • camptothecin compound is advantageously administered in a dosage of 0. 1 to
  • irinotecan in a dosage of about 1 00 to 350 mg/m and for topotecan in about 1 to 2 mg/m per course of treatment.
  • the anti-tumour podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m ) of body surface area, for example 50 to
  • the anti-tumour vinca alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg/m ) of body surface area, particularly for vinblastine in a
  • the anti-tumour nucleoside derivativ e is adv antageously administered in a dosage of 200 to 2500 mg per square meter (mg/m ) of body surface area, for example 700 to
  • the alkylating agents such as nitrogen mustard or nitrosourea is advantageously administered in a dosage of 100 to 500 mg per square meter (mg/m ) of body surface area, for example 1 20 to 200 mg/m , particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m , for chlorambucil in a dosage of about 0. 1 to 0.2 mg kg, for carmustine in a dosage of about 1 50 to 200 mg/m , and for lomust ine in a dosage of about 1 00 to 1 50 mg/m per course of treatment.
  • the anti-tumour anthracycline deriv ative is adv antageously administered in a dosage of 10 to 75 mg per square meter (mg/m ) of body surface area, for example 1 5 to
  • doxorubicin in a dosage of about 40 to 75 mg/m
  • daunorubicin in a dosage of about 25 to 45mg/m
  • idarubicin in a dosage of about 10 to 1 5 mg/m per course of treatment.
  • the antiestrogen agent is advantageously administered in a dosage of about 1 to 100 mg daily depending on the particular agent and the condition being treated.
  • Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect.
  • Toremifene is adv antageously administered orally in a dosage of about 60mg once a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect.
  • Anastrozole is adv antageously administered orally in a dosage of about 1 mg once a day.
  • Droloxifene is advantageously administered orally in a dosage of about 20- l OOmg once a day.
  • Raloxifene is advantageously administered orally in a dosage of about 60mg once a day.
  • Excmestane is advantageously
  • Antibodies are adv antageously administered in a dosage of about 1 to 5 mg per square meter (mg/m ) of body surface area, or as known in the art, if different.
  • Trastuzumab is advantageously administered in a dosage of 1 to 5 mg per square meter (mg/m ) of body surface area, particularly 2 to 4 mg/m per course of treatment.
  • These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 2 1 or 28 days.
  • the following examples illustrate the present invention. In case no specific
  • stereochemistry is indicated for a stereocenter of a compound, this means that the compound was obtained as a mixture of the R and the S enantiomers.
  • NaH sodium hydride (60% in mineral oil);
  • DCM dichloromethane;
  • q.s.” means quantum sufficit;
  • Int.” Means intermediate;
  • Co.” means compound;
  • DCE means 1,2-dichloroethane;
  • DIPE means diisopropyl ether,
  • Boc means tert-butoxycarbonyl;
  • ACN means acetonitrile;
  • BDS means base deactivated silica”;
  • NMP means l-methyl-2-pyrrolidinone;
  • DMA means N,N- dimethylacetamide;
  • MeOH means methanol;
  • LC means liquid chromatography;
  • LCMS means Liquid Chromatography/Mass spectrometry;
  • HATU means 1- [bis(dimethylamino)methylene]- lH-[ 1 ,2,3]triazolo[4,5-b]pyridin- 1 -ium 3-oxide hexafluoride,
  • BINAP means [l, -binaphthalene]-2,2'-diylbis[diphenylphosphine] (racemic);
  • TFA trifluoroacetic acid
  • m.p melting point
  • N 2 nitrogen
  • RP reversed phase
  • min means minute(s)
  • h means hour(s)
  • EtOAc means ethyl acetate
  • EtsN means triethylamine
  • PE means petroleum ether
  • EtOH means ethanol
  • THF means tetrahydrofuran
  • Celite ® means diatomaceous earth
  • DMF means N,N-dimethyl formamide
  • DMSO means dimethyl sulfoxide
  • iPrOH means 2-propanol
  • iPrNH 2 means isopropylamine
  • SFC means
  • DIPEA means N,N-diisopropylethylamine
  • HBTU means l-[bis(dimethylamino)methylene]-lH-benzotriazol-l-ium 3-oxide hexafluorophosphate
  • w/v means weight/volume
  • NaBH(OAc) 3 means sodium triacetoxyborohydride
  • Ph 3 means triphenylphosphine
  • Et 2 0 means diethyl ether
  • Pd/C means palladium on carbon
  • Pt/C means platina on carbon
  • Pd(OAc) 2 means palladium(II) acetate
  • Pd 2 (dba) 3 means tris(dibenzylideneacetone)dipalladium
  • Et means ethyl
  • Me means methyl
  • PdCl 2 (dppf)-DCM means [1,1 * -
  • the solid was purified by preparative LC (Irregular SiOH 20-45 ⁇ 1000 g DAVISIL). Mobile phase (60 % Heptane, 3 % MeOH, 37 % EtOAc). The desired fractions were collected and the solvent was evaporated.

Abstract

The present invention relates to substituted macrocylic pyrimidine derivatives of Formula (I) wherein the variables have the meaning defined in the claims. The compounds according to the present invention have EF2K inhibitory activity and optionally also Vps34 inhibitory activity. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

Description

MACROCYLIC PYRIMIDINE DERIVATIVES
Field of the Invention
The present invention relates to substituted macrocylic pyrimidine derivatives having EF2K inhibitory activity and optionally also Vps34 inhibitory activity. The invention further relates to processes for preparing such compounds, pharmaceutical
compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
Background of the invention
In all eukaryotic cell types, protein elongation is a critical and energetically expensive step in the synthesis of new proteins. The rate of protein elongation is therefore strictly regulated to coordinate the availability of resources (energy, amino acids) with the demand for newly synthesised proteins. Eukaryotic elongation factor 2 (EF2) is essential for protein elongation: its affinity for the ribosome, and hence protein elongation rate, is controlled by its phosphorylation state. Phosphorylation of eEF2 at Threonine 56 by the elongation factor 2 kinase (EF2K or eEF2K) decreases the affinity of EF2 for the ribosome, and reduces protein elongation rates (Browne et al., Eur J Biochem. 2002, 269(22):5360-5368). This regulation is critical under various forms of cellular stress, such as nutrient limitation and hypoxia, or conditions of increased energy expenditure, such as muscle exercise. In addition, local subcellular regulation of EF2 phosphorylation by EF2K at nerve growth cones or at the synapse ensures preferential translation of certain nerve growth factors and neurotransmitters.
Dysregulation of EF2 (Thr56) phosphorylation has been associated with several devastating pathologies, including cancer and depression. Tumour cells often experience various forms of stress (hypoxia, nutrient deprivation), and therefore activate eEF2K activity to balance protein elongation rates with the high demand for de novo protein synthesis. Indeed, EF2 is highly phosphoryated in tumour tissue compared to normal tissue as an adaptive response to nutrient limitation (Leprivier et al., Cell 2013, 153(5): 1064-1079). Deregulation of this control through inhibition of eEF2K is thought to fatally increase energy expenditure in tumour cells, and represent an anti- tumour strategy through induction of metabolic crisis (Hait et al, Clin Cancer Res. 2006, 12: 1961-1965; Jin et al, J Cell Sci. 2007, 120(3):379-83; Leprivier et al, Cell 2013, 153(5): 1064-1079). Increased local translation of synaptic proteins such as BDNF (brain-derived neurotrophic factor) plays a critical role in the fast-acting anti- depressant activity of NMD A (N-Methyl-D-aspartic acid) antagonists (such as ketamine); reduced phosphorylation levels of EF2 are thought to be critical to enable BDNF translation, and hence EF2K inhibition has been proposed as a fast-acting antidepressant therapy (Kavalali et al., Am J Psychiatry 2012, 169(11): 1150-1156).
Consistent with its role under hypoxia and starvation, EF2K is activated by direct phosphorylation by AMPK, whereas EF2K is regulated through inhibitory phosphorylation by growth and cell cycle kinases, such as S6K and CDK2. In addition, EF2K is a Ca2+/calmodulin-dependent kinase; this regulation may be key for the synaptic regulation of EF2K. (Browne et al., Eur J Biochem. 2002, 269(22):5360- 5368).
EF2K is an atypical kinase: the primary sequence of its catalytic domain is only remotely related to that of canonical kinases, such as serine/threonine kinases, tyrosine kinases, or lipid kinases. Compounds with EF2K inhibitory activity, may prevent the stress-induced phosphorylation of eEF2 in cells and in xenografted tumours in mice. In addition to strict regulation of protein synthesis under cellular stress as described above, many cell types utilize autophagy as a recycling mechanism to cope with low nutrient availability, hypoxia and other forms of cellular stress. Autophagy is a catabolic process, in which cytosolic content, including proteins, protein aggregates and entire organelles are engulfed in vesicles (autophagosomes) which fuse to lysosomes to enable degradation of macromolecules to recuperate building blocks (amino acids, fatty acids, nucleotides) and energy (Hait et al, Clin Cancer Res. 2006, 12: 1961-1965). The double membrane of autophagosomes critically consists of phosphatidylinositol- (3)-phosphate [PI(3)P], the product of the class III PI3K, Vps34 (also called PIK3C3). Vps34, and the adaptor protein, Beclinl, are both essential for autophagy in mammalian cells (Amaravadi et al., Clin Cancer Res. 2011, 17:654-666). Autophagy is upregulated in tumors, and inhibition of autophagy using the lysosomotropic agent, chloroquine (which inhibits the fusion of lysosomes to autophagosomes), or R Ai approaches can impair tumorigenesis. Moreover, inhibition of autophagy has been shown to sensitize tumors to chemotherapeutic agents, radiation, proteasome inhibitors, and kinase inhibitors (such as the receptor tyrosine kinases EGFR, class I PI3K, mTOR, and Akt) (Amaravadi et al., Clin Cancer Res. 2011, 17:654-666). The clinical utility of chloroquine in treating patients with malaria, rheumatoid arthritis, lupus and HIV suggest potential utility of autophagy inhibitors for those pathologies as well (Ben-Zvi et al, Clin Rev Allergy Immunol. 2012, 42(2): 145-53). Inhibition of the class III PI3K, Vps34, may inhibit autophagy in cancer cells under stress. Moreover it was found that cancer cells, partially deficient in autophagy through knockdown of Beclin, are especially sensitive to Vps34 inhibition, suggesting that autophagy-deficient tumors (e.g. because of mono-allelic deletion of beclinl, as frequently found in breast, ovarian and prostate cancer, or other genetic lesions (Maiuri et al, Cell Death Differ. 2009, 16(l):87-93) may be most susceptible to Vps34 inhibition.
WO 2009/112439 describes 4-aryl-2-anilino-pyrimidines as PLK kinase inhibitors.
There is a strong need for novel compounds which have EF2K inhibitory activity and optionally also have Vps34 inhibitory activity, thereby opening new avenues for the treatment of cancer. It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. It is accordingly an object of the present invention to prov ide such novel compounds.
Summary of the invention
It has been found that the compounds of the present invention have EF2 inhibitory activity and optionally also have Vps34 inhibitory activity. The compounds according to the invention and the pharmaceutical compositions comprising such compounds may be useful for treating or preventing, in particular treating, diseases such as cancer, depression, and memory and learning disorders. In particular, the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment of a haematological malignancy or solid tumour. In a specific
embodiment said solid tumour is selected from the group consisting of glioblastoma, meduUoblastoma, prostate cancer, breast cancer, ovarian cancer and colorectal cancer, and the like.
This invention concerns compounds of Formula (I)
Figure imgf000005_0001
tautomers and stereochemical^ isomeric forms thereof, wherein
Xa, Xb and Xc each independently represent CH or N; -Xi- represents -(CHRi2)s-NRi-Xe-Ci_4alkanediyl-(S02)p3- or
-(CH2)s-0-Xe-Ci_4alkanediyl-(S02)p3-; wherein each of said Ci_4alkanediyl moieties optionally substituted with hydroxyl or hydroxyCi_4alkyl;
-Xe- represents -C(R2)2- or -C(=0)-;
a represents -NR4-C(=0)-[C(R5b)2]r- or -NR4-C(R5b)2-C(=0)- or
-C(=0)-NR4-C(R5b)2-;
b represents
Figure imgf000006_0001
, wherein said b ring may contain extra bonds to form a bridj ring system selected from 2,5-diazabicyclo[2.2.2]octanyl, 3,8- diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,9- diazabicyclo[3.3.1 ]nonyl;
Xdi represents CH or N;
Xd2 represents CH2 or NH;
provided that at least one of Xdi and Xd2 represents nitrogen;
-0-, -NR5a-, -S02-, or -SO-;
Figure imgf000006_0002
Ri represents hydrogen, Ci_4alkyl, C2-4alkenyl, C2-4alkynyl, cyanoCi_4alkyl,
-C(=0)-Ci_4alkyl, -C(=0)-haloCi_4alkyl, hydro xyCi_4alkyl, haloCi_4alkyl,
Ci_4alkyloxyCi_4alkyl, haloCi_4alkyloxyCi_4alkyl, -C(=0)NR7R8, -S02-NR7R8, -S02-R9, Rii, Ci_4alkyl substituted with Rn, -C(=0)-Rn, or -C(=0)-Ci_4alkyl-Rn;
each R2 independently represents hydrogen, Ci_4alkyl, Ci_4alkyl substituted with C3_6cycloalkyl, hydroxyCi_4alkyl, Ci_4alkyloxyCi_4alkyl, carboxyl, -C(=0)-0-Ci_4alkyl wherein Ci_4alkyl is optionally substituted with Ci_4alkyloxy, -C(=0)-NH2, -C(=0)- NH(Ci_4alkyl) wherein Ci_4alkyl is optionally substituted with Ci_4alkyloxy, or -C(=0)- N(Ci_4alkyl)2 wherein each Ci_4alkyl is optionally substituted with Ci_4alkyloxy;
or Ri and one R2 are taken together to form Ci_4alkanediyl or C2-4alkenediyl, each of said Ci_4alkanediyl and C2-4alkenediyl optionally being substituted with 1 to 4 substituents each independently selected from hydroxyl, oxo, halo, cyano, N3, hydroxyC i_4alkyl, -NR7R8, -S02-NR7R8, -NH-S02-NR7R8, -C(=0)-NR7R8, or -NH- C(=0)-NR7R8;
or Ri and Ri2 are taken together to form Ci_4alkanediyl or C2_4alkenediyl, each of said Ci_4alkanediyl and C2_4alkenediyl optionally being substituted with 1 to 4 substituents each independently selected from hydroxyl, oxo, halo, cyano, N3, hydroxyC i_4alkyl, -NR7R8, -S02-NR7R8, -NH-S02-NR7R8, -C(=0)-NR7R8, or -NH-C(=0)-NR7R8;
each R3 independently represents hydrogen; oxo; hydroxyl; carboxyl; -NR3aR3b;
-C(=0)-NR3aR3b; hydroxyC i_4alkyl; haloCi_4alkyl; -(C=0)-Ci_4alkyl;
-C(=0)-0-Ci_4alkyl wherein said Ci_4alkyl may optionally be substituted with phenyl; Ci_4alkyl optionally substituted with cyano, carboxyl, Ci_4alkyloxy,
-C(=0)-0-C1_4alkyl, -0-C(=0)-C1_4alkyl, -NR3eR3f, -C(=0)-NR3eR3f, -S02-NR3eR3f, Q,
-C(=0)-Q, or -S02-Q; hydroxyC i_4alkyloxyCi_4alkyl; Ci_4alkyloxyhydroxyCi_4alkyl; hydroxyCi_4alkyloxyhydroxyCi_4alkyl; or Ci_4alkyloxyCi_4alkyl optionally substituted with cyano, carboxyl, Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, -0-C(=0)-Ci_4alkyl, -NR3eR3f, -C(=0)-NR3eR3f, -S02-NR3eR3f, Rio, -C(=O)-R10, or -SO2-R10;
or two R3 substituents attached to the same carbon atom are taken together to form
C2_5alkanediyl or -(CH2)p-0-(CH2)p-;
each R3a and R3b independently represent hydrogen; -(C=0)-Ci_4alkyl; -S02-NR3cR3d; or Ci_4alkyl optionally substituted with Ci_4alkyloxy; or
R3a and R3b are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 or 2 further heteroatoms selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
each R3c and R3d independently represent hydrogen, Ci_4alkyl or -(C=0)-Ci_4alkyl; or R3c and R3d are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 or 2 further heteroatoms selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
each R3e and R3f independently represent hydrogen, Ci_4alkyl optionally substituted with Ci_4alkyloxy, -(C=0)-Ci_4alkyl, or -S02-NR3cR3d;
R4 represents hydrogen, Ci_4alkyl or Ci_4alkyloxyCi_4alkyl;
each R5a independently represents hydrogen or Ci_4alkyl; or
two R5a substituents attached to the same carbon atom are taken together to form C2_5alkanediyl or -(CH2)p-0-(CH2)p-; R5a' represents hydrogen or Ci_4alkyl;
each R5b independently represents hydrogen; Ci_4alkyl; Ci_4alkyl substituted with NR5biR5b2; C1-4alkyloxyC1-4alkyl; hydroxyCi_4alkyl; hydroxyl; C3_6cycloalkyl; or phenyl optionally substituted with Ci_4alkyl, halo, hydroxyl or Ci_4alkyloxy; or two Rsb substituents attached to the same carbon atom are taken together to form C2_5alkanediyl or -(CH2)p-0-(CH2)p-;
R5bi and R5b2 independently represent hydrogen, Ci_4alkyl optionally substituted with Ci_4alkyloxy, -(C=0)-Ci_4alkyl, or -S02-NR5b3R5b4;
R5b3 and R5b4 independently represent hydrogen, Ci_4alkyl or -(C=0)-Ci_4alkyl; or R5b3 and Rsb4 are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 or 2 further heteroatoms selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
each R<5 independently represents hydrogen, halo, hydroxyl, carboxyl, cyano, Ci_4alkyl,
Ci_4alkyloxyCi_4alkyl, hydroxyCi_4alkyl, haloCi_4alkyl, C2_4alkenyl, C2_4alkynyl,
-NR6aR6b, or -C(=0)NR6aR6b;
each R6a and R6b independently represent hydrogen or Ci_4alkyl;
each R7 and Rg independently represent hydrogen, Ci_4alkyl, haloCi_4alkyl, or
C3_6cycloalkyl; or
R7 and Rg are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 further heteroatom selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
Rg represents Ci_4alkyl, haloCi_4alkyl, or C3_6cycloalkyl;
each Rio independently represents a 4 to 7 membered saturated monocyclic
heterocyclic ring containing up to 2 heteroatoms selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each
independently selected from Ci_4alkyl, halo, hydroxyl or haloCi_4alkyl;
each Rii independently represents C3_6cycloalkyl, phenyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
each Ri2 independently represents hydrogen or Ci_4alkyl;
Q represents a 4 to 7 membered saturated monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl or haloCi_4alkyl;
n represents an integer of value 1 or 2;
m represents an integer of value 1 or 2 ;
p represents an integer of value 1 or 2;
pi represents an integer of value 1 or 2;
each p2 independently represents an integer of value 0, 1 or 2;
r represents an integer of value 0, 1 or 2;
each p3 independently represents an integer of value 0 or 1 ;
each s independently represents an integer of value 0, 1 or 2;
and the pharmaceutically acceptable addition salts, and the solvates thereof.
The present invention also concerns methods for the preparation of compounds of the present invention and pharmaceutical compositions comprising them.
The com ounds of the present invention were found to hav e EF2K inhibitory activ ity and optionally also have Vps34 inhibitory activ ity. Therefore the compounds of the present invention may be useful in the treatment or prev ention, in particular in the treatment, of diseases such as cancer, depression, neuroplasticity (synaptic
plasticity and non-synaptic plasticity), and memory and learning disorders. In particular, the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment of a haematological malignancy or solid tumour. In a specific embodiment said solid tumour is selected from the group consisting of glioblastoma, meduUoblastoma, prostate cancer, breast cancer, ovarian cancer and colorectal cancer, and the like.
In view of the aforementioned pharmacology of the compounds of Formula (I) and pharmaceutically acceptable addition salts, and solv ates thereof, it follows that they may be suitable for use as a medicament.
In particular the compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, may be suitable in the treatment or prev ention, in particular in the treatment, of cancer.
The present invention also concerns the use of compounds of Formula (I) and pharmaceutically acceptable addition salts, and solv ates thereof, for the manufacture of a medicament for the treatment or prevention, in particular treatment, of diseases such as cancer, depression, neuroplasticity (synaptic plasticity and non-synaptic plasticity), and memory and learning disorders. The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or
advantageous.
Detailed description
When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise.
Combinations of substituents and/or variables are permissible only if such
combinations result in chemically stable compounds. "Stable compound" is meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
When any variable occurs more than one time in any constituent or in any Formula (e.g. Formula (I)), its definition in each occurence is independent of its definition at every other occurrence.
Whenever a radical or group is defined as "optionally substituted" in the present invention, it is meant that said radical or group is unsubstituted or is substituted.
Lines drawn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms.
Whenever the term "substituted with 1 to 4 substituents" is used in the present invention, it is meant, to indicate that from 1 to 4 hydrogens, in particular from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using "substituted" are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
Whenever the term "substituted with" without an indication of the number of substituents is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one 1 hydrogen, on the atom or radical indicated in the expression using "substituted" is replaced with a substituent from the indicated group, provided that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent. For example "Ci_4alkyl substituted with cyano" means a Ci_4alkyl group substituted with one cyano. "Ci_4alkyl optionally substituted with cyano" means unsubstituted Ci_4alkyl or Ci_4alkyl substituted with one cyano.
The prefix "Cx_y" (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a Ci_4alkyl group contains from 1 to 4 carbon atoms, a C3_6cycloalkyl group contains from 3 to 6 carbon atoms, a Ci_4alkyloxy group contains from 1 to 4 carbon atoms, and so on.
The term "halo" as a group or part of a group is generic for fluoro, chloro, bromo, iodo unless otherwise is indicated or is clear from the context.
The term "Ci_4alkyl" as a group or part of a group refers to a hydrocarbyl radical of Formula CnH2n+i wherein n is a number ranging from 1 to 4. Ci_4alkyl groups comprise from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. Ci_4alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Ci_4alkyl includes all linear, or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes methyl, ethyl, n-propyl, /-propyl, 2-methyl-ethyl, butyl and its isomers (e.g. n-butyl, /sobutyl and tert-butyl), and the like.
The term "Ci_4alkyloxy" as a group or part of a group refers to a radical having the
Formula -ORc wherein Rc is Ci_4alkyl. Non-limiting examples of suitable Ci_4alkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy and /er/-butyloxy.
The term "C3_6cycloalkyl" alone or in combination, refers to a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms. Non- limiting examples of suitable C3_6cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term 'hydroxyCi_4alkyl' as used herein as a group or part of a group refers to a Ci_ 4alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a hydroxyl group. The term 'hydroxyCi_4alkyl' therefore includes
monohydroxyCi_4alkyl and also polyhydroxyCi_4alkyl. There may be one, two, three or more hydrogen atoms replaced with a hydroxyl group, so the hydroxyCi_4alkyl may have one, two, three or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.
In a particular embodiment 'hydroxyCi_4alkyl' is limited to monohydroxyCi_4alkyl. The term 'hydroxyCi_4alkyloxy' as used herein as a group or part of a group refers to a hydroxyCi_4alkyl-0- group wherein "hydroxyCi_4alkyl" is as defined before.
The term 'hydroxyCi_4alkyloxyCi_4alkyl' as used herein as a group or part of a group refers to a hydroxyCi_4alkyl-0-Ci_4alkyl- group wherein "hydroxyCi_4alkyl" and "Ci_4alkyl" are as defined before.
The term 'Ci_4alkyloxyhydroxyCi_4alkyl' as used herein as a group or part of a group refers to a Ci_4alkyl-0-hydroxyCi_4alkyl- group wherein "hydroxyCi_4alkyl" and "Ci_4alkyl" are as defined before.
The term 'hydroxyCi_4alkyloxyhydroxyCi_4alkyl' as used herein as a group or part of a group refers to a hydroxyCi_4alkyl-0-hydroxyCi_4alkyl- group wherein
"hydroxyCi_4alkyl" is as defined before.
The term 'haloCi_4alkyl' as used herein as a group or part of a group refers to a
Ci_4alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen. The term 'haloCi_4alkyl' therefore includes monohaloCi_4alkyl and also polyhaloCi_4alkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi_4alkyl may have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and the like.
The term "cyanoCi_4alkyl" as used herein refers to a Ci_4alkyl group as defined herein which is substituted with one cyano group.
The term 'Ci_4alkoxyCi_4alkyl' as used herein as a group or part of a group refers to a Ci_4alkyl-0-Ci_4alkyl group wherein Ci_4alkyl is as defined herein. Examples of such groups include methoxyethyl, ethoxyethyl, propoxymethyl, butoxypropyl, and the like.
The term 'haloCi_4alkyloxy' as used herein as a group or part of a group refers to a -O- Ci_4alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen. The term 'haloCi_4alkyloxy' therefore include monohaloCi_ 4alkyloxy and also polyhaloCi_4alkyloxy. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi_4alkyloxy may have one, two, three or more halogens. Examples of such groups include -fluoroethyloxy, 2- fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like.
The term ' haloC i _4al ky lox yC i _4al k y I ' as used herein as a group or part of a group means C'i .4alkyl substituted with one haloCi_4alkyloxy. The term
"haloC i _4alkyloxyC i 4alky Γ therefore refers to a haloCY4alkyloxy-Ci_4alkyl- group wherein "haloCi_4alkyloxy" and "Ci_4alkyl" are as defined above. Examples of such groups include 1 -fluoroethyloxymethyl, 2-fluoroethyloxymethyl, 2-(2,2,2- tri fi uoroetho y )-eth y 1 and the like.
The term "C2_4alkenyl" as used herein as a group or part of a group refers to a linear or branched hydrocarbon group containing from 2 to 4 carbon atoms and containing a carbon carbon double bond such as, but not limited to, ethenyl, propenyl, butenyl, and the like.
The term "C2-4alkynyl" as used herein as a group or part of a group refers to a linear or branched hydrocarbon group having from 2 to 4 carbon atoms and containing a carbon carbon triple bond.
Examples of 4 to 7 membered saturated monocyclic heterocyclic rings containing up to 2 heteroatoms selected from N, O or S02 (e.g. in the definition of Rio), include, but are not limited to, morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and the like.
4 to 7 membered monocyclic heterocyclic rings containing up to 3 heteroatoms selected from N, O or S02 (e.g. in the definition of Rn), include both aromatic and non- aromatic ring systems. This includes unsaturated, partially saturated and saturated heterocyclic ring systems. Examples include, but are not limited to, pyridinyl, pyrimidinyl, morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and the like.
The term "Ci_4alkanediyl" as a group or part of a group defines bivalent straight or branched chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene or methanediyl, ethan-l,2-diyl, ethan-l,l-diyl or ethylidene, propan-l,3-diyl, propan-l,2-diyl, butan-l,4-diyl, and the like.
The term "C2-5alkanediyl" as a group or part of a group defines bivalent straight or branched chained saturated hydrocarbon radicals having from 2 to 5 carbon atoms such as, for example, ethan-l,2-diyl, ethan-l,l-diyl or ethylidene, propan-l,3-diyl, propan- 1,2-diyl, butan-l,4-diyl, pentan-l,5-diyl, pentan-l,l-diyl, 2-methylbutan-l,4-diyl, and the like.
The term "C2-4alkenediyl" as a group or part of a group defines straight or branched chain bivalent hydrocarbon radicals having from 2 to 4 carbon atoms and having a double bond such as 1 2-ethenedi l 1 3- ro enedi -butenediyl, and the like.
Figure imgf000013_0001
is an alternative representation for The bonds via which e.g. ring b is attached to the remainder of the molecule are indicated as:
Figure imgf000014_0001
Whenever ring b is substituted with one or two R3 substituents, those R3 substituents may replace any hydrogen atom bound to a carbon or nitrogen atom in ring b, including atoms of the bridge, including NH and CH groups in the definition of Xd2, and including CH groups in the definition of Xdi. When two R3 substituents are present, these may be present on the same or different atoms. For instance when Xd2 represents NH, then the R3 substituent may be present on said nitrogen atom whenever possible. In said case, Xd2 represents NR3. Or for instance, when Xdi or Xd2 represent a carbon atom, then the R3 substituent may be present on said carbon atom. In said case, Xdi may represent CR3 and Xd2 may represent CHR3 or C(R3)2. Or for instance, when p2 is other than 0, the R3 substituent may be present on any of the carbon atom represented by
(CH2)p2.
Unless otherwise is indicated or is clear from the context, ring b can be attached to variable 'a' via replacement of a hydrogen atom on any carbon or nitrogen atom in ring b, including carbon and nitrogen atoms in the definition of Xd2.
In a particular embodiment, in the 'b substituent', the linker with the 'a substituent' is present on Xd2 or is present on a carbon atom in the alpha position of Xd2.
In a particular embodiment, in the 'b substituent', the linker with the 'a substituent' is present on Xd2.
In the present invention, the b ring is linked to the remainder of the molecule as follows
Figure imgf000014_0002
In the present invention, the a linker (-a-) is linked to the remainder of the molecule depicted below: -X1-NR4-C(=0)-[C(R5b)2]r-b-; -X1-NR4-C(R5b)2-C(=0)-b-; -X C(=0)- NR4-C(R5b)2- b-.
In the present invention, Xi being -(CHRi2)s-NRi-Xe-Ci_4alkanediyl-(S02)P3- or -(CH2)s-0-Xe-Ci_4alkanediyl-(S02)p3- is attached to the remainder of the molecule as follows:
α β
-(CHR12)s-NR1 -Xe-C1.4alkanediyl-(S02)p3- (Χι') , or
α β
-(CH2)s-0-Xe-C1_4alkanediyl-(S02)p3- (Χ ) is attached with the carbon atom, the nitrogen atom (when s is 0 in Formula (Xi')) or the oxygen atom (when s is 0 in Formula (Xi ' ')) in position a to the ring containing Xa, Xb and Xc, and is attached with the group in position β ((S02)P3 or Ci_4alkanediyl (when p3 is 0)) to variable a. In both Xi Formulas Ci_4alkanediyl is optionally substituted according to the scope.
For example when -Xi- represents-(CHRi2)s-NRi-Xe-Ci_4alkanediyl-(S02)P3-, a compound of Formula (Γ) is formed:
Figure imgf000015_0001
The term "subject" as used herein, refers to an animal, preferably a mammal (e.g. cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, observation or experiment.
The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.
The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
The term "treatment", as used herein, is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.
The term "compounds of the invention" as used herein, is meant to include the compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof.
As used herein, any chemical Formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers.
Whenever one of the ring systems, is substituted with one or more substituents, those substituents may replace any hydrogen atom bound to a carbon or nitrogen atom of the ring system.
Hereinbefore and hereinafter, the term "compound of Formula (I)" is meant to include the stereoisomers thereof and the tautomeric forms thereof.
The terms "stereoisomers", "stereoisomeric forms" or "stereochemically isomeric forms" hereinbefore or hereinafter are used interchangeably.
The invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.
Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a racematc or racemic mixture.
Atropisomers (or atropoisomers) are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. For the compounds of the present invention this may be caused by the linker ( X(-a-b-c-) of the macrocycle. All atropisomeric forms of the compounds of Formula (I ) are intended to be included within the scope of the present invention.
Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Therefore, the invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.
The meaning of all those terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.
The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers. Thus, when a compound of Formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of Formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound of Formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
Some of the compounds of Formula (I) may also exist in their tautomeric form. Such forms in so far as they may exist, are intended to be included within the scope of the present invention.
It follows that a single compound may exist in both stereoisomeric and tautomeric form.
For therapeutic use, salts of the compounds of Formula (I) and solvates thereof, are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention. The pharmaceutically acceptable addition salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of Formula (I) and solvates thereof, are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
The compounds of Formula (I) and solvates thereof containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers,
dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.
The term solvate comprises the hydrates and solvent addition forms which the compounds of Formula (I) are able to form, as well as pharmaceutically acceptable addition salts thereof. Examples of such forms are e.g. hydrates, alcoholates and the like.
The compounds of the invention as prepared in the processes described below may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures. A manner of separating the enantiomeric forms of the compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, involves liquid chromatography using a chiral stationary phase. Said pure
stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
In the framework of this application, an element, in particular when mentioned in relation to a compound of Formula (I), comprises all isotopes and isotopic mixtures of this element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. Radiolabeled compounds of Formula
2 3 11 18 122
(I) may comprise a radioactive isotope selected from the group of H, H, C, F, I, 123I, 125I, I, 75Br, 76Br, 77Br and 82Br. Preferably, the radioactive isotope is selected
2 3 11 18
from the group of H, H, C and F. More preferably, the radioactive isotope
In particular, deuterated compounds are intended to be included within the scope of the present invention
As used in the specification and the appended claims, the singular forms "a", "an" and "the" also include plural referents unless the context clearly dictates otherwise. For example, "a compound" means 1 compound or more than 1 compound.
In an embodiment, the present invention concerns novel compounds of Formula (I), tautomers and stereoisomeric forms thereof, wherein
Xa, Xb and Xc each independently represent CH or N;
-Xi- represents -(CHRi2)s-NRi-Xe-Ci_4alkanediyl-(S02)p3- or -(CH2)s-0-Xe-Ci_ 4alkanediyl-(S02)P3-; wherein each of said Ci_4alkanediyl moieties are optionally substituted with hydroxyl or hydroxyCi_4alkyl;
-Xe- represents -C(R2)2- or -C(=0)-;
a represents -NR4-C(=0)-[C(R5b)2]r- or -NR4-C(R5b)2-C(=0)-;
b represents
Figure imgf000019_0001
Xdi represents CH or N;
Xd2 represents CH2 or NH;
provided that at least one of Xdi and Xd2 represents nitrogen;
c represents a bond, -[C(R5a)2]m-, -C(=0)-, -S02-, or -SO-; A ring represents phenyl or pyridyl;
Ri represents hydrogen, Ci_4alkyl, C2-4alkenyl, C2_4alkynyl, cyanoCi_4alkyl, -C(=0)-C1- 4alkyl, -C(=0)-haloCi_4alkyl, hydroxyCi_4alkyl, haloCi_4alkyl, Ci_4alkyloxyCi_4alkyl, haloCi_4alkyloxyCi_4alkyl, -C(=0)NR7R8, -S02-NR7R8, -S02-R9, Rn, Ci_4alkyl substituted with Ri i , -C(=0)-Ri i , or -C(=0)-C i_4alkyl-Ri i ;
R2 is hydrogen;
or Ri and one R2 are taken together to form Ci_4alkanediyl or C2_4alkenediyl, each of said Ci_4alkanediyl and C2_4alkenediyl optionally being substituted with 1 to 4 hydroxyl substituents;
or Ri and Ri2 are taken together to form Ci_4alkanediyl or C2_4alkenediyl, each of said Ci_4alkanediyl and C2_4alkenediyl optionally being substituted with 1 to 4 hydroxyl substituents;
each R3 independently represents hydrogen; oxo; hydroxyl; carboxyl; -NR3aR3b; - C(=0)-NR3aR3b; hydroxyCi_4alkyl; haloCi_4alkyl; -(C=0)-Ci_4alkyl; -C(=0)-0-Ci_ 4alkyl wherein said Ci_4alkyl may optionally be substituted with phenyl; Ci_4alkyl optionally substituted with cyano, carboxyl, Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, -O- C(=0)-Ci_4alkyl, -NR3eR3f, -C(=0)-NR3eR3f, or -S02-NR3eR3f; hydroxyCi_4alkyloxyCi_ 4alkyl; Ci_4alkyloxyhydroxyCi_4alkyl; hydroxyCi_4alkyloxyhydroxyCi_4alkyl; or Ci_4alkyloxyCi_4alkyl optionally substituted with cyano, carboxyl, Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, -0-C(=0)-Ci_4alkyl, -NR3eR3f, -C(=0)-NR3eR3f, -S02-NR3eR3f, Rio, -C(=0)-Rio, or -SO2-R10;
each R3a and R3b independently represent hydrogen; -(C=0)-Ci_4alkyl; or Ci_4alkyl optionally substituted with Ci_4alkyloxy;
each R3e and R3f independently represent hydrogen, Ci_4alkyl optionally substituted with Ci_4alkyloxy, or -(C=0)-Ci_4alkyl;
R4 represents hydrogen, Ci_4alkyl or Ci_4alkyloxyCi_4alkyl;
each R5a independently represents hydrogen or Ci_4alkyl;
each R5b independently represents hydrogen; Ci_4alkyl; Ci_4alkyloxyCi_4alkyl;
hydroxyCi_4alkyl; hydroxyl; C3_6cycloalkyl; or phenyl optionally substituted with Ci_ 4alkyl, halo, hydroxyl or Ci_4alkyloxy;
each Re independently represents hydrogen, halo, hydroxyl, carboxyl, cyano, Ci_4alkyl,
Ci_4alkyloxyCi_4alkyl, hydroxyCi_4alkyl, haloCi_4alkyl, C2_4alkenyl, C2_4alkynyl, -
Figure imgf000020_0001
each R6a and R6b independently represent hydrogen or Ci_4alkyl; each R7 and Rg independently represent hydrogen, Ci_4alkyl, haloCi_4alkyl, or C3_ 6cycloalkyl; or
R7 and Rg are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 further heteroatom selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
Rg represents Ci_4alkyl, haloCi_4alkyl, or C3_6cycloalkyl;
each Rio independently represents a 4 to 7 membered saturated monocyclic
heterocyclic ring containing up to 2 heteroatoms selected from N or O, said
heterocyclic ring being optionally substituted with 1 to 4 substituents each
independently selected from Ci_4alkyl, halo, hydroxyl or haloCi_4alkyl;
each Rii independently represents C3_6cycloalkyl, phenyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 to 4 substituents each
independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
each Ri2 independently represents hydrogen or Ci_4alkyl; in particular Ri2 represents hydrogen;
n represents an integer of value 1 or 2;
m represents an integer of value 1 or 2 ;
pi represents an integer of value 1 or 2;
each p2 independently represents an integer of value 0, 1 or 2;
r represents an integer of value 0, 1 or 2;
each p3 independently represents an integer of value 0 or 1 ;
each s independently represents an integer of value 0, 1 or 2;
and the pharmaceutically acceptable addition salts, and the solvates thereof.
In an embodiment, the present invention concerns novel compounds of Formula (I), tautomers and stereoisomeric forms thereof, wherein
Xa, Xb and Xc each independently represent CH or N;
-Xi- represents -(CHRi2)s-NRi-Xe-Ci_4alkanediyl-(S02)p3- or -(CH2)s-0-Xe-Ci_ 4alkanediyl-(S02)p3-; wherein each of said Ci_4alkanediyl moieties are optionally substituted with hydroxyl or hydroxyCi_4alkyl;
-Xe- represents -C(R2)2- or -C(=0)-;
a represents -NR4-C(=0)-[C(R5b)2]r- or -NR4-C(R5b)2-C(=0)-;
b represents
Figure imgf000022_0001
Xdi represents CH or N; Xd2 represents NH;
c represents a bond, -[C(R5a)2]m-, -C(=0)-, -S02
ring
Figure imgf000022_0002
phenyl or pyridyl;
Ri represents hydrogen, Ci_4alkyl, C2_4alkenyl, C2_4alkynyl, cyanoCi_4alkyl, -C(=0)-Ci_ 4alkyl, -C(=0)-haloCi_4alkyl, hydroxyCi_4alkyl, haloCi_4alkyl, Ci_4alkyloxyCi_4alkyl, haloCi_4alkyloxyCi_4alkyl, -C(=0)NR7R8, -S02-NR7R8, -S02-R9, Rn, Ci_4alkyl substituted with Rn, -C(=0)-Rn, or -C(=0)-Ci_4alkyl-Rn;
R2 is hydrogen;
or Ri and one R2 are taken together to form Ci_4alkanediyl or C2_4alkenediyl, each of said Ci_4alkanediyl and C2_4alkenediyl optionally being substituted with 1 to 4 hydroxyl substituents;
each R3 independently represents hydrogen; oxo; hydroxyl; carboxyl; -NR3aR3b; -
C(=0)-NR3aR3b; hydroxyCi_4alkyl; haloCi_4alkyl; -(C=0)-Ci_4alkyl; -C(=0)-0-Ci_ 4alkyl wherein said Ci_4alkyl may optionally be substituted with phenyl; Ci_4alkyl optionally substituted with cyano, carboxyl, Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, -O-
C(=0)-Ci_4alkyl, -NR3eR3f, -C(=0)-NR3eR3f, or -S02-NR3eR3f;
hydroxyC i_4alkyloxyC i_4alkyl; C i_4alkyloxyhydroxyCi_4alkyl;
hydroxyCi_4alkyloxyhydroxyCi_4alkyl; or
Ci_4alkyloxyCi_4alkyl optionally substituted with cyano, carboxyl, Ci_4alkyloxy,
-C(=0)-0-Ci_4alkyl, -0-C(=0)-Ci_4alkyl, -NR3eR3f, -C(=0)-NR3eR3f, -S02-NR3eR3f,
Rio, -C(=0)-Rio, or -SO2-Ri0;
each R3a and R3b independently represent hydrogen;
each R3e and R3f independently represent hydrogen, Ci_4alkyl optionally substituted with Ci_4alkyloxy, or -(C=0)-Ci_4alkyl;
R4 represents hydrogen, Ci_4alkyl or Ci_4alkyloxyCi_4alkyl;
each R5a independently represents hydrogen; each R5b independently represents hydrogen; Ci_4alkyl; Ci_4alkyloxyCi_4alkyl;
hydroxyCi_4alkyl; hydroxyl; C3_6cycloalkyl; or phenyl optionally substituted with Ci_ 4alkyl, halo, hydroxyl or Ci_4alkyloxy;
each Re independently represents hydrogen, halo, hydroxyl, carboxyl, cyano, Ci_4alkyl, Ci_4alkyloxyCi_4alkyl, hydroxyCi_4alkyl, haloCi_4alkyl, C2-4alkenyl, C2_4alkynyl, - NRea sb, or
Figure imgf000023_0001
each R6a and R6b independently represent hydrogen or Ci_4alkyl;
each R7 and Rg independently represent hydrogen; or
R7 and Rg are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 further heteroatom selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
R represents Ci_4alkyl or haloCi_4alkyl;
each Rio independently represents a 4 to 7 membered saturated monocyclic
heterocyclic ring containing up to 2 heteroatoms selected from N or O, said
heterocyclic ring being optionally substituted with 1 to 4 substituents each
independently selected from Ci_4alkyl, halo, hydroxyl or haloCi_4alkyl;
each R11 independently represents C3_6cycloalkyl, phenyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 to 4 substituents each
independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
each Ri2 independently represents hydrogen;
n represents an integer of value 1 or 2;
m represents an integer of value 1 or 2 ;
pi represents an integer of value 1 or 2;
each p2 independently represents an integer of value 0, 1 or 2;
r represents an integer of value 1 ;
each p3 independently represents an integer of value 0 or 1 ;
each s independently represents an integer of value 0, 1 or 2;
and the pharmaceutically acceptable addition salts, and the solvates thereof.
In an embodiment, the present invention concerns novel compounds of Formula (I), tautomers and stereoisomeric forms thereof, wherein
Xa is CH or N;
Xb and Xc represent CH; -Xi- represents -(CHRi2)s-NRi-Xe-Ci_4alkanediyl-(S02)p3- or -(CH2)s-0-Xe-Ci_ 4alkanediyl-(S02)P3-; wherein each of said Ci_4alkanediyl moieties are optionally substituted with hydroxyl;
-Xe- represents -C(R2)2- or -C(=0)-;
a represents -NR4-C(=0)-[C(R5b)2]r- or -NR4-C(R5b)2-C(=0)-;
b represents
Figure imgf000024_0001
Xdi represents CH or N;
Xd2 represents CH2 or NH;
provided that at least one of Xdi and Xd2 represents nitrogen;
or -S02-;
Figure imgf000024_0002
Ri represents hydrogen, Ci_4alkyl, C2_4alkenyl, C2_4alkynyl, cyanoCi_4alkyl, -C(=0)- haloCi_4alkyl, Ci_4alkyloxyCi_4alkyl, haloCi_4alkyloxyCi_4alkyl, -S02-NR7R8, -S02-R9, C i_4alkyl substituted with Ri i , or -C(=0)-Ri i ;
each R2 independently represents hydrogen;
or Ri and one R2 are taken together to form Ci_4alkanediyl optionally being substituted with 1 hydroxyl substituent;
each R3 independently represents hydrogen; oxo; hydroxyl;
Figure imgf000024_0003
hydroxyCi_4alkyl; haloCi_4alkyl; -C(=0)-0-Ci_4alkyl wherein said Ci_4alkyl may optionally be substituted with phenyl; Ci_4alkyl optionally substituted with -0-C(=0)-
Ci_4alkyl; hydroxyCi_4alkyloxyCi_4alkyl; or Ci_4alkyloxyCi_4alkyl optionally substituted with cyano, Ci_4alkyloxy, -NR3eR3f, or Rio;
R3a and R3b represent hydrogen;
R3e and R3f represent C i_4alkyl;
R4 represents hydrogen, Ci_4alkyl or Ci_4alkyloxyCi_4alkyl;
R5a represents hydrogen;
each R5b independently represents hydrogen; Ci_4alkyl; Ci_4alkyloxyCi_4alkyl;
hydroxyCi_4alkyl; or phenyl; each Re independently represents hydrogen, halo, hydroxyl, carboxyl, cyano, Ci_4alkyl,
Figure imgf000025_0001
each R<5a and R6b independently represent hydrogen or Ci_4alkyl;
R7 and Rg represent hydrogen;
Rg represents Ci_4alkyl;
each Rio independently represents a 4 to 7 membered saturated monocyclic
heterocyclic ring containing up to 2 heteroatoms selected from N or O, said
heterocyclic ring being optionally substituted with 1 Ci_4alkyl substituent;
each Rii independently represents C3_6cycloalkyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 oxygen atoms;
each Ri2 independently represents hydrogen;
n represents an integer of value 1 ;
m represents an integer of value 1 or 2 ;
pi represents an integer of value 1 ;
each p2 independently represents an integer of value 1 or 2;
r represents an integer of value 0 or 1 ;
each p3 independently represents an integer of value 0;
each s independently represents an integer of value 0 or 1 ;
and the pharmaceutically acceptable addition salts, and the solvates thereof.
Another embodiment of the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein one or more of the following restrictions apply:
(i) Xa is CH or N; Xb and Xc represent CH;
(ii) -Xi- represents -(CHRi2)s-NRi-Xe-Ci_4alkanediyl-(S02)p3- or -(CH2)s-0- Xe-Ci_4alkanediyl-(S02)P3-; wherein each of said Ci_4alkanediyl moieties are optionally substituted with hydroxyl;
NR4-C(=0)-[C(R5b)2]r- or -NR4-C(R5b)2-C(=0)-;
Figure imgf000025_0002
(v) c represents a bond, -[C(R5a)2]m-, -C(=0)-, or -S02-; (vi) Ri represents hydrogen, Ci_4alkyl, C2-4alkenyl, C2_4alkynyl, cyanoCi_4alkyl, -C(=0)-haloCi_4alkyl, Ci_4alkyloxyCi_4alkyl, haloCi_4alkyloxyCi_4alkyl, - S02-NR7R8, -S02-R9, Ci_4alkyl substituted with Rn, or -C(=0)-Rn;
each R2 independently represents hydrogen; or
Ri and one R2 are taken together to form Ci_4alkanediyl optionally being substituted with 1 hydroxyl substituent;
(vii) each R3 independently represents hydrogen; oxo; hydroxyl; -C(=0)- NR3aR3b; hydroxyCi_4alkyl; haloCi_4alkyl; -C(=0)-0-Ci_4alkyl wherein said Ci_4alkyl may optionally be substituted with phenyl; Ci_4alkyl optionally substituted with -0-C(=0)-Ci_4alkyl; hydroxyCi_4alkyloxyCi_4alkyl; or
Ci_4alkyloxyCi_4alkyl optionally substituted with cyano, Ci_4alkyloxy, -NR3eR3f, or Rio;
(viii) R3a and R3b represent hydrogen;
(ix) R3e and R3f represent Ci.4alkyl;
(x) R4 represents hydrogen, Ci_4alkyl or Ci_4alkyloxyCi_4alkyl;
(xi) R5a represents hydrogen;
(xii) each R5b independently represents hydrogen; Ci_4alkyl; Ci_4alkyloxyCi_
4alkyl; hydroxyCi_4alkyl; or phenyl;
(xiii) each R<5 independently represents hydrogen, halo, hydroxyl, carboxyl, cyano, d_4alkyl, or -C(=0)NR6aR6b;
(xiv) each R6a and Rf,i, independently represent hydrogen or Ci_4alkyl;
(xv) R7 and R8 represent hydrogen;
(xvi) R«> represents Ci_4alkyl;
(xvii) each Rio independently represents a 4 to 7 membered saturated monocyclic heterocyclic ring containing up to 2 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 Ci_4alkyl substituent;
(xviii) each Rn independently represents C3_6cycloalkyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 oxygen atoms;
(xix) each Ri2 independently represents hydrogen;
(xx) n represents an integer of value 1;
(xxi) pi represents an integer of value 1;
(xxii) each p2 independently represents an integer of value 1 or 2;
(xxiii) r represents an integer of value 0 or 1 ;
(xxiv) each p3 independently represents an integer of value 0;
(xxv) each s independently represents an integer of value 0 or 1. Another embodiment of the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein one or more of the following restrictions apply:
(i) Xa, Xb and Xc represent CH;
(ii) -Xi- represents -(CHRi2)s-NRi-Xe-Ci_4alkanediyl-;
(iii) -Xe- represents -C(R2)2-;
(iv) a represents -NR4-C(=0)-[C(R5b)2]r- or -NR4-C(R5b)2-C(=0)-; in particular a represents -NR4-C(=0)-[C(R5b)2]r-;
(v) b represents
Figure imgf000027_0001
, provided that the linker with the 'a substituent' is present on
Xd2 or is present on a carbon atom in the alpha position of Xd2;
(vi) c represents CH2 or a bond; in particular c represents CH2; in particular c represents a bond;
(vii) r is 1.
In an embodiment, the present invention concerns novel compounds of Formula (I), tautomers and stereoisomeric forms thereof, wherein
Xa is CH or N;
Xb and Xc represent CH;
-Xi- represents -(CHRi2)s-NRi-Xe-Ci_4alkanediyl- or -(CH2)s-0-Xe-Ci_4alkanediyl-; wherein each of said Ci_4alkanediyl moieties are optionally substituted with hydroxyl; -Xe- represents -C(R2)2- or -C(=0)-;
a represents -NR4-C(=0)-[C(R5b)2]r- or -NR4-C(R5b)2-C(=0)-;
b represents
Figure imgf000027_0002
Xdi represents CH or N;
Xd2 represents CH2 or NH; provided that at least one of Xdi and Xd2 represents nitrogen;
c represents a bond, -[C(R5a)2]m-, -C(=0)-, or -S02-;
ring
Figure imgf000028_0001
phenyl or pyridyl;
Ri represents hydrogen, Ci_4alkyl, C2_4alkenyl, l-propyn-3-yl, 2-cyanoethyl, -C(=0)- CF3, methyloxyethyl, trifluoromethyloxyCi_4alkyl, -S02-NR7Rg, -S02-R9, Ci_4alkyl substituted with Rn, or -C(=0)-Rn;
each R2 independently represents hydrogen;
or Ri and one R2 are taken together to form Ci_4alkanediyl optionally being substituted with 1 hydroxyl substituent;
each R3 independently represents hydrogen; oxo; hydroxyl;
Figure imgf000028_0002
hydroxyCi_4alkyl; CF3; -C(=0)-0-methyl wherein said methyl may optionally be substituted with phenyl; methyl optionally substituted with -0-C(=0)-methyl;
hydroxyethyloxymethyl; Ci_4alkyloxymethyl optionally substituted with cyano, methyloxy, -NR3eR3f, or R10;
R3a and R3b represent hydrogen;
R3e and R3f represent methyl;
R4 represents hydrogen, methyl, isopropyl or methoxyethyl;
R5a represents hydrogen;
each R5b independently represents hydrogen; methyl; methyloxymethyl;
hydroxymethyl; or phenyl;
each Re independently represents hydrogen, chloro, fluoro, hydroxyl, carboxyl, cyano, methyl, or -C(=0)NR6aR6b;
each R6a and R6b independently represent hydrogen or methyl;
R7 and Rg represent hydrogen;
R represents methyl;
each Rio independently represents a 6 membered saturated monocyclic heterocyclic ring containing 2 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 methyl substituent;
each Rn independently represents C3_6cyclopropyl, or a 5 to 6 membered monocyclic heterocyclic ring containing 1 oxygen atom;
each Ri2 independently represents hydrogen;
n represents an integer of value 1 ;
m represents an integer of value 1 or 2 ;
pi represents an integer of value 1; each p2 independently represents an integer of value 1 or 2;
r represents an integer of value 0 or 1 ;
each p3 independently represents an integer of value 0;
each s independently represents an integer of value 0 or 1 ;
and the pharmaceutically acceptable addition salts, and the solvates thereof.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein b represents
Figure imgf000029_0001
, in particular wherein b represents
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein b represents
Figure imgf000029_0002
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
r is 1;
-Xi- represents -(CHRi2)-NRi-Xe-Ci_4alkanediyl- wherein Ci_4alkanediyl is optionally substituted with hydroxyl or hydroxyCi_4alkyl; or -Xi- represents -NRi-Xe-C2_ 4alkanediyl- wherein C2-4alkanediyl is optionally substituted with hydroxyl or hydroxyC i_4alkyl;
m is 1;
R6 is other than Ci_4alkyl;
R3 is other than hydroxyC i_4alkyloxyCi_4alkyl; and b represents
Figure imgf000030_0001
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
r is 1;
-Xi- represents -(CHRi2)-NRi-Xe-Ci_4alkanediyl- wherein Ci_4alkanediyl is optionally substituted with hydroxyl or hydroxyCi_4alkyl; or -Xi- represents -NRi-Xe-C2_ 4alkanediyl- wherein C2-4alkanediyl is optionally substituted with hydroxyl or hydroxyC i_4alkyl;
m is 1;
R6 is other than Ci_4alkyl;
R3 is other than hydroxyC i_4alkyloxyCi_4alkyl; and
b represents
Figure imgf000030_0002
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
r is 1;
-Xi- represents -(CHRi2)-NRi-Xe-Ci_4alkanediyl- wherein Ci_4alkanediyl is optionally substituted with hydroxyl or hydroxyCi_4alkyl; or -Xi- represents
-NRi-Xe-C2_4alkanediyl- wherein C2_4alkanediyl is optionally substituted with hydroxyl or hydroxyC i_4alkyl;
c is CH2;
R6 is other than Ci_4alkyl;
R3 is other than hydroxyC i_4alkyloxyCi_4alkyl; and b represents
Figure imgf000031_0001
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein b represents
Figure imgf000031_0002
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein r is l , and b represents
Figure imgf000031_0003
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ring b does not contain extra bonds to form a bridged ring system.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein r is 1 and Xd2 is NH.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Xa, X|, and Xc represent CH; r is 1 ; and Xd2 is NH.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein r is 1 , Xji is
N, and Xd2 is NH.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Xji is N, and Xd2 is NH; and c represents a bond, -[C(R5a)2]m-, -C(=0)-, -S02-, or -SO-.
In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein XJI is CH, and Xd2 is NH; and c represents 0-.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein when XJ I is N, then c represents a bond, -[C(R5a)2]m-, -C(=0)-, -S02-, or -SO-; in particular when XJ I is N, then c represents a bond, -[C(R5a)2]m-, or -C(=0)-; more in particular when Xdi is N, then c represents -[C(R5a)2]m-; even more in particular when Xdl is N, then c represents -CH2-.
In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein when b
represents
Figure imgf000032_0001
, then c is other than -O- or - R5a-
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein when b
represents
Figure imgf000033_0001
, then c is other than -O- or -N .¾-.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein c represents a bond or -[C(R5a)2]m- when Xdl represents CH or N; or c may also represent -O- or -NR5a'- when Xdl represents CH.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein c represents a bond, -[C(R5a)2]m-, -C(=0)-, -S02-, or -SO- when Xdl represents CH or N; or c may also represent -O- or -NR5a'- when Xdi represents CH.
In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein r is 1 or 2; in particular wherein r is 1 .
In an embodiment, the present invention relates to those com ounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Xd l represents CH and Xd2 represents NH.
In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein s is 1.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein p3 is 0.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein s is 0. In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein s is 0 or 1 .
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein s is 0 and p3 is O.
In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein s is 1 , p3 is 0 and R i 2 is H.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein m is 1 .
In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein p2 is 1 .
In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Xa is CH.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Xa, X(, and Xc represent CH.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ring A is phenyl.
In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ring A is pyridyl.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ri represents Ci_4alkyl, C2_4alkenyl, C2_4alkynyl, -C(=0)-Ci_4alkyl, -C(=0)-haloCi_4alkyl, hydroxyC i_4alkyl, haloCi_4alkyl, Ci_4alkyloxyCi_4alkyl, haloCi_4alkyloxyCi_4alkyl, -C(=0)NR7R8, -SO2-R9, R11, Ci_4alkyl substituted with Rn, -C(=0)-Rn, or
-C(=0)-Ci_4alkyl-Rn.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ri represents Ci_4alkyl, C2_4alkenyl, C2-4alkynyl, or Ci_4alkyloxyCi_4alkyl; in particular Ri represents Ci_4alkyl, C2_4alkenyl, or Ci_4alkyloxyCi_4alkyl.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ri represents Ci_4alkyl, C2_4alkenyl, C2_4alkynyl, -C(=0)-Ci_4alkyl, -C(=0)-haloCi_4alkyl, hydroxyC i_4alkyl, haloCi_4alkyl, Ci_4alkyloxyCi_4alkyl, haloCi_4alkyloxyCi_4alkyl, -C(=0)NR7R8, -SO2-R9, R11, Ci_4alkyl substituted with Rn, -C(=0)-Rn, or
-C(=0)-Ci_4alkyl-Rn; or Ri is taken together with one R2 or Ri2.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, w herein Ri represents Ci_4alkyl, C2_4alkenyl, C2_4alkynyl, -C(=0)-Ci_4alkyl, -C(=0)-haloCi_4alkyl, hydroxyC i_4alkyl, haloCi_4alkyl, Ci_4alkyloxyCi_4alkyl, haloCi_4alkyloxyCi_4alkyl, -C(=0)NR7R8, -SO2-R9, R11, Ci_4alkyl substituted with Rn, -C(=0)-Rn, or
-C(=0)-Ci_4alkyl-Rn; or Ri is taken together with one R2.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein when Ri and R2 are taken together, they form C3_4alkanediyl or C3_4alkenediyl, each of said
C3_4alkanediyl and C3_4alkenediyl optionally being substituted with 1 to 4 substituents each independently selected from hydroxyl, oxo, halo, cyano, N3, hydroxyC i_4alkyl, -NR7R8, -S02-NR7R8, -NH-S02-NR7R8, -C(=0)-NR7R8, or -NH-C(=0)-NR7R8.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein when Ri and R12 are taken together, they form C3_4alkanediyl or C3_4alkenediyl, each of said C3_4alkanediyl and C3_4alkenediyl optionally being substituted with 1 to 4 substituents each independently selected from hydroxyl, oxo, halo, cyano, N3, hydroxyC i_4alkyl, -NR7R8, -S02-NR7R8, -NH-S02-NR7R8, -C(=0)-NR7R8, or -NH-C(=0)-NR7R8.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
Ri represents hydrogen, Ci_4alkyl, C2_4alkenyl, C2_4alkynyl, cyanoCi_4alkyl,
-C(=0)-Ci_4alkyl, -C(=0)-haloCi_4alkyl, hydroxyC i_4alkyl, haloCi_4alkyl,
Ci_4alkyloxyCi_4alkyl, haloCi_4alkyloxyCi_4alkyl, -C(=0)NR7R8, -S02-NR7R8, -S02-R9, Rii, Ci_4alkyl substituted with Rn, -C(=0)-Rn, or -C(=0)-Ci_4alkyl-Rn;
R2 is hydrogen;
or Ri and one R2 are taken together to form C3_4alkanediyl or C3_4alkenediyl, each of said C3_4alkanediyl and C3_4alkenediyl optionally being substituted with 1 to 4 hydroxyl substituents.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ri is other than hydrogen.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R2 represents hydrogen.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R2 represents hydrogen; or R and R2 are taken together.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ri and one R2 are taken together to form Ci_4alkanediyl optionally being substituted with 1 hydroxyl substituent; and wherein the other R2 variables are hydrogen.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein each Rw independently represents a 6 membered saturated monocyclic heterocyclic ring containing up to 2 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 Ci_4alkyl substituent.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein each Rm independently represents morpholinyl or piperazinyl optionally substituted with 1 Ci_4alkyl substituent.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein each Rm independently represents 4-morpholinyl, 1 -piperazinyl or 4-methyl-l -piperazinyl.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein each Rn independently represents C3_6cycloalkyl, or a 4 to 7 membered monocyclic heterocyclic ring containing one oxygen atom.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein each Rn independently represents C3_6cycloalkyl, or a 4 to 7 membered monocyclic heterocyclic ring containing one oxygen atom.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein each Rn independently represents C3_6cycloalkyl, tetrahydropyranyl or tetrahydrofuranyl.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein c represents a bond, -C(=0)-, -0-, -NR5a-, -S02-, or -SO-; in particular a bond, -C(=0)-, or -S02-. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein c represents a bond, -[C(R5a)2]m-, -C(=0)-, or -S02-. In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein CHR 2 is CH2.
In an embodiment, the present invention relates to those com ounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 12 is H
In an embodiment, the present inv ention relates to those com ounds of Formula (I) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein c represents CH2.
In an embodiment, the present inv ention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, w herein c represents -[C(R5a)2]m-.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein a represents -NR4-C(R5b)2-C(=0)-.
In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein a represents -NR4-C(=0)-[C(R5b)2]r-.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein a represents
Figure imgf000038_0001
In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein a represents -C(=0)-NR4-C(R5b)2-.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein in the "b substituent', the linker with the 'a substituent' is present on Xd2 or is present on a carbon atom in the alpha position of Xd2.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein in the "b substituent', the linker with the 'a substituent' is present on Xd2.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein in the "b substituent', the linker with the 'a substituent' is present on Xd2; and wherein pi is 1.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -X\- represents -(CHRi2)-NRi-Xe-Ci_4alkanediyl- wherein Ci_4alkanediyl is optionally substituted with hydro xyl or hydro xyCi_4alkyl; or -Xi- represents
-NRi-Xe-C2_4alkanediyl- wherein C2_4alkanediyl is optionally substituted with hydroxyl or hydroxyCi_4alkyl.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -X\- represents -(CHRi2)-NRi-Xe-Ci_4alkanediyl-; or -Xi- represents
-NRi-Xe-C2-4alkanediyl-.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 is I I.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R() is H.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
-Xi- represents -CH2-NRi-CH2-Ci_4alkanediyl-, -NRi- CH2-C2_4alkanediyl-, or -Xi- represents one of the following groups wherein -(CH2)2- is attached to 'variable a':
Figure imgf000040_0001
Ri represents Ci_4alkyl, C2-4alkenyl, or Ci_4alkyloxyCi_4alkyl;
a represents -NR4-C(=0)-CH2-;
b represents
Figure imgf000040_0002
each R3 independently represents hydrogen; Ci_4alkyloxyCi_4alkyl optionally substituted with cyano; or hydroxyCi_4alkyloxyCi_4alkyl; in particular R3 is hydrogen; c is CH2.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
Xa, Xb and Xc are CH;
-Xi- represents -CH2-NRi-CH2-Ci_4alkanediyl-, -NRi-CH2-C2_4alkanediyl-, or -Xi- represents one of the following groups wherein -(CH2)2- is attached to 'variable a':
Figure imgf000040_0003
Ri represents Ci_4alkyl, C2_4alkenyl, C2_4alkynyl, Ci_4alkyloxyCi_4alkyl; in particular Ri represents Ci_4alkyl, C2_4alkenyl, or Ci_4alkyloxyCi_4alkyl;
a represents
b represents
Figure imgf000040_0004
pi is 1; R3 represents hydrogen; Ci_4alkyloxyCi_4alkyl optionally substituted with cyano; or hydroxyCi_4alkyloxyCi_4alkyl; in particular R3 is hydrogen;
c is CH2; and
R6 represents H.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
-Xi- represents -CH2-NRi-CH2-Ci_4alkanediyl-, -NRi-CH2-C2_4alkanediyl-, or -Xi- represents one of the following groups wherein -(CH2)2- is attached to 'variable a':
Figure imgf000041_0001
Ri represents Ci_4alkyl, C2-4alkenyl, C2-4alkynyl, Ci_4alkyloxyCi_4alkyl; in particular Ri represents Ci_4alkyl, C2-4alkenyl, or Ci_4alkyloxyCi_4alkyl;
a represents -NR4-C(=0)-[C(R5b)2]r- or -NR4-C(R5b)2-C(=0)-; in particular a represents
Figure imgf000041_0002
more in particular a represents -NR4-C(=0)-CH2-.
Another embodiment of the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein one or more of the following restrictions apply:
(i) Xa, Xb and Xc are CH;
(ii) -Xi- represents -CH2-NRi-CH2-Ci_4alkanediyl-, -NRi-CH2-C2-4alkanediyl-, or -Xi- represents one of the following groups wherein -(CH2)2- is attached to 'variable a' :
Figure imgf000041_0003
(iii) Ri represents Ci_4alkyl, C2-4alkenyl, C2-4alkynyl, Ci_4alkyloxyCi_4alkyl; in particular Ri represents Ci_4alkyl, C2-4alkenyl, or Ci_4alkyloxyCi_4alkyl; (iv) a represents -NR4-C(=0)-CH2-;
(v) b represents
Figure imgf000042_0001
(vi) pi is 1
(vii) R3 represents hydrogen; Ci_4alkyloxyCi_4alkyl optionally substituted with cyano; or hydroxyCi_4alkyloxyCi_4alkyl; in particular R3 is hydrogen;
(viii) R6 represents H;
(ix) r represents 1 ;
(x) c is CH2.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -X \- represents -CH2-NRi-CH2-Ci_4alkanediyl- or -NRi-CH2-Ci_4alkanediyl-.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -X \- represents one of the following groups wherein -(CH2)2- is attached to 'variable a' :
Figure imgf000042_0002
a represents -NR4-C(=0)-[C(R5b)2]r- or -NR4-C(R5b)2-C(=0)-; in particular a represents
Figure imgf000042_0003
more in particular a represents -NR4-C(=0)-CH2-.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -Xi- represents one of the following groups wherein Ci_4alkanediyl is attached to 'variable a' :
Figure imgf000043_0001
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein if R i is taken together with R2, then
-Xi- represents one of the following groups wherein Ci_4alkanediyl is attached to 'variable a' :
Figure imgf000043_0002
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein if R i is taken together with one R2, the bond towards the second R2 substituent is oriented as shown hereunder:
Figure imgf000044_0001
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
Xa, Xb and Xc are CH;
ring A represents phenyl;
R6 is hydrogen;
n is 1;
c represents -[C(R5a)2]m-;
m is 1;
R5a is hydrog
b represents
Figure imgf000044_0002
a represents -NR4-C(=0)-[C(R5b)2]r;
R4 represents hydrogen;
r represents 1;
R5b represents hydrogen;
-Xi- represents -CH2-NRi-(CH2)2-;
Figure imgf000044_0003
Ri represents Ci_4alkyl, C2_4alkenyl, Ci_4alkyloxyCi_4alkyl, or Ci_4alkyl substituted with Rii;
Rii is C3_6cycloalkyl; or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 or 2 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl; in particular Rn is cyclopropyl or tetrahydrofuranyl.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
a represents -NR4-C(=0)-[C(R5b)2]r; -Xi- represents -CH2-NRi-(CH2)2-;
Figure imgf000045_0001
It will be clear for the skilled person that in the above embodiments wherein
-Xi- represents e.g. -CH2-NRi-(CH2)2-;
Figure imgf000045_0002
the -(CH2)2- group is attached to 'variable a' .
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
Figure imgf000045_0003
the linker with the 'a substituent' is present on Xd2 or is present on a carbon atom in the alpha position of Xd2;
-Xi- represents -NH-Xe-C2_4alkanediyl- in which case a represents -NR4-C(=0)-CH2- or -NR4-CH2-C(=0)-; or
-Xi- represents -N(CH3)-Xe-C2_4alkanediyl- in which case a represents -NR4-CH2- C(=0)-; or
-Xi- represents one of the following groups wherein -(CH2)2- is attached to 'variable a' :
Figure imgf000045_0004
in which case a represents -NR4-C(=0)-CH2;
c is CH2; and
each Re independently represents hydrogen, halo, or -C(=0)NH2.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
Xdi and Xd2 are N; the linker with the 'a substituent' is present on Xd2 or is present on a carbon atom in the alpha position of Xd2;
-Xi- represents -NH-Xe-C2-4alkanediyl- in which case a represents -NR4-C(=0)-CH2- or -NR4-CH2-C(=0)-; or
-Xi- represents -N(CH3)-Xe-C2_4alkanediyl- in which case a represents -NR4-CH2- C(=0)-; or
-Xi- represents one of the following groups wherein -(CH2)2- is attached to 'variable a' :
Figure imgf000046_0001
in which case a represents -NR4-C(=0)-CH2;
R3 is hydrogen;
c is CH2; and
each ¾ independently represents hydrogen, halo, or -C(=0)NH2.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein if Ri is taken together with one R2, the bond towards the second R2 substituent is oriented as shown hereunder:
Figure imgf000046_0002
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R is always taken together with one R2.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ri is always taken together with one R2, and the bond towards the second R2 substitucnt is oriented as shown hereunder:
Figure imgf000047_0001
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein each R3 independently represents hydrogen; oxo; hydroxyl; carboxyl; -NR3aR3b; -C(=0)- NR3aR3b; hydroxyCi_4alkyl; haloCi_4alkyl; -(C=0)-Ci_4alkyl; -C(=0)-0-Ci_4alkyl wherein said Ci_4alkyl may optionally be substituted with phenyl; Ci_4alkyl optionally substituted with cyano, carboxyl, Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, -0-C(=0)-Ci_
4alkyl, -NR3eR3f, -C(=0)-NR3eR3f, or -S02-NR3eR3f; hydroxyCi_4alkyloxyCi_4alkyl; Ci_ 4alkyloxyhydroxyCi_4alkyl; hydroxyCi_4alkyloxyhydroxyCi_4alkyl; or
Ci_4alkyloxyCi_4alkyl optionally substituted with cyano, carboxyl, Ci_4alkyloxy,
-C(=0)-0-C1_4alkyl, -0-C(=0)-C1_4alkyl, -NR3eR3f, -C(=0)-NR3eR3f, -S02-NR3eR3f, R10, -C(=O)-R10, or -SO2-R10.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutical ly acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
a represents -NR4-C(=0)-[C(R5b)2]r-; and
c represents a bond, -[C(R5a)2]m-, -O- or -NR5a'-.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
a represents -NR4-C(=0)-[C(R5b)2]r-; r is 1 ; and
c represents a bond, -[C(R5a)2]m-, -O- or -NR5a'-.
In an embodiment, the present invention relates to those com ounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
a represents -NR4-C(=0)-[C(R5b)2]r-; r is 1 ; and c represents -[C(R5a)2]m-.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
a represents -NR4-C(=0)-[C(R5b)2]r-; r is 1 ; and c represents -CH2-.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein two R5b substituents attached to the same carbon atom are taken together to form
C2-5alkanediyl or -(CH2)p-0-(CH2)p-, in particular C2-5alkanediyl.
In an embodiment, the present invention relates to those com ounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
a represents
Figure imgf000048_0001
and wherein two R5b substituents attached to the same carbon atom are taken together to form C2_5alkanediyl or -(CH2)p-0-(CH2)p-, in particular C2_5alkanediyl.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
a represents -NR4-C(=0)-[C(R5b)2]r-; r is 1 ; and wherein the two R5b substituents attached to the same carbon atom are taken together to form C2_5alkanediyl or
-(CH2)p-0-(CH2)p-, in particular C2_5alkanediyl.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
a represents -NR4-C(=0)-[C(R5b)2]r-; r is 1 ; wherein the two R5b substituents attached to the same carbon atom are taken together to form C2_5alkanediyl or
-(CH2)p-0-(CH2)p-, in particular C2_5alkanediyl; and c represents -CH2-.
In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
-Xi- represents -NRi-Xe-Ci_4alkanediyl- wherein said Ci_4alkanediyl moiety is optionally substituted with hydroxyl or hydroxyC i_4alkyl;
-Xe- represents -C(R2)2-; and
Ri is taken together with R2 to form Ci_4alkanediyl or C2-4alkenediyl, each of said Ci_4alkanediyl and C2-4alkenediyl optionally being substituted with 1 to 4 substituents each independently selected from hydroxyl, oxo, halo, cyano, N3, hydroxyC 1-4alkyl, - NR7R8, -S02-NR7R8, -NH-S02-NR7R8, -C(=0)-NR7R8, or -NH-C(=0)-NR7R8. In an embodiment, the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
-Xi- represents -NRi-Xe-Ci_4alkanediyl- wherein said Ci_4alkanediyl moiety is optionally substituted with hydroxyl or hydroxyC i_4alkyl;
-Xe- represents -C(R2)2-; and
Ri is taken together with R2 to form Ci_4alkanediyl substituted with 1 hydroxyl substituent.
In an embodiment, the present invention relates to those com ounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -X\-
Figure imgf000049_0001
wherein -(CH2)2- is attached to 'variable a'.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein -X\- represents one of the following groups wherein -(CH2)2- is attached to 'variable a':
Figure imgf000049_0002
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
a represents
Figure imgf000049_0003
r is 1; wherein the two R5b substituents attached to the same carbon atom are taken together to form C2_5alkanediyl;
c represents -CH2-;
-Xi- represents -NRi-Xe-Ci_4alkanediyl- wherein said Ci_4alkanediyl moiety is optionally substituted with hydroxyl or hydroxyC i_4alkyl;
-Xe- represents -C(R2)2-; and
Ri is taken together with R2 to form Ci_4alkanediyl substituted with 1 hydroxyl substituent. In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
a represents -NR4-C(=0)-[C(R5b)2]r-; r is 1; wherein the two R5b substituents attached to the same carbon atom are taken together to form C2-5alkanediyl;
c represents -CH2-;
-Xi- represents -NRi-Xe-Ci_4alkanediyl- wherein said Ci_4alkanediyl moiety is optionally substituted with hydroxyl or hydroxyC i_4alkyl;
-Xe- represents -C(R2)2-; and
Ri is taken together with R2 to form Ci_4alkanediyl or C2_4alkenediyl, each of said
Ci_4alkanediyl and C2-4alkenediyl optionally being substituted with 1 to 4 substituents each independently selected from hydroxyl, oxo, halo, cyano, N3, hydroxyC i_4alkyl, - NR7R8, -S02-NR7R8, -NH-S02-NR7R8, -C(=0)-NR7R8, or -NH-C(=0)-NR7R8.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
a represents
Figure imgf000050_0001
r is 1; wherein the two R5b substituents attached to the same carbon atom are taken together to form C2_5alkanediyl;
Figure imgf000050_0002
wherein -(CH2)2- is attached to 'variable a'.
In an embodiment, the present invention relates to those compounds of Formula (I ) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
a represents -NR4-C(=0)-[C(R5b)2]r-; r is 1; wherein the two R5b substituents attached to the same carbon atom are taken together to form C2-5alkanediyl;
c represents -CH2-; and
-Xi- represents one of the following groups wherein -(CH2)2- is attached to 'variable
Figure imgf000050_0003
In an embodiment, the present invention relates to a subgroup of Formula ( I ) as defined in the general reaction schemes.
In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 43, 96, 37, 88, 45, 62, 38, 91, 42, 1, 102 and 105,
tautomers and stereoisomeric forms thereof,
and the pharmaceutically acceptable addition salts, and the solvates thereof.
In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 70, 56, 71, 59, 48, 61, 89, 15, 112, 134, 3, 5, 83, 25, 86, 137 and 54, tautomers and stereoisomeric forms thereof,
and the pharmaceutically acceptable addition salts, and the solvates thereof.
In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 88, 91, 45, 35, 37, 42, 38, 40 and 43,
tautomers and stereoisomeric forms thereof,
and the pharmaceutically acceptable addition salts, and the solvates thereof.
In an embodiment the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds,
tautomers and stereoisomeric forms thereof,
and the free bases, the pharmaceutically acceptable addition salts, and the solvates thereof.
All possible combinations of the above-indicated embodiments are considered to be embraced within the scope of this invention.
Methods for the Preparation of Compounds of Formula (I)
In this section, as in all other sections unless the context indicates otherwise, references to Formula (I) also include all other sub-groups and examples thereof as defined herein.
The general preparation of some typical examples of the compounds of Formula (I) is described hereunder and in the specific examples, and are generally prepared from starting materials which are either commercially available or prepared by standard synthetic processes commonly used by those skilled in the art. The following schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.
Alternatively, compounds of the present invention may also be prepared by analogous reaction protocols as described in the general schemes below, combined with standard synthetic processes commonly used by those skilled in the art of organic chemistry. Additionally, compounds of the present invention may also be prepared by analogous reaction protocols as described in the general schemes below combined with methods described in WO2009112439. Starting materials may also be prepared by methods as described in the literature for example by the procedures described in WO 2011008788, WO 2004105765, WO 2005058318, WO 2005058913, WO2006061415, WO2006061417, WO2009016132, WO2008155421 and WO 2007003525; or Burger et al, Medicinal Chemistry Letters (2011), 2(1), 34-38.
The skilled person will realize that in the reactions described in the Schemes, it may be necessary to protect reactive functional groups, for example hydroxy, amino (for example NHR4 in an intermediate of Formula (V-a) wherein Ri and R4 are different), or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in
accordance with standard practice. This is illustrated in the specific examples. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The skilled person will realize that in the reactions described in the Schemes, it may be advisable or necessary to perform the reaction under an inert atmosphere, such as for example under N2-gas atmosphere, for example when NaH is used in the reaction. It will be apparent for the skilled person that it may be necessary to cool the reaction mixture before reaction work-up (refers to the series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, extraction).
The skilled person will realize that heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions microwave heating may be used instead of conventional heating to shorten the overall reaction time.
The skilled person will realize that another sequence of the chemical reactions shown in the Schemes below, may also result in the desired compound of Formula (I).
The skilled person will realize that intermediates and final compounds shown in the schemes below may be further functionalized according to methods well-known by the person skilled in the art. Examples are shown in the specific experimental part.
The skilled person will realize that more Compounds of Formula (I) can be prepared by using similar synthetic protocols as described in the Schemes below. For example, in
Scheme 1, an intermediate of Formula (III) can be replaced by an intermediate of Formula (LXVI). Or an intermediate of Formula (V-a) can typically be replaced by an intermediate of Formula -NHRi-Xe-Ci_4alkanediyl-(S02)P3-NHR4-. In case one of the starting materials is available as a salt form, the skilled person will realize that it may be necessary to first treat the salt with a base, such as for example DIPEA.
Although not shown in the general schemes, the rings in the position of ring b, may also contain extra bonds to form a bridged ring according to the scope.
In the schemes below, the Ci_4alkanediyl moiety in the intermediates and the final compounds, such as for example the Ci_4alkanediyl moiety in Formula (V-a), (VI), (VII) and (I-a) of scheme 1 , is optionally substituted as defined in the scope.
All variables are defined as mentioned hereabove unless otherwise is indicated or is clear from the context.
In general, compounds of Formula (I-a) can be prepared according to Scheme 1 :
Scheme 1
Figure imgf000054_0001
In scheme 1, 'halo' is defined as Br, CI or F; 'PG' is defined as a protecting group such as for example fert-butoxycarbonyl, methoxycarbonyl or ethoxycarbonyl; 'ci' is defined as a bond, -[C(R5a)2]m-, -C(=0)-, -S02-, or -SO-; and 'ra' is defined as 1 or 2. All other variables in Scheme 1 are defined according to the scope of the present invention.
In Scheme 1, the following reaction conditions apply: 1: The reduction of the nitro group in an intermediate of Formula (II) was performed a) under hydrogenation conditions: H2-gas atmosphere in the presence of a catalyst such as for example Raney Ni, Pd/C (for example 5 wt % or 10 wt %) or Pt/C (for example 5 wt %) in a suitable solvent such as for example methanol (MeOH), ethanol (EtOH) or tetrahydrofuran (THF); or
b) in the presence of Fe and NH4C1 in a suitable mixture of solvents such as for example THF/H20/MeOH;
2: in the presence of phenyl formate, and a suitable solvent such as for example dichloromethane (DCM);
3: in the presence of a base such as for example NaH, and a suitable solvent such as for example N,N-dimethyl formamide (DMF);
4: optionally in the presence of a suitable base, such as for example Na2C03, optionally in the presence of a suitable solvent such as for example N,N-dimethylacetamide (DMA) or 1 -methyl-2-pyrrolidinone (NMP) or mixture of solvents such as for example DMA/DMSO ("DMSO" means dimethyl sulfoxide);
5: in the presence of an acid such as for example trifluoroacetic acid (TFA) in a solvent such as for example DCM; or
alternatively in the presence of an acid such as for example HCl in a solvent such as for example 1 ,4-dioxane optionally in the presence of water; or
alternatively first in the presence of a base such as for example NaOH, and
subsequently in the presence of an acid such as for example HCl, in the presence of a suitable solvent such as for example THF;
6: in the presence of a coupling agent such as for example diethyl cyanophosphonate, ( 1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), l-[bis(dimethylamino)methylene]-l H-benzotriazol- 1-ium 3-oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH- [l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et3N) or N,N- diisopropylethylamine (DIPEA), in a suitable solvent such as for example DMF.
The compounds of Formula (I) may also be converted into each other via art-known reactions or functional group transformations.
For instance, a compound of Formula (I), in particular a compound of Formula (I-a), wherein R6 represents aminocarbonyl can be converted to a compound wherein R6 represents carboxyl, by reaction with a suitable acid such as for example HCl. During this reaction, ring-opening of the macrocycle may occur. In this case, it is necessary to react the outcome of the reaction with a coupling agent such as for example diethyl cyanophosphonate, in the presence of a base such as for example triethylamine in a suitable solvent such as for example DMF, to close the macrocylic ring.
Intermediates of Formula (II) and (Il-a) can be prepared according to Scheme 1
Scheme la
Figure imgf000056_0001
In scheme la, 'halo' is defined as Br, CI or F; 'PC is defined as a protecting group such as for example tert-butoxycarbonyl, methoxycarbonyl or ethoxycarbonyl; 'ci' is defined as a bond, -[C(R5a)2]m-, -C(=0)-, -S02-, or -SO-; 'ra' is defined as 1 or 2; and all other variables are defined according to the scope of the present invention.
In Scheme la, the following reaction conditions apply:
1 : in the presence of a base such as for example NaH, Et3N or DIPEA, in a suitable solvent such as for example DMF; 2: in the presence of a base such as for example K2CO3, Et3N or DIPEA, in a suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA);
3: in the presence of a suitable reducing agent such as sodium triacetoxyborohydride, in suitable solvent or mixtures of solvents such as acetic acid or DCM.
An intermediate of Formula (IX) is commercially available or can be prepared by standard means obvious to those skilled in the art. Examples are shown in the specific experimental part.
In general, compounds of Formula (I-b) can be prepared according to Scheme 2:
Scheme 2
halo
Figure imgf000058_0001
In scheme 2, Y is defined as O (in case the intermediate of Formula (X-a) was used in step 1) or Y is defined as NRi (in case the intermediate of Formula (X-b) was used in step 1); 'PG' and 'halo' are as defined before in the general reaction schemes; 'ra' is defined as 1 or 2; and all other variables are defined according to the scope of the present invention.
In Scheme 2, the following reaction conditions apply:
la (Y is defined as O): in a suitable solvent such as for example 2-methyl-2-propanol or NMP, in the presence of a base such as for example potassium tert-butoxide;
lb (Y is defined as NRi): optionally in the presence of a suitable base, such as for example Na2C03, optionally in the presence of a suitable solvent such as for example N,N-dimethylacetamide (DMA) or l-methyl-2-pyrrolidinone (NMP) or mixture of solvents such as for example DMA/DMSO ("DMSO" means dimethyl sulfoxide); 2: in the presence of an oxidizing agent such as for example Mn02, in the presence of a suitable solvent such as for example DCM;
3: in the presence of a reducing agent such as for example sodium
triacetoxyborohydride (NaBH(OAc)3), and in the presence of a suitable solvent such as for example 1 ,2-dichloroethane (DCE);
4: in the presence of an acid such as for example trifluoroacetic acid (TFA) in a solvent such as for example DCM; or
alternatively in the presence of an acid such as for example HCl in a solvent such as for example 1 ,4-dioxane optionally in the presence of water; or
alternatively first in the presence of a base such as for example NaOH, and
subsequently in the presence of an acid such as for example HCl, in the presence of a suitable solvent such as for example THF;
5: in the presence of a coupling agent such as for example diethyl cyanophosphonate, ( 1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), 1 - [bis(dimethy lamino)methylene] - 1 H-benzotriazol- 1 -ium 3 -oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH-
[l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et3N) or diisopropylethylamine (DIPEA), in a suitable solvent such as for example DMF.
In case 'ra' is 0 in an intermediate of Formula (XIII), hereby named an intermediate of Formula (XIII-a), a compound of Formula (I-bl) can be obtained as shown in Scheme 2a:
Figure imgf000060_0001
In scheme 2a the following conditions apply:
1 : in the presence of an acid such as for example trifluoroacetic acid (TFA) in a solvent such as for example DCM; or
alternatively in the presence of an acid such as for example HCl in a solvent such as for example 1 ,4-dioxane optionally in the presence of water; or
alternatively first in the presence of a base such as for example NaOH, and
subsequently in the presence of an acid such as for example HCl, in the presence of a suitable solvent such as for example THF;
2 : in the presence of a carbonyl source such as for example 4-nitrophenyl
chloroformate in the presence of a base such as for example triethylamine (Et3N) or diisopropylethylamme (DIPEA), in a suitable solvent such as for example DMF or 1 ,4- dioxane. In general, compounds of Formula (I-c) can be prepared according to Scheme 3a:
Scheme 3a
Figure imgf000061_0001
In scheme 3a, 'Ms' means mesyl (methanesulfonyl); 'rb' represents an integer of value 1 or 2 in case [C(R5b)2]rb is attached to the ring via Xd2 and Xd2 represents N, or 'rb' represents an integer of value 0, 1 or 2 in case [C(R5b)2]rb is attached to ring via a carbon atom; all other variables are defined according to the scope of the present invention. In Scheme 3, the following reaction conditions apply:
1 : in the presence of methanesulfonyl chloride, in the presence of a base such as for example DIPEA, in the presence of a suitable solvent such as for example DCM;
2: coupling reaction between an intermediate of Formula (XXI) and an intermediate of Formula (XLI), in the presence of a suitable base such as for example K2CO3, in the presence of a suitable solvent such as for example DMF;
3: in the presence of an acid such as for example trifluoroacetic acid (TFA) in a solvent such as for example DCM; or
alternatively in the presence of an acid such as for example HCl in a solvent such as for example 1,4-dioxane optionally in the presence of water; or
alternatively first in the presence of a base such as for example NaOH, and
subsequently in the presence of an acid such as for example HCl, in the presence of a suitable solvent such as for example THF;
4: in the presence of a coupling agent such as for example diethyl cyanophosphonate, (1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), 1 - [bis(dimethy lamino)methylene] - 1 H-benzotriazol- 1 -ium 3 -oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH- [l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et3N) or diisopropylethylamine (DIPEA), in a suitable solvent such as for example DMF.
An intermediate of Formula (XLI) is commercially available or can be prepared by standard means obvious to those skilled in the art. Examples are shown in the specific experimental part. The skilled person will also realize that obvious deviations from Scheme 3a are possible, such as illustrated in Example A15.
In general, an intermediate of Formula (XX-a), a subgroup of (XX), may be prepared according to Scheme 3b:
Scheme 3b
halo
Figure imgf000063_0001
In scheme 3b, 'halo' and 'PC are as defined before in the general reaction schemes; and all other variables are defined according to the scope of the present invention. In Scheme 3b, the following reaction conditions apply:
1 : in the presence of phenyl formate, and a suitable solvent such as for example dichloromethane (DCM);
2: coupling reaction between an intermediate of Formula (XVI) and an intermediate of Formula (IV-a) (see Scheme 1), in the presence of a base such as for example NaH, and a suitable solvent such as for example N,N-dimethyl formamide (DMF);
3: in the presence of a reducing agent such as for example NaBH4, in the presence of a suitable solvent such as for example THF or a mixture of solvents such as for example MeOH/THF; or LiAlH4 in the presence of a suitable solvent such as for example THF; 4: coupling reaction between an intermediate of Formula (XVIII) and an intermediate of Formula (V-a) (see Scheme 1), optionally in the presence of a suitable base, such as for example Na2C03, optionally in the presence of a suitable solvent such as for example N,N-dimethylacetamide (DMA) or l-methyl-2-pyrrolidinone (NMP) or mixture of solvents such as for example DMA/DMSO ("DMSO" means dimethyl sulfoxide); 5: introduction of a protecting group, by using for example di-tert-butyl dicarbonate, the presence of a suitable mixture of solvents such as for example DCM/MeOH.
In general, an intermediate of Formula (XX) may be prepared according to Scheme 3
Scheme 3c
halo
Figure imgf000064_0001
In scheme 3c, 'PC is as defined before; and all other variables are defined according to the scope of the present invention.
In Scheme 3c, the following reaction conditions apply:
1 : coupling reaction between an intermediate of Formula (IV-a) and an intermediate of Formula (XLIV-a), in a suitable solvent such as for example n-butanol;
2: in a suitable solvent such as for example 2-methyl-2-propanol or NMP, optionally in the presence of a base such as for example K2CO3;
3: coupling reaction between an intermediate of Formula (IV-a) and an intermediate of Formula (XLV-a), in a suitable solvent such as for example n-butanol; or
coupling reaction between an intermediate of Formula (IV-a) and an intermediate of Formula (XLV-b) in the presence of a base such as for example NaH, and a suitable solvent such as for exam le N,N-dimethyl formamide (DMF);
Figure imgf000065_0001
4: in the presence of a deprotecting agent such as for example tetrabutyl ammonium fluoride (TBAF) in THF; or alternatively in the presence of an acid such as for example HCl in H20; or alternatively in the presence of CH3COOH optionally in the presence of water;
5: in a suitable solvent such as for example 2-methyl-2-propanol or NMP, optionally in the presence of a base such as for example K2CO3;
6: in the presence of a deprotecting agent such as for example TBAF in THF; or alternatively in the presence of an acid such as for example HCl in H20; or
alternatively in the presence of CH3COOH optionally in the presence of water.
The skilled person will realize that an intemediate of Formula (X-b) in Scheme 3c can be replaced by an intermediate of Formula -NHRi-Xe-Ci_4alkanediyl-(S02)P3-
In general, compounds of Formula (I-d) can be prepared according to Scheme 4: Scheme 4
Figure imgf000066_0001
In scheme 4, 'PC is as defined before; 'ra' is defined as 1 or 2; and all other variables are defined according to the scope of the present invention.
In Scheme 4, the following reaction conditions apply:
1: in the presence of a reducing agent such as for example sodium
triacetoxyborohydride (NaBH(OAc)3), in the presence of a suitable solvent such as for example DCM (anhydrous);
2: in the presence of di-tert-butyl dicarbonate, in the presence of a suitable solvent such as for example DCM;
3: in the presence of bis(pinacolato)diboron, in the presence of a suitable base such as for example potassium acetate, in the presence of a suitable catalyst such as for example [1,1 '-bis(diphenylphosphino-KP)ferrocene] dichloropalladium-dichloromethane (1 :1) (PdCl2(dppf)-DCM), in the presence of a suitable solvent such as for example 1,4- dioxane;
4: coupling reaction between an intermediate of Formula (XXXV) and 2,4- dichloropyrimidine, in the presence of a suitable catalyst such as for
example(PdCl2(dppf)-DCM), in the presence of a suitable base such as for example Na2C03, in the presence of a suitable solvent such as for example 1,4-dioxane;
5: coupling reaction between an intermediate of Formula (XXXVI) and an intermediate of Formula (IV), in the presence of a base such as for example NaH, in the presence of a suitable solvent such as for example N,N-dimethylacetamide (DMA);
6: in the presence of an acid such as for example trifluoroacetic acid (TFA) in a solvent such as for example DCM; or
alternatively in the presence of an acid such as for example HCl in a solvent such as for example 1 ,4-dioxane optionally in the presence of water; or
alternatively first in the presence of a base such as for example NaOH, and
subsequently in the presence of an acid such as for example HCl, in the presence of a suitable solvent such as for example THF;
7: in the presence of a coupling agent such as for example diethyl cyanophosphonate, (1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), 1 - [bis(dimethy lamino)methylene] - 1 H-benzotriazol- 1 -ium 3 -oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH- [l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et3N) or diisopropylethylamine (DIPEA), in a suitable solvent such as for example DMF. In general, compounds of Formula (I-d) can be converted to compounds of Formula (I- d-2) as shown in Scheme 5:
Scheme 5
Figure imgf000068_0001
In Scheme 5, a compound of Formula (I-d) is reacted with an intermediate of Formula Ri-Br, to result in a compound of Formula (I-d-2). This reaction typically is performed in the presence of a suitable base such as for example DIPEA, in the presence of a suitable solvent such as for example DMF.
Analogous functionalization reactions can be performed by replacing RiBr, for example, with alkylsulfonyl chlorides, acid chlorides or sulfamides. Other functional groups can also be introduced via reductive amination. All these reactions can be performed under standard reaction conditions well-known by the skilled person.
In general, a compound of Formula (I-f) can be prepared according to Scheme 6
Figure imgf000069_0001
In scheme 6, 'PC and 'halo' are as defined before in the general reaction schemes; 'ra' is defined as 1 or 2; and all other variables are defined according to the scope of the present invention.
In Scheme 6, the following reaction conditions apply:
1 : in the presence of phenylformate, in a suitable solvent such as for example DCM; 2: coupling reaction between an intermediate of Formula (XLIX) and an intermediate of Formula (IV-a), in the presence of a base such as for example NaH, and a suitable solvent such as for example N,N-dimethyl formamide (DMF); 3: in the presence of NH2Ri (e.g. NH3 in case Ri represents H), in a suitable solvent such as for example THF;
4: in the presence of a ketone such as acetone, an acid such as p-toluenesulfonic acid and in the presence of H20;
5: coupling reaction between an intermediate of Formula (Lll-a) and an intermediate of Formula (LII), in the presence of a coupling agent such as for example diethyl cyanophosphonate, ( 1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), 1 - [bis(dimethylamino)methylene] - 1 H-benzotriazol- 1 - ium 3 -oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH- [l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et3N) or N,N- diisopropylethylamine (DIPEA), in a suitable solvent such as for example THF or DMF;
6: coupling reaction between an intermediate of Formula (LIII) and an intermediate of Formula (IX), in the presence of a reducing agent such as for example sodium triacetoxyborohydride (NaBH(OAc)3), and in the presence of a suitable solvent such as for example 1 ,2-dichloroethane (DCE);
7: in the presence of an acid such as for example trifluoroacetic acid (TFA) in a solvent such as for example DCM; or
alternatively in the presence of an acid such as for example HCl in a solvent such as for example 1 ,4-dioxane optionally in the presence of water; or
alternatively first in the presence of a base such as for example NaOH, and
subsequently in the presence of an acid such as for example HCl, in the presence of a suitable solvent such as for example THF;
8: in the presence of a coupling agent such as for example diethyl cyanophosphonate, ( 1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), 1 - [bis(dimethy lamino)methylene] - 1 H-benzotriazol- 1 -ium 3 -oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH- [l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et3N) or N,N- diisopropylethylamine (DIPEA), in a suitable solvent such as for example DMF.
In general, a compound of Formula (I-g) can be prepared according to Scheme 7a: Scheme 7a
Figure imgf000071_0001
In scheme 7a, 'PC is as defined before; 'LC means leaving group such as for exampli chloro or mesylate; and all other variables are defined according to the scope of the present invention.
The skilled person will realize that protecting groups can be easily converted into each other by using well-known reactions as illustrated in the specific examples. In Scheme 7a, the following reaction conditions apply:
1 : deprotection of the hydroxyl group by addition of an appropriate hydrolyzing agent such as for example tctrabutylammonium fluoride, in the presence of a suitable solvent such as for example THF;
2: deprotection of the piperazinyl moiety in the presence of H2-gas atmosphere and a catalyst such as for example Pd/C (for example 5 wt % or 10 wt %) in a suitable solvent such as for example MeOH;
3: introduction of a leaving group (LG) using sulfonyl chlorides such as for example methanesulfonyl chloride (MsCl) or p-toluenesulfonyl chloride (TsCl) in the presence of a suitable base such as for example DIPEA, in the presence of a suitable solvent such as for example DCM;
4: deprotection of the piperazinyl moiety in the presence of an acid such as for example TFA in a solvent such as for example DCM; or alternatively in the presence of an acid such as for example HCl in a solvent such as for example 1,4-dioxane optionally in the presence of water;
5: in the presence of a deprotecting agent such as for example TBAF in THF; or alternatively in the presence of an acid such as for example HCl in H20; or
alternatively in the presence of CH3COOH optionally in the presence of water;
6: deprotection of the piperazinyl moiety in the presence of an acid such as for example TFA in a solvent such as for example DCM; or alternatively in the presence of an acid such as for example HCl in a solvent such as for example 1,4-dioxane optionally in the presence of water;
7: introduction of a leaving group (LG) using for example thionyl chloride in the presence of a suitable solvent such as for example 1 ,2-dichloroethane;
8: in the presence of a suitable base, such as for example K2C03, in the presence of a suitable solvent such as for example DMF;
In general, an intermediate of Formula (LVI) can be prepared according to Scheme 7b:
Figure imgf000073_0001
In scheme 7b, 'PC and 'halo' are as defined before in the general reaction schemes; and all other variables are defined according to the scope of the present invention.
In Scheme 7b, the following reaction conditions apply:
1 : in the presence of a base such as for example NaH, and a suitable solvent such as for example N,N-dimethyl formamide (DMF);
2: reaction with an intermediate of Formula V-al):
Figure imgf000073_0002
optionally in the presence of a suitable base, such as for example Na2C03, optionally in the presence of a suitable solvent such as for example DMA or NMP, or in a mixture of solvents such as for example DMA/DMSO ("DMSO" means dimethyl sulfoxide); 3: firstly reaction with an intermediate of Formula (LXIV-a) in the presence of a suitable base, such as for example Et3N, in the presence of a suitable solvent such example CH3CN; and subsequently addition of (LXIV-b) to the mixture:
Figure imgf000074_0001
4: reaction with an intermediate of Formula (LXV):
Figure imgf000074_0002
in the presence of a suitable base, such as for example K2CO3, in the presence of a suitable solvent such as for example DMF.
An intermediate of Formula (LXV) is commercially available or can be prepared by standard means obvious to those skilled in the art or as described in the specific experimental part.
As mentioned before, the skilled person will realize that compounds of Formula (I) may be further functionalized according to methods well-known by the person skilled in the art.
For example, compounds of Formula (I) wherein R3 represents hydroxyCi_4alkyl, may be further functionalized to compounds of Formula (I) wherein R3 represents optionally substituted Ci_4alkyloxyCi_4alkyl, according to methods well-known by the person skilled in the art. It may be necessary to protect reactive functional groups to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice. For example 2-(trimethylsilyl)ethoxymethyl can be used to protect the amino group between the pyrimidinyl ring and ring A.
For example, in case R3 represents Ci_4alkyloxyCi_4alkyl substituted with an hydroxy group, said hydroxy group may be functionalized to a leaving group (via reaction with for example methanesulfonyl chloride) after which it may be reacted with a
functionalized nitrogen atom (-NR3eR3f or Rio) to obtain other compounds of Formula (I) according to the scope. In general, a compound of Formula (I-h) can be prepared according to Scheme 8:
Figure imgf000075_0001
In Scheme 8, 'PG' and 'halo' are as defined before in the general reaction schemes; 'ra' is defined as 1 or 2; and all other variables are defined according to the scope of the present invention.
In Scheme 8, the following reaction conditions apply:
1 : An intermediate of Formula (LXVI) can be reacted with an intermediate of Formula (IV-a) in the presence of a suitable acid such as for example p-toluenesulfonic acid monohydrate in a suitable solvent such as, for example, 1,4-dioxane, or a mixture of suitable solvents such as, for example, a mixture of 1,4-dioxane and 2-propanol;
2: An intermediate of Formula (LXVII) can be reacted with an intermediate of Formula -NHRi-Xe-Ci_4alkanediyl-(S02)p3-NHR4- optionally in the presence of a suitable base, such as for example Na2C03, optionally in the presence of a suitable solvent such as for example N,N-dimethylacetamide (DMA) or l-methyl-2-pyrrolidinone (NMP) or mixture of solvents such as for example DMA/DMSO ("DMSO" means dimethyl sulfoxide);
3: in the presence of an acid such as for example trifluoroacetic acid (TFA) in a solvent such as for example DCM; or
alternatively in the presence of an acid such as for example HCl in a solvent such as for example 1 ,4-dioxane optionally in the presence of water; or
alternatively first in the presence of a base such as for example NaOH, and
subsequently in the presence of an acid such as for example HCl, in the presence of a suitable solvent such as for example THF;
4: in the presence of a coupling agent such as for example diethyl cyanophosphonate, ( 1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), 1 - [bis(dimethy lamino)methylene] - 1 H-benzotriazol- 1 -ium 3 -oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH- [l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et3N) or N,N- diisopropylethylamine (DIPEA), in a suitable solvent such as for example DMF.
An intermediate of Formula (LXVI) is commercially available or can be prepared by standard means obvious to those skilled in the art or as described in the specific experimental part.
In case the Boc group is directly attached to the nitrogen atom in an intermediate of Formula (LXVIII) (this is when r is 0 in the scope), the nitrogen atom can be deprotected, for example under acidic conditions (e.g. HCl in dioxane). Subsequently, the obtained intermediate may be reacted with RG-[C(Rsb)2]ra-Boc wherein RG is a reactive group such as, for example, bromo.
In general, a compound of Formula (I-i) can be prepared according to Scheme 9:
Scheme 9
Figure imgf000077_0001
In Scheme 9a, 'PC is as defined before; 'Boc' is tert-butoxycarbonyl; and all other variables are defined according to the scope of the present invention.
In Scheme 9a, the following reaction conditions apply:
1 : in the presence of a suitable base such as for example Et3N or DIPEA, in a suitable solvent such as for example DCM;
2: firstly in the presence of a suitable base such as for example CS2CO3 in a suitable solvent such as for example DMF; and subsequently in the presence of a deprotecting group such as for example thiophenol;
3: firstly a reaction with tert-butoxycarbonyl anhydride in the presence of a suitable catalyst such as DMAP in a suitable solvent such as for example DCM; and
subsequently in the presence of a suitable base such as for example
tetrabutylammonium fluoride (TBAF) in a suitable solvent such as for example THF;
4: firstly in the presence of methanesulfonyl chloride, in the presence of a base such as for example DIPEA, in the presence of a suitable solvent such as for example DCM or DMF; and subsequenlty a coupling reaction with an intermediate of Formula (LXIV-c);
5: in the presence of an acid such as for example trifluoroacetic acid (TFA) in a solvent such as for example DCM; or
alternatively in the presence of an acid such as for example HCl in a solvent such as for example 1 ,4-dioxane optionally in the presence of water; or
alternatively first in the presence of a base such as for example NaOH, and
subsequently in the presence of an acid such as for example HCl, in the presence of a suitable solvent such as for example THF;
6: in the presence of a coupling agent such as for example diethyl cyanophosphonate, ( 1 H-benzotriazol- 1 -yloxy)(tripyrrolidin- 1 -yl)phosphonium hexafluorophosphate (PyBOP), l-[bis(dimethylamino)methylene]-l H-benzotriazol- 1-ium 3-oxide hexafluorophosphate (HBTU) or l-[bis(dimethylamino)methylene]-lH- [l,2,3]triazolo[4,5-b]pyridin-l-ium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as for example triethylamine (Et3N) or N,N- diisopropylethylamine (DIPEA), in a suitable solvent such as for example DMF.
In scheme 9, an intermediate of Formula (LXXIII) can be replaced by an intermediate of Formula (XX) which can be reacted further according to analogues reaction protocols as described in Scheme 9 to obtain compounds of Formula (I-i2):
Figure imgf000079_0001
In general, an intermediate of Formula (LXXIX) can be prepared according to Scheme 10:
Scheme 10
Figure imgf000079_0002
An intermediate of Formula (LXXIX) subsequently can be further reacted according to similar reaction protocols as described in Scheme 1 steps 4, 5 and 6. In Scheme 10, 'PC, 'halo' and 'Ms' is as defined before in the general reaction schemes; and all other variables are defined according to the scope of the present invention.
In Scheme 10, the following reaction conditions apply:
1 : in the presence of methanesulfonyl chloride, in the presence of a base such as for example DIPEA, in the presence of a suitable solvent such as for example DCM;
2: coupling reaction between an intermediate of Formula (LXXVI) and an intermediate of Formula (LXIV-c), in the presence of a suitable base such as for example K2CO3, in the presence of a suitable solvent such as for example DMF;
3: in the presence of an acid such as for example trifluoroacetic acid (TFA) in a solvent such as for example DCM; or
alternatively in the presence of an acid such as for example HCl in a solvent such as for example 1 ,4-dioxane optionally in the presence of water; or
alternatively first in the presence of a base such as for example NaOH, and
subsequently in the presence of an acid such as for example HCl, in the presence of a suitable solvent such as for example THF;
4: reaction between an intermediate of Formula (LXXVIII) and an intermediate of Formula (LXXVIII-a) in the presence of a suitable base such as for example Et3N in a suitable solvent such as for example DCM.
Compounds of Formula (I) wherein Ri and R2, or Ri and R12, are taken together to form Ci_4alkanediyl or C2-4alkenediyl, and which are substituted with hydroxyl on said Ci_ 4alkanediyl or C2-4alkenediyl, may be converted to other compounds of Formula (I) by the following reactions:
- hydroxyl to azide ion: in a suitable solvent such as THF, in the presence of a ligand such as triphenylphosphine (PPh3), an azide source such as diphenylphosphoryl. azide (DPPA) and in the presence of an
azodicarboxylate such as for example diisopropyl azodicarboxylatc (DIAD); azide to NH2: via reduction reaction in the presence of H2-gas atmosphere and a catalyst such as for example Pt/C or Pd/C (for example 5 wt % or 10 wt %) in a suitable solvent such as for example MeOH or THF;
NH2 to NH2-S(=0)2-NH-: via reaction with sulfamide in a suitable solvent such as for example dioxane;
hydroxyl to oxo: Swern oxidation to a ketone using oxalyl chloride, dimethyl sulfoxide (D SO) and an organic base such as for example Eh ; hydroxy! to cyano: first conversion of the hydroxy! group to CH3-S(=0)2-0- via reaction with mesylchloride in a suitable solvent such as DCM in the presence of a suitable base such as for example DIPEA; second conversion of CH3-S(=0)2-0- to the cyano group by reaction with e.g. NaCN in a suitable solvent such as for example DMSO;
hydroxyl to fluoro: in a suitable solvent such as THF in the presence of a suitable base (promotor) such as for example 1,8- diazabicyclo[5.4.0]undecene-7 (DBU) in the presence of a fluorinating reagent such as (diethylamino)difluorosulfonium tetrafluoroborate (XtalFluor-E®).
In all these preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and
chromatography. In particular, stereoisomers can be isolated chromatographically using a chiral stationary phase such as, for example, Chiralpak® AD (amylose 3,5 dimethyl- phenyl carbamate) or Chiralpak® AS, both purchased from Daicel Chemical Industries, Ltd, in Japan, or by Supercritical Fluid Chromatography (SFC).
The chirally pure forms of the compounds of Formula (I) form a preferred group of compounds. It is therefore that the chirally pure forms of the intermediates and their salt forms are particularly useful in the preparation of chirally pure compounds of Formula (I). Also enantiomeric mixtures of the intermediates are useful in the preparation of compounds of Formula (I) with the corresponding configuration.
Pharmacology
It has been found that the compounds of the present invention have EF2 inhibitory activity and optionally may also have Vps34 inhibitory activity.
The compounds according to the invention and the pharmaceutical compositions comprising such compounds may be useful for treating or preventing, in particular treating, diseases such as cancer, depression, neuropiasticity (synaptic
plasticity and non-synaptic plasticity), and memory and learning disorders.
In particular, the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or the prevention, in particular in the treatment, of a haematological malignancy or solid tumour. In a specific embodiment said solid tumour is selected from the group consisting of glioblastoma, medulloblastoma, prostate cancer, breast cancer, ovarian cancer and colorectal cancer.
In particular, the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or the prevention, in particular in the treatment, of brain tumours, in particular glioblastoma and medulloblastoma.
In particular, the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or the prevention, in particular in the treatment, of prostate cancer, breast cancer, ovarian cancer and colorectal cancer. Examples of other cancers which may be treated (or inhibited) include, but are not limited to, a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g. colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, urothelial, uterus, epidermis, liver, lung (for example adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, squamous lung cancer), oesophagus, head and neck, gall bladder, ovary, pancreas (e.g. exocrine pancreatic carcinoma), stomach, gastrointestinal (also known as gastric) cancer (e.g. gastrointestinal stromal tumours), cervix, endometrium, thyroid, prostate, or skin (for example squamous cell carcinoma or dermatofibrosarcoma protuberans); pituitary cancer, a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (e.g. diffuse large B-cell lymphoma), T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumour of myeloid lineage, for example leukemias, acute and chronic myelogenous leukemias, chronic myelomonocytic leukemia (CMML), myeloproliferative disorder, myeloproliferative syndrome, myelodysplasia syndrome, or promyelocytic leukemia; multiple myeloma; thyroid follicular cancer; hepatocellular cancer, a tumour of mesenchymal origin (e.g. Ewing's sarcoma), for example fibrosarcoma or rhabdomyosarcoma; a tumour of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma (such as glioblastoma multiforme) or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma. In particular, squamous lung cancer, breast cancer, colorectal cancer, glioblastoma, astrocytomas, prostate cancer, small cell lung cancer, melanoma, head and neck cancer, thyroid cancer, uterine cancer, gastric cancer, hepatocellular cancer, cervix cancer, multiple myeloma, bladder cancer, endometrial cancer, urothelial cancer, colon cancer, rhabdomyosarcoma, pituitary gland cancer. The compounds according to the invention and the pharmaceutical compositions comprising such compounds may also be useful for treating or preventing, in particular treating, diseases such as malaria, rheumatoid arthritis, lupus and HIV.
The compounds of the invention and compositions thereof can also be used in the treatment of hematopoetic diseases of abnormal cell proliferation whether pre- malignant or stable such as myeloproliferative diseases. Myeloproliferative diseases ("MPD"s) are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplasia syndrome.
Myeloproliferative diseases include polycythemia vera, essential thrombocythemia and primary myelofibrosis. A further haemato logical disorder is hypereosinophilic syndrome. T-cell lymphoproliferative diseases include those derived from natural Killer cells.
Thus, in the pharmaceutical compositions, uses or methods of this invention for treating a disease or condition comprising abnormal cell growth, the disease or condition comprising abnormal cell growth in one embodiment is a cancer.
The compounds of the present invention also have therapeutic applications in sensitising tumour cells for radiotherapy and chemotherapy.
Hence the compounds of the present invention can be used as "radiosensitizer" and/or "chemosensitizer" or can be given in combination with another "radiosensitizer" and/or "chemosensitizer".
The term "radiosensitizer", as used herein, is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of the cells to ionizing radiation and/or to promote the treatment of diseases which are treatable with ionizing radiation.
The term "chemosensitizer", as used herein, is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and/or promote the treatment of diseases which are treatable with chemotherapeutics. Several mechanisms for the mode of action of radiosensitizers have been suggested in the literature including: hypoxic cell radiosensitizers ( e.g., 2- nitroimidazole compounds, and benzotriazine dioxide compounds) mimicking oxygen or alternatively behave like bioreductive agents under hypoxia; non-hypoxic cell radiosensitizers (e.g., halogenated pyrimidines) can be analogoues of DNA bases and preferentially incorporate into the DNA of cancer cells and thereby promote the radiation-induced breaking of DNA molecules and/or prevent the normal DNA repair mechanisms; and various other potential mechanisms of action have been hypothesized for
radiosensitizers in the treatment of disease.
Many cancer treatment protocols currently employ radiosensitizers in conjunction with radiation of x-rays. Examples of x-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5- iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives of the same.
Photodynamic therapy (PDT) of cancers employs visible light as the radiation activator of the sensitizing agent. Examples of photodynamic radiosensitizers include the following, but are not limited to: hematoporphyrin derivatives, Photo frin,
benzoporphyrin derivatives, tin etioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same.
Radiosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds which promote the incorporation of radiosensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; chemotherapeutic agents which act on the tumour with or without additional radiation; or other therapeutically effective compounds for treating cancer or other diseases. Chemosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds which promote the incorporation of chemosensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; chemotherapeutic agents which act on the tumour or other therapeutically effective compounds for treating cancer or other disease. Calcium antagonists, for example verapamil, are found useful in combination with antineoplastic agents to establish chemosensitivity in tumor cells resistant to accepted chemotherapeutic agents and to potentiate the efficacy of such compounds in drug-sensitive malignancies.
The invention relates to compounds of Formula (I ) and pharmaceutically acceptable addition salts, and solvates thereof, for use as a medicament.
The invention also relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for use in the inhibition of EF2 and optionally also for use in the inhibition of Vps34. The compounds of the present invention can be "anti-cancer agents", which term also encompasses "anti-tumor cell growth agents" and "anti-neoplastic agents".
The invention also relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for use in the treatment of diseases mentioned above.
The invention also relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the treatment or prevention, in particular for the t reatment, of said diseases.
The invention also relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the treatment or prevention, in particular in the treatment, of EF2 mediated diseases or conditions.
The invention also relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the treatment or prevention, in particular in the treatment, of EF2K. and optional ly Vps34 mediated diseases or conditions.
The invention also relates to the use of compounds of Formula ( 1 ) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament.
The invention also relates to the use of compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament for the inhibition of EF2 and optionally also for the inhibition of Vps34.
The invention also relates to the use of compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament for the treatment or prevention, in particular for the treatment, of any one of the disease conditions mentioned hereinbefore.
The invention also relates to the use of compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned hereinbefore.
The compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, can be administered to mammals, preferably humans for the treatment or prevention of any one of the diseases ment ioned hereinbefore.
The compounds of the present invention may also be used in the optimisation of industrial protein production. In view of the utility of the compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, there is provided a method of treating warmblooded animals, including humans, suffering from or a method of preventing warmblooded animals, including humans, to suffer from any one of the diseases mentioned hereinbefore.
Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of a compound of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, to warm-blooded animals, including humans.
Those of skill in the treatment of such diseases could determine the effective therapeutic daily amount from the test results presented hereinafter. An effectiv e therapeutic daily amount would be from about 0.005 mg/kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg body weight, more in particular from 0.01 mg/kg to 25 mg/kg body weight, preferably from about 0.01 mg/kg to about 1 5 mg/kg, more preferably from about 0.01 mg kg to about 10 mg/kg, even more preferably from about
0.01 mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1 mg/kg body weight. The amount of a compound according to the present inv ention, also referred to here as the activ e ingredient, which is required to achieve a therapeutically effect will of course, vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
A method of treatment may also include administering the activ e ingredient on a regimen of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably formulated prior to
administration. As described herein below, suitable pharmaceutical formulations are prepared by know n procedures using well known and readily av ailable ingredients.
The compounds of the present invention, that can be suitable to treat or prevent cancer or cancer-related conditions, may be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula ( I ), a pharmaceutically acceptable addition salt, or a solvate thereof, and one or more additional therapeutic agents, as wel l as administration of the compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, and each additional therapeutic agents in its own separate pharmaceutical dosage formulation. For example, a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solv ate thereof, and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.
While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition.
Accordingly, the present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof.
The carrier or diluent must be '"acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
For ease of administration, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. The compounds according to the invention, in particular the compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup or combination thereof may be formulated into v arious pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemical ly administering drugs.
To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound as the activ e ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ea.se in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mi ture of saline and glucose solution. Injectable solutions containing a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, may be formulated in an oil for prolonged action. Appropriate oils for this purpose are. for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations that are intended to be converted, shortly before use. to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acid or base addition salts of compounds of Formula (I) due to their increased water solubility over the corresponding base or acid form, are more suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical composit ions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quant ity of active ingredient calculated to produce the desired therapeutic effect in association with the required
pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets ), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
In order to enhance the solubility and/or the stability of the compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, in pharmaceutical compositions, it can be advantageous to employ α-, β- or γ-cyclodextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl- β-cyclodextrin or su 1 fobuty I -β-cyclodextri n . Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds according to the invent ion in pharmaceutical compositions.
Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0. 1 to 70 % by weight, even more preferably from 0. 1 to 50 % by weight of the compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, and from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
As another aspect of the present invention, a combination of a compound of the present invention with another anticancer agent is envisaged, especially for use as a medicine, more specifically for use in the treatment of cancer or related diseases.
For the treatment of the above conditions, the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents, more particularly, with other anti-cancer agents or adjuvants in cancer therapy.
Examples of anti-cancer agents or adjuvants (supporting agents in the therapy) include but are not limited to:
platinum coordination compounds for example cisplatin optionally combined with amifostine, carboplatin or oxaliplatin;
taxane compounds for example paclitaxel, paclitaxel protein bound particles (Abraxane™) or docetaxel;
topoisomerase I inhibitors such as camptothecin compounds for example irinotecan, SN-38, topotecan, topotecan hcl;
- topoisomerase II inhibitors such as anti-tumour epipodophyllotoxins or
podophyllotoxin derivatives for example etoposide, etoposide phosphate or teniposide;
anti-tumour vinca alkaloids for example vinblastine, vincristine or vinorelbine;
- anti-tumour nucleoside derivatives for example 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hcl, capecitabine, cladribine, fludarabine, nelarabine; alkylating agents such as nitrogen mustard or nitrosourea for example cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan (melphalan), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide optionally in combination with mesna, pipobroman, procarbazine, streptozocin, temozolomide, uracil;
anti-tumour anthracycline derivatives for example daunorubicin, doxorubicin optionally in combination with dexrazoxane, doxil, idarubicin, mitoxantrone, epirubicin, epirubicin hcl, valrubicin;
molecules that target the IGF-1 receptor for example picropodophilin;
- tetracarcin derivatives for example tetrocarcin A;
- glucocorticoids for example prednisone; antibodies for example trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328;
- estrogen receptor antagonists or selective estrogen receptor modulators or
inhibitors of estrogen synthesis for example tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole;
aromatase inhibitors such as exemestane, anastrozole, letrazole, testolactone and vorozole;
- differentiating agents such as retinoids, vitamin D or retinoic acid and retinoic acid metabolism blocking agents (RAMBA) for example accutane;
DNA methyl transferase inhibitors for example azacytidine or decitabine;
antifolates for example premetrexed disodium;
antibiotics for example antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, mithramycin;
antimetabolites for example clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine;
- apoptosis inducing agents and antiangiogenic agents such as Bcl-2 inhibitors for example YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 or decanoic acid;
tubuline -binding agents for example combrestatin, colchicines or nocodazole; kinase inhibitors (e.g. EGFR (epithelial growth factor receptor) inhibitors, MTKI (multi target kinase inhibitors), mTOR inhibitors) for example flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib ditosylate, sorafenib, sunitinib, sunitinib maleate, temsirolimus;
farnesyltransferase inhibitors for example tipifarnib;
histone deacetylase (HDAC) inhibitors for example sodium butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide (FR 901228), NVP- LAQ824, R306465, JNJ-26481585, trichostatin A, vorinostat;
- Inhibitors of the ubiquitin-proteasome pathway for example PS-341, MLN .41 or bortezomib;
- Yondelis;
Telomerase inhibitors for example telomestatin;
Matrix metalloproteinase inhibitors for example batimastat, marimastat, prinostat or metastat;
Recombinant interleukins for example aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon alfa 2b; - MAPK inhibitors;
Retinoids for example alitretinoin, bexarotene, tretinoin;
- Arsenic trioxide;
- Asparaginase;
- Steroids for example dromostanolone propionate, megestrol acetate, nandrolone
(decanoate, phenpropionate), dexamethasone;
Gonadotropin releasing hormone agonists or antagonists for example abarelix, goserelin acetate, histrelin acetate, leuprolide acetate;
- Thalidomide, lenalidomide;
- Mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase,
rasburicase;
BH3 mimetics for example ABT-737;
- MEK inhibitors for example PD98059, AZD6244, CI- 1040;
colony-stimulating factor analogs for example filgrastim, pegfilgrastim, sargramostim; erythropoietin or analogues thereof (e.g. darbepoetin alfa);
interleukin 11; oprelvekin; zoledronate, zoledronic acid; fentanyl;
bisphosphonate; palifermin;
a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitor (CYP17), e.g. abiraterone, abiraterone acetate;
- Glycolysis inhibitors, such as 2-deoxyglucose;
mTOR inhibitors such as rapamycins and rapalogs, and mTOR kinase inhibitors;
PI3K inhibitors and dual mTOR/PI3K inhibitors;
- autophagy inhibitors, such as chloroquinc and h yd ro x y-c h 1 o o q u i n e ;
- B-raf inhibitors, e.g. vemurafenib;
androgen receptor antagonist drugs, e.g. enzalutamide or ARN-509.
The present invention further relates to a product containing as first active ingredient a com ound according to the invention and as further active ingredient one or more anticancer agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.
The one or more other medicinal agents and the compound according to the present invention may be administered simultaneously (e.g. in separate or unitary
compositions) or sequentially in either order. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It w ill be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.
The weight ratio of the compound according to the present invention and the one or more other anticancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of
administration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administrat ion and general physical condition of the particular patient, the mode of administration as well as other medication the indiv idual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated sub ject and/or depending on the evaluation of the physician prescribing the compounds of the instant inv ention. A particular weight ratio for the present compound of Formula ( I ) and another anticancer agent may range from 1 / 10 to 10/1 , more in particular from 1 /5 to 5 1 , even more in particular from 1/3 to 3/ 1 .
The platinum coordination compound is advantageously administered in a dosage of 1
2 2 to 500mg per square meter (mg/m ) of body surface area, for example 50 to 400 mg/m , particularly for cisplatin in a dosage of about 75 mg/m and for carboplatin in about 300mg/m per course of treatment.
The taxane compound is advantageously administered in a dosage of 50 to 400 mg per
2 2
square meter (mg/m ) of body surface area, for example 75 to 250 mg/m , particularly for paclitaxel in a dosage of about 1 75 to 250 mg/m. and for docetaxel in about 75 to 1 50 mg/m per course of treatment.
The camptothecin compound is advantageously administered in a dosage of 0. 1 to
2 2 400 mg per square meter (mg/m ) of body surface area, for example 1 to 300 mg/m ,
2
part icularly for irinotecan in a dosage of about 1 00 to 350 mg/m and for topotecan in about 1 to 2 mg/m per course of treatment.
The anti-tumour podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m ) of body surface area, for example 50 to
2 2
250mg 'm , particularly for etoposide in a dosage of about 35 to 1 00 mg/m and for
2
teniposide in about 50 to 250 mg/m per course of treatment. The anti-tumour vinca alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg/m ) of body surface area, particularly for vinblastine in a
2 2 dosage of about 3 to 12 mg/m , for vincristine in a dosage of about 1 to 2 mg/m , and for vinorelbine in dosage of about 10 to 30 mg/m per course of treatment.
The anti-tumour nucleoside derivativ e is adv antageously administered in a dosage of 200 to 2500 mg per square meter (mg/m ) of body surface area, for example 700 to
2 2
1 500 mg/m , particularly for 5-FU in a dosage of 200 to 500mg/m , for gemcitabine in
2
a dosage of about 800 to 1 200 mg/m and for capecitabine in about 1000 to
2500 mg/m per course of treatment.
The alkylating agents such as nitrogen mustard or nitrosourea is advantageously administered in a dosage of 100 to 500 mg per square meter (mg/m ) of body surface area, for example 1 20 to 200 mg/m , particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m , for chlorambucil in a dosage of about 0. 1 to 0.2 mg kg, for carmustine in a dosage of about 1 50 to 200 mg/m , and for lomust ine in a dosage of about 1 00 to 1 50 mg/m per course of treatment.
The anti-tumour anthracycline deriv ative is adv antageously administered in a dosage of 10 to 75 mg per square meter (mg/m ) of body surface area, for example 1 5 to
2 2
60 mg/m , particularly for doxorubicin in a dosage of about 40 to 75 mg/m , for daunorubicin in a dosage of about 25 to 45mg/m , and for idarubicin in a dosage of about 10 to 1 5 mg/m per course of treatment.
The antiestrogen agent is advantageously administered in a dosage of about 1 to 100 mg daily depending on the particular agent and the condition being treated. Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Toremifene is adv antageously administered orally in a dosage of about 60mg once a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Anastrozole is adv antageously administered orally in a dosage of about 1 mg once a day. Droloxifene is advantageously administered orally in a dosage of about 20- l OOmg once a day. Raloxifene is advantageously administered orally in a dosage of about 60mg once a day. Excmestane is advantageously
administered orally in a dosage of about 25mg once a day.
Antibodies are adv antageously administered in a dosage of about 1 to 5 mg per square meter (mg/m ) of body surface area, or as known in the art, if different. Trastuzumab is advantageously administered in a dosage of 1 to 5 mg per square meter (mg/m ) of body surface area, particularly 2 to 4 mg/m per course of treatment.
These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 2 1 or 28 days. The following examples illustrate the present invention. In case no specific
stereochemistry is indicated for a stereocenter of a compound, this means that the compound was obtained as a mixture of the R and the S enantiomers.
When an intermediate is indicated as 'HCl salt' or 'TFA salt', this means that the number of equivalents of HCl or TFA was not determined.
Examples
Hereinafter, the term "NaH" means sodium hydride (60% in mineral oil); "DCM" means dichloromethane; "q.s." means quantum sufficit; "Int." Means intermediate; "Co." means compound; "DCE" means 1,2-dichloroethane; "DIPE" means diisopropyl ether, "Boc" means tert-butoxycarbonyl; "ACN" means acetonitrile; "BDS" means base deactivated silica"; "NMP" means l-methyl-2-pyrrolidinone; "DMA" means N,N- dimethylacetamide; "MeOH" means methanol; "LC" means liquid chromatography; "LCMS" means Liquid Chromatography/Mass spectrometry; "HATU" means 1- [bis(dimethylamino)methylene]- lH-[ 1 ,2,3]triazolo[4,5-b]pyridin- 1 -ium 3-oxide hexafluorophosphate; "HPLC" means high-performance liquid chromatography;
"BINAP" means [l, -binaphthalene]-2,2'-diylbis[diphenylphosphine] (racemic);
"TFA" means trifluoroacetic acid; "m.p." means melting point; "N2" means nitrogen; "RP" means reversed phase; "min" means minute(s); "h" means hour(s); "EtOAc" means ethyl acetate; "EtsN" means triethylamine; "PE" means petroleum ether;
"EtOH" means ethanol; "THF" means tetrahydrofuran; "Celite®" means diatomaceous earth; "DMF" means N,N-dimethyl formamide; "DMSO" means dimethyl sulfoxide; 'iPrOH" means 2-propanol; "iPrNH2" means isopropylamine; "SFC" means
Supercritical Fluid Chromatography; "DIPEA" means N,N-diisopropylethylamine; "HBTU" means l-[bis(dimethylamino)methylene]-lH-benzotriazol-l-ium 3-oxide hexafluorophosphate; "w/v" means weight/volume; "NaBH(OAc)3" means sodium triacetoxyborohydride; "PPh3" means triphenylphosphine; "Et20" means diethyl ether; "Pd/C" means palladium on carbon; "Pt/C" means platina on carbon; "Pd(OAc)2" means palladium(II) acetate; "Pd2(dba)3" means tris(dibenzylideneacetone)dipalladium; "Et" means ethyl; "Me" means methyl; "PdCl2(dppf)-DCM" means [1,1*- bis(diphenylphosphino-KP)ferrocene]dichloropalladium-dichloromethane (1 : 1); and "TLC" means thin layer chromatography.
A. Preparation of the Intermediates
Example Al
a) Preparation of Int. 1
Figure imgf000095_0001
The synthesis protocol was conducted twice on the same quantities of l-(3- nitrobenzyl)piperazine (20 g; 84.74 mmol).
NaH (60 % in mineral oil) (8.7 g; 216.94 mmol) was added portionwise to a stirred solution of l-(3-Nitrobenzyl)piperazine (40 g; 180.784 mmol) in DMF (190 mL) at room temperature. The reaction mixture was stirred for 20 minutes. Tert-butyl bromoacetate (26.5 mL; 180.784 mmol) was added dropwise at 5 °C. The reaction mixture was stirred for 20 minutes. Water and EtOAc were added and the layers were separated. The organic layer was dried (MgS04), filtered and evaporated to dryness. The solid was purified by preparative LC (Irregular SiOH 20-45 μιη 1000 g DAVISIL). Mobile phase (60 % Heptane, 3 % MeOH, 37 % EtOAc). The desired fractions were collected and the solvent was evaporated.
Total yield: 44.5 g of Int. 1 (73 %).
b) Preparation of Int. 2
Figure imgf000095_0002
The synthesis protocol was conducted twice on the same quantities of Int. 1 (9 g;
26.833 mmol).
A mixture of Int. 1 (18 g; 53.667 mmol) in MeOH (650 mL) was hydrogenated under H2-gas atmosphere at atmospheric pressure at room temperature in the presence of Raney nickel (19 g; 322.819 mmol) as a catalyst. The catalyst was filtered off on a pad of Celite® and the filtrate was evaporated. Total yield 15.3 g of Int. 2 (93 %).
c) Preparation of Int. 3
Figure imgf000095_0003
Phenyl formate (12.1 mL, 110.667 mmol) was added to a solution of Int. 2 (16.9 g; 55.334 mmol) in DCM (7 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. Subsequently, the solvent was evaporated to give 30.5 of a brown oil. This oil was purified by preparative LC (irregular SiOH 15-40 μιη 300 g MERCK). Mobile phase (40 % Heptane, 10 % MeOH, 50% EtOAc). The desired fractions were collected and the solvent was evaporated. Yield: 14.9 g of Int. 3 (81 %). d) Preparation of Int. 4
Figure imgf000096_0001
NaH (60 % dispersion in mineral oil) (1.327 g, 33.176 mmol) was added to a stirred solution of Int. 3 (3.687 g, 11.059 mmol) in DMF (200 ml) under N2 atmosphere at room temperature, and the mixture was stirred for 20 minutes at room temperature. 2- Chloro-4-(6-chloro-3-pyridinyl)-pyrimidine (WO 2009112439) (2.5 g, 11.059 mmol) was added and the reaction mixture was then stirred for 18 h at room temperature. Subsequently, 5 mL of glacial acetic acid was added and the reaction was quenched by the addition of water. The product was extracted 3 times with EtOAc. The combined organic layer was washed with water and brine, dried with MgS04, filtered and the filtrate was evaporated. Yield: 7.21 g of Int. 4 (92 %).
e) Preparation of Int. 10
Figure imgf000096_0002
1 3
A mixture of Int. 4 (2 g, 2.828 mmol) and and N ,N -dimethyl- 1, 3 -propanediamine (3.568 mL, 28.281 mmol) was stirred at 125 °C for 1 h. The reaction mixture was cooled, diluted with EtOAc, and washed with a saturated aqueous NaHC03 solution, then washed with water, dried with MgS04, filtered and the filtrate was evaporated. The residue was dissolved in DCM and purified by chromatography over a Si02 column, type Grace Reveleris SRC, 80 g, Si 40, on a Armen Spot II Ultimate purification system using DCM and MeOH as eluents in a gradient starting from 100 % DCM and ending with 5 % MeOH and 95 % DCM. The fractions containing the product were combined and the solvent was evaporated. Yield: 1.63 g of Int. 10 (99.7 %).
f) Preparation of Int. 11
Figure imgf000097_0001
HCl salt
HCl (4 M in dioxane) (5.4 mL, 21.62 mmol) was added to a stirred solution of Int. 10 (1.25 g, 2.162 mmol) in 1,4-dioxane (80 ml) at room temperature. The reaction mixture was stirred at 60 °C for 2 h. A yellow precipitate was formed. The solvent was evaporated yielding 1.8 g of Int. 11.
f-2) Preparation of Int. 59
Int. 4 was reacted with N^A^-dimethyl-l^-butanediamine according to analogous synt hesis protocols as described successively for Int. 10 (Al .e) and Int. 11 (Al .f), to obtain Int. 59, which was used for the synthesis of compound 20:
Figure imgf000097_0002
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 59:
Figure imgf000098_0001
nt. rom nt. an -sopropy- , - amnoet ane; use or o.
Example A2
a) Preparation of Int.5
Figure imgf000098_0002
A solution of 2-bromomethyl-4-nitrobenzoic acid methyl ester (110 g, 401 mmol), piperazine-1 -acetic acid tert-butyl ester (81 g, 405 mmol) and K2CO3 (q.s.) in ACN (1000 ml) was stirred for 6 h at 50 °C. The precipitate was filtered off and the solvent was removed. The residue was purified by column chromatography over silica gel (gradient eluent: PE/EtOAc from 10/1 to 1/1). The desired fractions were collected and the solvent was evaporated. Yield: 130 g of Int.5 (93 %). b) Preparation of Int. 6
Figure imgf000099_0001
A solution of Int. 5 (91 g, 231.3 mmol) and LiOH (1 mol/L in water; 693.9 mL, 693.9 mmol) in THF (700 mL) was stirred for 3 h at room temperature. The pH of the reaction was adjusted to to pH 4-5 by addition of 2 N HCl. The organic solvent was evaporated under reduced pressure. The mixture was cooled to room temperature, and filtered to give 70 g of Int. 6 (80 %).
c) Preparation of Int. 7
Figure imgf000099_0002
A solution of Int. 6 (33 g, 87 mmol), ammonium hydrochloride (6.52g, 121.8 mmol), 1- hydroxy-lH-benzotriazole hydrate (14.11 g, 104.4 mmol), 3 -ethyl- 1 -(3- dimethylaminopropyl)carbodiimide .HCl (20.01 g, 104.4 mmol) and Et3N (35.21 g, 348 mmol) in DMF (250ml) was stirred overnight at room temperature. The mixture was evaporated in vacuo, water was added to the residue and this aqueous mixture was extracted with DCM. The organic phase was washed by water, brine, dried over
Na2S04 and filtered. The solvent was evaporated and the crude product was purified by column chromatography over silica gel (eluent: EtOAc). The desired fractions were collected and the solvent was evaporated. Yield: 18.8 g of Int. 7 (57 %).
The intermediates in the tabic below were prepared according to an analogous reaction protocol as used for Int. 7: Int. 39 (starting from Int. 6 and Int. 50 (starting from Int. 6 and mcthylaminc hydrochloride) dimethylamine hydrochloride) d) Preparation of Int. 8
Figure imgf000100_0001
Pt/C (5 %)(1 g, 5.1 mmol) was added as a catalyst to a solution of Int. 7 (18.8 g , 49.7 mmol) in EtOH (350 ml) and the resulting suspension was hydrogenated under a hydrogen atmosphere for 15 h at 40 °C. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. Yield: 16.0 g of Int. 8 (92 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 8:
Figure imgf000100_0003
e) Preparation of Int. 9
Figure imgf000100_0002
Phenyl formate (5.748 mL 51.658 mmol) was added to a solution of Int. 8 (4.5 g; 12.915 mmol) in DCM (62 ml) at room temperature. The reaction mixture was stirred at room temperature for 7 days. The precipitate was filtered off and dried. Yield: 3.3 g of Int. 9 (68 %).
The Intermediates in the tabic below were prepared according to an analogous reaction protocol as used for Int. 9:
Figure imgf000101_0001
. . f) Preparation of Int. 38
Int. 9 was further reacted according to analogous synthesis protocols as described successively for Int. 4 (Al .d), Int. 10 (Al .e) and Int. 11 (Al .f), to obtain Int. 38, which was used for the synthesis of compound 10:
Figure imgf000101_0002
HC1 salt
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 38:
Figure imgf000101_0003
Figure imgf000102_0001
propane am ne; use or o.
Example A3
a- 1) Pre aration of Int. 12
Figure imgf000102_0002
Piperazine-1 -acetic acid tert-butyl ester (25.67 g, 128mmol) was added to a suspension of 3-bromomethyl-4-fluoronitrobenzene (Journal of Medicinal
Chemistry (1994), 37(9), 1362-70) (30 g, 128 mmol) and K2C03 (35.3 g, 256 mmol) in CH3CN (400 ml). The mixture was stirred at room temperature for 2 h and was then filtered.
The organic solvent was evaporated in vacuo. The residue was purified by
chromatography on silica gel (PE/EtOAc 8/1 to EtOAc). The desired fractions were collected and the solvent was evaporated. Yield: 28 g of Int. 12 (62 % yield).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 12:
Figure imgf000102_0003
Int. 20 (starting from l-(bromomethyl)-2- fluoro-3 -nitro-benzene)
a-2) Preparation of Int. 16
Figure imgf000103_0001
Acetic acid (29.8 g, 400 mmol) was added to a solution of 3-nitro-4- fluorobenzaldehyde
(49 g, 290mmol) and piperazine-1 -acetic acid tert-butyl ester (66.3 g, 331mmol) in DCM (400ml) and the mixture was stirred for 60 minutes .Then sodium
triacetoxyborohydride (77 g, 364mmol) was added and the reaction mixture was stirred overnight. Water was added to the mixture (200 ml) and the resulting biphasic mixture was extracted twice with DCM (200 ml). The organic layer was washed with saturated NaCl, dried, filtered and the solvent was evaporated. The residue was purified by chromatography on silica gel (PE/EtOAc 40/1 to 10/1). The desired fractions were collected and the solvent was evaporated. Yield: 45 g of Int. 16 (44 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 16:
Figure imgf000103_0003
a-3) Preparation of Int. 68
Figure imgf000103_0002
A solution of 3-nitrobenzenesulfonyl chloride (5 g, 22.561 mmol ) in DCM (20 ml) was added dropwise to a stirred solution of Et3N (10.035 mL, 72.195 mmol) and piperazine- 1 -acetic acid tert-butyl ester (22.561 mmol) in DCM (80 ml) at room temperature. After addition, the reaction mixture was stirred at room remperature for 18 h. The reaction was quenched by the addition of water and the aqueous mixture was extracted twice with DCM. The organic layer was washed with water, dried with MgS04, filtered and the filtrate was evaporated. Yield: 10.08 g of Int. 68.
a-4) Preparation of Int. 72
Figure imgf000104_0001
A solution of 3-nitrobenzoyl chloride (11.03 g, 59.44 mmol) in DCM (100 mL) was added dropwise to a stirred solution of piperazine-1 -acetic acid tert-butyl ester (12.297 mL, 59.44 mmol) and DIPEA (11.267 mL, 65.384 mmol ) in DCM (300 mL) at room temperature. After addition the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of water. The mixture was diluted with DCM and then shaken vigorously. The organic layer was separated, washed with water, washed with brine, dried with MgS04, filtered and the solvents of the filtrate evaporated. Yield: 21.86 g of Int. 72 (100 %).
a-5) Preparation of Int. 76
Figure imgf000104_0002
A solution of 1 -(2 -bromoethyl)-3 -nitrobenzene (8.4 g, 36.512 mmol), piperazine-1- acetic acid tert-butyl ester (8043.937 mg, 40.163 mmol) and DIPEA (6.921 mL, 40.163 mmol) in DMA (73 ml) was stirred at 70 °C for 16 h. After cooling, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by flash liquid chromatography on silica gel (eluent DCM/MeOH 98/2). The desired fractions were collected and the solvent was evaporated. Yield: 10.5 g of Int. 76 (82
%). b-1) Pre aration of Int. 13
Figure imgf000105_0001
Int. 12 (28 g, 79.2 mmol) was dissolved in a mixture of THF (40 ml), H20 (40 ml) and MeOH (80 ml). Fe (44.2 g, 792 mmol) and NH4C1 (42.3 g,792 mmol) were added. The mixture was refluxed for 2 h. After cooling, the mixture was filtered. Brine and DCM were added to the filtrate. The organic layer was separated, dried over Na2S04 and evaporated to dryness. Yield: 24.3 g of Int. 13 (95 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 13:
Figure imgf000105_0003
b-2) Pre aration of Int. 25
Figure imgf000105_0002
A suspension of Int. 24 (12 g, 33.95 mmol) and Pt/C 5 % (1.5 g) as a catalyst in EtOH (300 ml) was hydrogenated overnight at room temperature under H2-gas atmosphere. The suspension was filtered under reduced pressure. The filtrate was evaporated and the residue was purified by column chromatography over silica gel (gradient eluent: PE/EtOAc from 2/1 to 1/1). The desired fractions were collected and the solvent was evaporated. Yield: 7.2 g of Int. 25 (65.6 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 25 : N H
Int. 30 (starting from Int. 29)
Int. 56 (starting from Int. 55)*
Int. 69 (starting from Int. 68)
Int. 73 (starting from Int. 72)
H2N
Int. 77 (starting from Int. 76)
* For the synthesis of Int. 56, 10 % Pd/C in MeOH was used under H2 atmosphere at 40 psi pressure for 5 h, after which the mixture was filtered on Celite®. The crude residue was purified by column chromatography over silica gel (eluent: PE/EtOAc 1/1).
c-1) Preparation of Int. 14
Figure imgf000106_0001
Phenyl formate (13.24 g, 108.45 mmol) was added to a solution of Int. 13 (23.4 g, 72.3 mmol) in DCM (200ml). The mixture was stirred at room temperature for 24 h. The organic solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc 8/1 to EtOAc). The desired fractions were collected and the solvent was evaporated. Yield: 17 g of Int. 14 (67 % yield).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 14:
Figure imgf000107_0001
nt. start ng rom nt.
c-2) Pre aration of Int. 70
Figure imgf000107_0002
Phenyl formate ( 2.098 mL, 19.239 mmol) was added dropwise to a stirred mixture of Int. 69 (4.85 g, 12.826 mmol) in DCM (100 ml) at room temperature. After addition the reaction mixture was stirred at room temperature for 2 days. The reaction was quenched by the addition of water. The mixture was diluted with DCM and then shaken vigorously. The organic layer was separated, washed with water, dried with MgS04, filtered and the filtrate was evaporated. The residue was dissolved in DCM and purified over a Si02 column, type Grace Reveleris SRC, 80 g, Si 40, on a Armen Spot II Ultimate purification system using DCM and MeOH as eluent in a gradient starting from 100 % DCM and ending with 5 % MeOH and 95 % DCM. The desired fractions were combined and the solvent was evaporated. Yield: 3.78 g of Int. 70 (76 %). The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 70:
Figure imgf000108_0001
d) Preparation of Int. 15
Int. 14 was further reacted according to analogous synthesis protocols as described successively for Int. 4 (Al .d), Int. 10 (Al .e) and Int. 11 (Al .f), to obtain Int. 15, which was used for the synthesis of compound 2:
Figure imgf000108_0002
HC1 salt
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 15:
Figure imgf000108_0003
propanediamine; used for Co. 3) propane am ne; use or o. 1,
9a)
Figure imgf000109_0001
Figure imgf000110_0001
Example A4
a) Preparation of Int. 44
Figure imgf000110_0002
NaH (60 % dispersion in mineral oil) (1.052 g, 26.298 mmol) was added portionwise to a stirred solution of Int. 9 (3.3 g, 8.766 mmol) in DMF (117ml) under nitrogen atmosphere at room temperature. The reaction mixture was stirred 20 minutes at room temperature under nitrogen atmosphere. 2-chloro-4-(6-chloro-3-pyridinyl)-pyrimidine (1.982 g, 8.766 mmol) was added to the reaction mixture and the resulting solution was stirred at room temperature for 16 h. The reaction mixture was poured out on ice/water. The water layer was stirred for 1 h at room temperature. The precipitate was filtered off and dissolved in EtOAc. The organic layer was dried, filtered and concentrated under reduced pressure. The residue was crystalized from ACN (60ml). The precipitate was filtered off and dried. Yield: 3.43g of Int. 44 (72 %).
b) Preparation of Int. 45
Figure imgf000111_0001
Trifluoroacetic anhydride (1.671 g, 7.955 mmol) was added dropwise to a solution of Int. 44 (2.14 g, 3.977 mmol) and Et3N (1.106 mL, 7.955 mmol) in DCM (24 ml) at room temperature. The solution was stirred for 1 h at room temperature. The solution was concentrated to 1/10 volume. After standing overnight at room temperature, the precipitate was filtered off and dried. Yield: 2.3g of Int. 45.
c) Pre aration of Int. 46
Figure imgf000111_0002
A mixture of Int. 45 (500 mg) and 1,3-diaminopropane (1.126 mL, 13.368 mmol) was stirred at 80 °C for 4 h. Subsequently, water (20 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 1 h. The water layer was decanted. The residue was stirred in DIPE at room temperature for 1 h. The DIPE layer was decanted. The residue was dried under vacuum. Yield: 330 mg of
Int. 46. d) Preparation of Int. 47
Figure imgf000112_0001
A solution of Int. 46 (330 mg, 0.592 mmol) in a mixture of trifluoroacetic anhydride (10 ml) and DCM (20 ml) was stirred at room temperature for 48 h. The solution was concentrated under reduced pressure. The residue was co-evaporated with toluene till dryness. Yield: 330 mg of Int. 47 (used for the synthesis of compound 14).
Example A5
a Preparation of Int. 49
Figure imgf000112_0002
Compound 15 (380 mg, 0.409 mmol) was stirred in HC1 (4 M in 1,4-dioxane) (8.929 mL, 35.716 mmol) at 60 °C for 32 h. HC1 (4 M in 1,4-dioxane) (4 mL) was added to the solution. The solution was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was co-evaporated twice with toluene (2x50 ml). The residue (crude Int. 49) was used as such in the next reaction step (the synthesis of compound 16).
Example A6
a) Preparation of Int. 80
Figure imgf000112_0003
A mixture of 2-chloro-4-(6-chloro-3-pyridinyl)-pyrimidine (WO 2009112439) (3 g, 13.271 mmol) and 3-aminobenzyl alcohol (1.63 g, 13.271 mmol) in n-butanol (16.8 mL) was heated in a microwave reactor at 180 °C for 5 minutes. The reaction mixture was taken up into MeOH, diluted with dichloromethane and washed with 10 % K2CO3 aqueous solution. The organic layer was separated, dried over MgS04, filtered and evaporated, yielding 13.27 g of an orange foam. The reaction was repeated 3 times. The combined residues were purified by preparative LC on irregular SiOH 20-45 μιη 1000 g DAVISIL using NH4OH, DCM, MeOH 0.1/97/3 as an eluent. The desired fractions were collected and the solvent was evaporated. Yield: 5.7 g of Int. 80 (45.77 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 80:
Figure imgf000113_0001
. 343 (from 5-amino-2-chloro
Int. 342 (from 5-amino-2- benzenemethanol)
(phenylmethoxy)-benzenemethanol) b-1) Preparation of Int. 81
Figure imgf000113_0002
Reaction was executed twice on the amounts described below.
A suspension of Int. 80 (0.5 g, 1.6 mmol) and 3-(N-tert-butoxycarbonyl-N- methylamino)propanol (1.5 g, 8 mmol) in potassium tert-butoxide 1 M in 2-methyl-2- propanol (14 mL, 14 mmol) was stirred at 110 °C for 5 minutes in a microwave (Biotage) in a sealed tube, monomode, 400 W. The reaction mixture was poured into water. The precipitate was filtered over Celite® and washed with DCM (3 x). The combined organic layers were separated, dried over MgS04, filtered and evaporated. The residue was purified by preparative liquid chromatography on irregular SiOH 15- 40 μιη 300 g (Merck). Mobile phase NH4OH, DCM, MeOH 0.1/97/3). The desired fractions were collected and the solvent was evaporated. The residue was purified by preparative LC (2-ethylpyridine 6 μιη 150 x 21.2 mm); mobile phase (iPrNH2, C02, MeOH 0.3/75/25). Yield: 332 mg of Int. 81 (22 %). b-2) Preparation of Int. 85
Figure imgf000114_0001
A mixture of Int. 80 (30 g, 96 mmol), N-(3-aminopropyl)-carbamic acid 1,1- dimethylethyl ester (84 g, 480 mmol) and NMP (120 ml) was stirred for 15 h at 80 °C. Subsequently, the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (PE/EtOAc) from 20/1 to 1/2). The desired fractions were collected and the solvent was evaporated. Yield: 17 g of Int. 85 (39 %). b-3) Preparation of Int. 344
Figure imgf000114_0002
A mixture of int. 80 (lg; 3.2 mmol) in ethylenediamine (2 ml) was stirred at 150 °C for 3 h. The reaction mixture was poured out onto ice water and the water layer was extracted with a mixture of DCM/MeOH 9/1. The organic layer was dried with MgS04, filtered and evaporated to dryness. The residue was taken up into DCM (75 ml) and was treated with di-tert-butyl dicarbonate (973 mg; 4.46 mmol) and stirred at room temperature for 16 h. The reaction mixture was washed with a saturated aqueous NaHCC"3 solution and water. The organic layer was dried with MgS04, filtered and evaporated to dryness. The crude residue (containing Int. 344) was used as such in the next reaction step. The intermediates in the table below were prepared according to an analogous reaction rotocol as used for Int. 344:
Figure imgf000115_0001
) Preparation of Int. 82
Figure imgf000116_0001
Manganese dioxide (3.4 g, 40.204 mmol) was added to a solution Int. 81 (340 mg, 0.73 mmol) in DCM (5 mL). The reaction mixture was stirred overnight at room
temperature. The reaction mixture was filtered through Celite® which was
subsequently washed with DCM (3x). The filtrate was evaporated. Yield: 209 mg of Int. 82 (62 %).
The Intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 82:
Figure imgf000116_0002
Figure imgf000117_0001
d) Preparation of Int. 83
Figure imgf000117_0002
Sodium triacetoxyborohydride (132 mg, 0.621 mmol) was added to a stirred solution of Int. 82 (192 mg, 0.414 mmol), DIPEA (142 L, 0.828 mmol) and piperazine-1 -acetic acid tert-butyl ester (166 mg, 0.828 mmol) in 1 ,2-dichloroethane (1.9 mL). The mixture was stirred at 120 °C for 20 minutes in a biotage microwave in a sealed tube, monomode, 400 W. Water, potassium carbonate 10 % and DCM were added. The reaction mixture was extracted with DCM (3x). The organic layer was separated, dried (MgS04), filtered and the solvent was evaporated. The residue was purified by liquid chromatography on silica gel (15-40 μιη / 30 g; eluent DCM gradient to
DCM-MeOH 4 %-NH4OH 0,4 %). The solvent was evaporated to give 196 mg of Int. 83 (73 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 83:
Figure imgf000118_0001
) Preparation of Int. 84
Figure imgf000119_0001
TFA salt
TFA (6.1 mL, 82.552 mmol) was added to a solution of Int. 83 (260 mg, 0.401 mmol) in DCM (6.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated to give 600 mg of Int. 84 which was used as such without purification for the next reaction step.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 88:
Figure imgf000119_0002
Figure imgf000120_0001
Example A7
aa) Preparation of Int. 96
Figure imgf000120_0002
A suspension of 3-amino-5-(methoxycarbonyl)pyridine (3.34g, 21.95mmol) and phenyl formate (4.8 mL, 43.90mmol) in DCM (10 mL) was stirred at room temperature for 72 h. The reaction mixture was diluted with diisopropylether. The precipitate was filtered off and dried. Yield: 4.59 g of Int. 96 as an off-white solid (69 %).
a) Preparation of Int. 89
Figure imgf000120_0003
NaH (60 % dispersion in mineral oil) (610 mg; 15.25 mmol) was added portionwise to a solution of 4-(formylamino)-2-pyridinecarboxylic acid, methyl ester (Journal of Antibiotics (1984), 37(5), 532-45) (2.29 g; 12.71 mmol) in DMF (50 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature and then 2- chloro-4-(6-chloro-3-pyridinyl)-pyrimidine (WO 2009112439) (3.45 g; 15.25 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water was added and the mixture was stirred for 1 h. The mixture was filtered. The precipitate was washed with water (2x), then dried. The residue was combined with the product of the same reaction conducted on 4-(formylamino)-2-pyridinecarboxylic acid, methyl ester (300 mg; 1.67 mmol) and 2-chloro-4-(6-chloro-3-pyridinyl)-pyrimidine (376 mg; 1.67 mmol). The combined residues were purified by preparative liquid chromatography on (Irregular SiOH 20-45 μπι, 450 g MATREX). Mobile phase (NH4OH, DCM, MeOH 0.1/96/4). The desired fractions were collected and the solvent was evaporated. Yield: 1.24 g of Int. 89 (yellow solid) (25 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 89:
Figure imgf000121_0001
I Int. 97 (from Int. 96; obtained as a beige solid) b) Preparation of Int. 90
Figure imgf000121_0002
NaBH4 (800 mg, 21 mmol) was added to a suspension of Int. 89 (1.2 g; 3.5 mmol) in MeOH (75 mL) and THF (75 mL).The reaction mixture was stirred for 12 h. Water was added and the organic solvents were evaporated. The precipitate was filtered off, washed with water and dried. The residue was purified by liquid chromatography over silica gel [(Irregular SiOH, 20-45 μιη, 40 g). Mobile phase: gradient from DCM, MeOH, NH4OH 97/3/0.1 to DCM, MeOH, NH4OH 90/10/0.1 The pure fractions were collected and the solvent was evaporated. Yield: 460 mg of Int. 90 (41 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 90:
Figure imgf000122_0001
Int. 98 (from Int. 97; LiAlH4 was used as
reducing agent (1 M in THF); THF was
used as solvent) c) Preparation of Int. 91
Figure imgf000122_0002
A mixture of Int. 90 (460 mg; 1.47 mmol) and N^A^-dimethyl-l^-propanediamine (1.2 g; 11.7 mmol) in NMP (3.5 mL) in a sealed tube was heated at 135 °C using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The solvent was evaporated. The residue was purified by preparative liquid chromatography (Stability Silica 5μιη 150x30.0 mm). Mobile phase: gradient from NH4OH, DCM, MeOH 0.5/95/5 to NH4OH, DCM, MeOH 0.5/75/25. The desired fractions were collected and the solvent was evaporated. Yield: 540 mg of Int. 91 (97 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 91 :
Figure imgf000123_0001
Int. om Int. d) Preparation of Int. 92
Figure imgf000123_0002
Di-tert-butyl dicarbonate (509 mg; 2.3 mmol) was added to a stirred solution of Int. 91 (0.54 g; 1.2 mmol) in DCM (10 mL) and MeOH (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 days. The solvent was evaporated. The residue was purified by preparative LC (Stability Silica 5μιη 150 x 30.0 mm). Mobile phase: gradient from DCM, MeOH, NH4OH 98/2/0.5 to DCM, MeOH, NH4OH 80/20/0.5. The pure fractions were evaporated and the solvent evaporated until dryness. Yield: 220 mg of Int. 92 (39 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 92:
Figure imgf000123_0003
Int. 100 (from Int. 99) ) Preparation of Int. 93
Figure imgf000124_0001
Methanesulfonyl chloride (136 μί; 1.75 mmol) was added dropwise to a solution of Int. 92 (210 mg; 0.44 mmol), DIPEA (383 mg; 2.2 mmol) in DCM (4 mL) at 5 °C under N2 flow. The reaction mixture was stirred at 5 °C for 10 min. Water and DCM were added. The mixture was extracted with DCM (2x). The organic layer was dried over MgS04, filtered and the solvent was evaporated. Yield: 280 mg of Int. 93.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 93 :
Figure imgf000124_0002
Int. 93 and 101 were typically obtained together with a derivative of these compounds wherein the mesylate moiety is replaced by a chloro moiety. These intermediates were used as mixtures (not quantified) in the next reaction step. f) Preparation of Int. 94
Figure imgf000125_0001
Piperazine-1 -acetic acid tert-butyl ester (279 mg; 1.4 mmol) was added to a suspension of Int. 93 (480 mg; 0.47 mmol) and K2C03 (257 mg; 1.86 mmol) in DMF (2.5 mL). The mixture was stirred at 70 °C for 3 h. Water was added. The mixture was extracted twice with EtOAc. The combined organic layers were washed with water, dried over MgS04, filtered and evaporated. The residue was purified by preparative liquid chromatography on (Stability Silica 5μιη 150x30. Omm). Mobile phase: gradient from NH4OH, DCM, MeOH 0.2/98/2 to NH4OH, DCM, MeOH 1.1/89/11). The desired fractions were collected and the solvent was evaporated. Yield: 133 mg of Int. 94 (yellow oil) (43 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 94:
Figure imgf000125_0002
Int. 102 (from Int. 101)
g) Preparation of Int. 95
Figure imgf000126_0001
HC1 (37 % in H20) (71 μΐ,; 0.86 mmol) and distilled water (0.5 mL) were added successively to a solution of intermediate 94 (133 mg; 0.17 mmol) in 1,4-dioxane (3 mL). The reaction mixture was stirred at 100 °C for 2 h. The solution was evaporated under reduced pressure and the residue was co-evaporated twice with toluene. Yield: 105 mg of Int. 95.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 95 :
Figure imgf000126_0002
103 (from Int. 102; used for Co. 33)
Example A8
a) Preparation of Int. 104
Figure imgf000126_0003
N-(tert-Butoxycarbonyl)-l,2-diaminoethane (8.613 g, 53.761 mmol) and MgS04 (9.707 g, 80.642 mmol) were added to a solution of 5-bromo-2-formylpyridine (10 g, 53.761 mmol) in DCM (208 ml). The reaction mixture was stirred 30 min at room temperature under N2-flow. NaBH(OAc)3 (10 g, 53.761 mmol) was added portion wise to the reaction mixture at room temperature, and was then stirred at room temperature for 16 h. Subsequently, the reaction mixture was washed twice with an aqueous 2 M NaHC03 solution (2x 100 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (21 g) was purified by silicagel filter: eluens DCM /
MeOH // from 99.5 / 0.5 to 96 / 4. The pure fractions were collected and concentrated under reduced pressure. Yield: 9.2 g of Int. 104 (51.82 %).
b) Preparation of Int. 105
Figure imgf000127_0001
Tert-Butyl dicarbonate (14.958 g; 68.535 mmol) was added to a solution of Int. 104
(9.2 g, 27.86 mmol) in DCM at room temperature. The reaction mixture was stirred for 72 h at room temperature, and was subsequently washed with water (2x 200 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (34 g) was stirred in DIPE (25ml). The precipitate was filtered off and dried under vacuum at 50 °C. Yield: 9.6 g of Int. 105 (80.07 %).
c) Preparation of Int. 106
Figure imgf000127_0002
PdCl2(dppf)-DCM (0.336g, 0.407mmol) was added to Int. 105 (5 g, 11.619mmol), potassium acetate (34.856 mmol) and bis(pinacolate)diboron (3.613 g, 13.942 mmol) in 1,4-dioxane (50 ml) at room temperature. The reaction mixture was stirred at 100 °C for 48 h and was then diluted with 1,4-dioxane (80 ml). The organic layer was filtered through Dicalite . The filtrate was concentrated under reduced pressure. The residue (Int. 106) was used as such in the next reaction step.
d) Preparation of Int. 107
Figure imgf000128_0001
PdCl2(dppf)-DCM (0.256 g, 0.349 mmol) was added to a solution of crude Int. 106 (5.547 g) and 2,4-dichloropyrimidine (5.193 g, 34.86 mmol) in 1,4-dioxane (50 ml) at room temperature. 2 M aqueous sodium carbonate (8.715 ml, 17.43 mmol) was added to the reaction mixture at room temperature. The mixture was stirred at 80 °C for 16 h and was then diluted with 1,4-dioxane (160 ml). The organic layer was filtered through Dicalite®. The filtrate was concentrated under reduced pressure. The residue (13.25 g) was purified by flash chromatography on silica gel: eluens DCM/MeOH // from 100/0 to 95/5. The pure fractions were collected and concentrated under reduced pressure. Yield: 5.15 g of Int. 107 (86.93 %).
e) Preparation of Int. 108
Figure imgf000128_0002
NaH (60 % dispersion in mineral oil) (0.577 g, 14.416 mmol) was added portion wise to a stirred solution of intermediate 3 (3.717 g, 11.148 mmol) in DMA (54.26 ml) under N2 atmosphere at room temperature. The reaction mixture was stirred 40 min at room temperature under N2 atmosphere. Int. 107 (2.1 g, 3.44 mmol) was added to the reaction mixture and was then stirred at room temperature for 16 h. Subsequently, the mixture was poured out on ice/water. The water layer was extracted with EtOAc (2x 200 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (14 g) was purified by Prep HPLC (Uptisphere® CI 8 ODB - 10 μιη, 200 g, 5 cm). Mobile phase: 0.25 % NH4HCO3 solution in water, MeOH. The desired fractions were collected and the solvent was evaporated. Yield: 1.513 g of Int. 108 (60.01 %).
f) Preparation of Int. 109
Figure imgf000129_0001
HC1 salt
Int. 108 (5 g, 6.822 mmol) was stirred in 4 M HC1 in 1,4-dioxane (200 ml) at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was co-evaporated twice with toluene (2x 50 ml). The residue (Int. 109) (6.8 g) was used as such in the next reaction step.
Example A9
a-1) Preparation of Int. 110
Figure imgf000129_0002
Tert-butyl bromoacetate (3.2 mL; 21.52 mmol) in ACN (20 mL) was added dropwise during 90 min to a solution of 2-piperazinemethanol (5 g; 43.04 mmol) and K2CO3 (4.5 g; 32.28 mmol) in ACN (30 mL) at 0 °C. After the addition the reaction mixture was filtered. The precipitate was washed with a mixture of DCM/MeOH (95/5) (3x). The filtrate was evaporated to yield 5.02 g of a yellow oil. The residue was purified by preparative LC (Irregular SiOH 20-45 μιη 450 g MATREX). Mobile phase: NH4OH, DCM,MeOH 1/87/12. The desired fractions were collected and the solvent was evaporated. Yield: 1.4 g of a Int. 110 as a yellow oil (28 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 110:
Figure imgf000130_0002
a-2) Preparation of Int. 115
Figure imgf000130_0001
Int. 115
1st step:
Tert-butyl bromoacetate (2.23 mL) was added dropwise to a suspension of 4-
(phenylmethyl)-2-piperazinecarboxamide (4 g; 18.24 mmol) in DCM (63 mL) at room temperature. The reaction mixture was stirred overnight at 50 °C. The suspension was filtered off. The precipitate was washed twice with DCM. The filtrate was evaporated to give 4.16 g of a off-white solid. The off-white solid (4.16 g) was purified by preparative LC (Stability Silica 50 μηι, 40 g). Mobile phase: DCM, MeOH, NH4OH 97/3/0.1). The pure fractions were collected and the solvent was evaporated until dryness, yielding 2.67 g of a white solid Int. 115a (53 %):
Figure imgf000131_0001
2m step:
A mixture of Int. 115a (1.47 g; 4.41 mmol) in MeOH (14.7 mL) was hydrogenated at room temperature with Pd/C (150 mg) as a catalyst under a pressure of 3 bar of H2 atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction was performed a 2nd time with 1.2 g (3.6 mmol) of Int. 115a, and both reaction mixtures were combined for work-up. The catalyst was filtered off on a pad of Celite® and filtrate was evaporated to give a white sticky solid. The solid was purified by preparative LC (Stability Silica 30-45 μιη, 24 g). Mobile phase: Gradient from DCM, MeOH, NH4OH 97/3/0.1 to DCM, MeOH, NH4OH 90/10/0.1). The pure fractions were collected and the solvent was evaporated until dryness to give Int. 115 as a off-white solid (71 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 115:
Figure imgf000131_0002
Int. 116 (starting from 3 -methyl- 1- (phenylmethyl)piperazine); (1st step of the
reaction: NaH was added, DMF was used
as solvent) a-3) Preparation of Int. 137
Figure imgf000132_0001
1 step:
Methyl bromoacetate (1.89 mL; 19.89 mmol) was added drop wise to a solution of 2- (aminocarbonyl)-l-piperazinecarboxylic acid, 1 , 1 -dimethylethyl ester (4.56 g; 19.89 mmol) and K2CO3 (4.1 g; 29.83 mmol) in DMF (45 mL) at room temperature. The reaction mixture was stirred at room temperature for 90 min. Water and EtOAc were added. The mixture was extracted with EtOAc (3x). The organic layer was washed with brine, dried over MgS04, filtered and the solvent was evaporated to give 6 g of a yellow oil. The oil was purified by preparative LC (Stability Silica 30-45 μιη, 80 g).
Mobile phase: Gradient: from pure DCM to DCM, MeOH, NH4OH 97/3/0.1). The pure fractions were collected and evaporated until dryness to give 5.32 g of a yellow oil Int. 137a (88 %):
Figure imgf000132_0002
2nd step:
TFA (13 mL; 170.24 mmol) was added to a solution of Int. 137a (5.13 g; 17.02 mmol) in DCM (33 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to yield 10.6 g of an off-white solid as a TFA salt
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 137:
Figure imgf000133_0001
a-4) Preparation of Int. 142
Figure imgf000133_0002
HC1 salt
MeOH (250 mL) was added to palladium hydroxide on activated charcoal (4.558 g, 32.454 mmol) under N2-gas atmosphere. Methyl l,4-dibenzylpiperazine-2-carboxylate (WO2004084898) (21.3 g; 40.907 mmol; 65 % purity), HC1 (6 M in iPrOH)(15 mL, 90.0 mmol) and H2 gas (1834.4 mL, 81.81 mmol) were added. The reaction mixture was hydrogenated at room temperature under H2-gas until 2 eq. H2 were absorbed. The catalyst was removed by filtration over Dicalite® under N2-gas atmosphere. The filtrate was evaporated. Yield: 13.52 g of Int. 142. b) Preparation of Int. 85 (alternative for the procedure in A6.b-2))
Figure imgf000134_0001
Int. 80 (1.54 g; 4.92 mmol) and N-(3-aminopropyl)-carbamic acid, 1,1-dimethylethyl ester (4.29 g; 24.62 mmol) in NMP (3.9 mL) were stirred at 140 °C for 6 h. Water and DCM were added. The reaction mixture was extracted with DCM. The organic layer was washed with brine, dried over MgS04, filtered and the solvent was evaporated. Yield: 4.48 g of a brown oil. The residue was purified by preparative LC (Irregular SiOH 20-45 μιη 450 g MATREX). Mobile phase: NH4OH, DCM, MeOH 0.1/93/7). The desired fraction were collected and the solvent was evaporated. Yield: 1.4 g of Int. 85.
The intermediates in the table below were prepared according to an analogous reaction protocol as used in A9.b) for Int. 85:
Figure imgf000134_0002
Int. 122 (starting from tert-butyl methyl[3-
Int. 149 (starting from tert-butyl methyl[2- (methylamino)propyl] carbamate)
(methylamino)ethyl] carbamate)
Figure imgf000135_0001
Int. 150 (starting from tert-butyl [3-(methy Int. 171(starting from N-[(25)-2-pyrrolidin lamino)propyl] carbamate) ylmethylj-carbamic acid, 1,1-dimethylethyl ester)
Figure imgf000135_0002
Int. 368(starting from Int. 80 and N-(3-ami
nopropyl)-N-methyl-carbamic acid, , 1,1 -d
imethylethyl ester
c) Preparation of Int. 112
Figure imgf000135_0003
Methanesulfonyl chloride (945 μί; 12.21 mmol) was added dropwise to a solution of Int. 85 (1.1 g; 2.44 mmol), DIPEA (2.13 mL; 12.21 mmol) in DCM (70 mL) at 5 °C under N2 flow. The reaction mixture was stirred at 5 °C for 15 min. Water and K2C03 were added. The mixture was extracted twice with DCM. The organic layer was dried (MgS04), filtered and the solvent was evaporated. Yield: 1.79 g of crude Int. 1 12 as a yellow solid, used as such in the next reaction step without further purification.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 1 12:
Figure imgf000136_0002
Int. 1 12, 123 and 172 were typically obtained together with a derivative of these compounds wherein the mesylate moiety is replaced by a chloro moiety. These intermediates were used as mixtures (not quantified) in the next reaction step. d
Figure imgf000136_0001
Int. 1 12 (1.87 g; 2.48 mmol) dissolved in DMF (5.4 mL) was added dropwise to a suspension of Int. 1 10 (1.14 g; 4.95 mmol) and K2C03 (1.37 g; 9.91 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 30 min. Water and EtOAc were added. The mixture was extracted with EtOAc (3x). The organic layer was dried over MgSC"4, filtered and the solvent was evaporated, yielding 2.78g of a brown oil. The residue was purified by preparative LC (irregular SiOH 15-40 μιη 300 g MERCK). Mobile phase: NH4OH, DCM, MeOH 0.1/94/6. The desired fractions were collected and the solvent was evaporated. Yield: 645 mg of Int. 113 as a yellow foam (39 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 113:
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
d-2) Preparation of Int. 151
Figure imgf000139_0002
Int. 149 (0.7 g; 1.51 mmol) and DIPEA (0.77 mL; 4.53 mmol) were dissolved in DMF (8 mL) at 0 °C under N2-gas atmosphere. Methanesulfonyl chloride (0.234 mL; 3.02 mmol) was added portionwise (3x 0.078 mL) at intervals of 5 min. The reaction mixture was allowed to warm up to room temperature. The mixture was reacted for 1 h, and then 1 ,2-piperazinedicarboxylic acid, l-(l , l-dimethylethyl) ester (0.738 g; 3.02 mmol) was added. The reaction mixture was heated at 80 °C overnight. Subsequently, the mixture was concentrated to dryness. The residue was dissolved in DCM/MeOH 10/1 v/v (25 mL) and this solution was washed with 1 M NaC03 solution in H20 (15 mL). The organic layers were combined, dried (MgSC^), filtered and concentrated to dryness. The residue was purified by column chromatography over silica gel eluting with a gradient from 100 % DCM to 100 % DCM/MeOH 9/1 v/v. The desired fractions were collected and the solvent was evaporated. Yield: 0.978 g of Int. 151 (94 %). The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 151 :
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
p peraz neacet c ac , met y ester e-1) Preparation of Int. 114
Figure imgf000142_0002
C1 salt
HC1 (37 % in H20) (334 μί; 4.0 mmol) then distilled water (2.9 mL) were added to a solution of Int. 113 (624 mg; 0.8 mmol) in 1,4-dioxane (22 mL). The reaction mixture was stirred at 100 °C for 2 h . The solution was evaporated under reduced pressure and the residue was co-evaporated twice with toluene. The residue was dried in vacuo at 70 °C. Yield: 674 mg of Int. 114 as a brown foam which was used as such without further purification for the next reaction step.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 114:
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
e-2) Preparation of Int. 15
Figure imgf000146_0001
HCl salt
Int. 151 (0.978 g; 1.42 mmol) was dissolved in a mixture of NaOH (1 M; 14.2 mL; 14.2 mmol), THF (7 mL) and MeOH (2 mL). The reaction mixture was heated at 40 °C overnight. Subsequently, HCl (37 % in H20) (3 mL) was added and the reaction mixture was heated at 40 °C for 7 h. The reaction mixture was concentrated to dryness and dried under high vacuum (at room temperature). The residue, containing Int. 152, was used as such in the next reaction step (preparation of Co. 68 and Co. 69).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 152:
Figure imgf000146_0002
Figure imgf000147_0001
Figure imgf000148_0001
Int. 7 rom Int. 7 ; use or o.
Example A10
a) Preparation of Int. 153
Figure imgf000148_0002
A solution of triphenylmethyl chloride (27.9g, O.lmmol) in DCM (150 mL) was added dropwise to an ice cold solution of N-benzyl-l,2-ethanediamine (15 g, 0.1 mmol) and Et3N (10.5 mL, 0.075 mmol ) in DCM (20 ml) over 3 h. The mixture was then allowed to warm up to room temperature and stirred for an additional hour. The insoluble material was filtered off and the filtrate concentrated. The residue was purified by chromatography over silica gel eluting with a gradient of EtOAc in heptane from 20 to 100 %. The desired fractions were collected and the solvent was evaporated. Yield: 11.6 g of Int. 153 (30 %). ) Preparation of Int. 154
Figure imgf000149_0001
A solution of (E)-4-bromo-2-butenoic acid ethyl ester (7.6 g, 29.5 mmol, 75 % purity) in DCM (200ml) was added dropwise to a solution of Int. 153 (11.6 g, 29.5 mmol ) and K2C03 (8.17 g, 59.1 mmol) in DCM (200 ml) over 3 h. The mixture was then stirred overnight. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromato-graphy over silica gel eluting with a gradient of EtOAc in heptane from 20 to 100 %. The desired fractions were collected and the solvent was evaporated. Yield: 13.6 g of Int. 154.
c) Preparation of Int. 155
Figure imgf000149_0002
Acetyl chloride (32 mL, 450 mmol) was added to MeOH (225 mL) with ice cooling under N2-gas atmosphere. The mixture was then allowed to warm up to room temperature and stirred for 30 min. The resulting 2 M HC1 solution in MeOH was added to Int. 154 (13.6 g, 26.9 mmol) and the mixture refluxed for 10 min. The reaction was allowed to cool to room temperature and concentrated. The residue was partitioned between DCM (150 mL) and 2 M Na2C03 (250 mL; aqueous solution). The organic layer was separated, dried over MgS04, filtered and concentrated. The oil was then purified by column chromatography over silica gel eluting first with DCM and then with 10 % MeOH in DCM. The desired fractions were collected and the solvent was evaporated. Yield: 5.93 g of Int. 155 (88 %). ) Preparation of Int. 156
Figure imgf000150_0001
A solution of tert-butoxycarbonyl anhydride (5.2g, 23.8 mmol) in DCM (50 ml) was added dropwise to Int. 155 (5.93 g, 23.8 mmol) with ice cooling. The mixture was then allowed to warm up to room temperature and stirred for 4 h. The solvent was evaporated under reduced pressure. The crude oil obtained was then purified by column chromatography over silica gel eluting with a mixture 8 to 1 of heptane/EtOAc (v/v). The desired fractions were collected and the solvent was evaporated. Yield: 5.64 g of Int. 156 (68 %).
e) Preparation of Int. 157
Figure imgf000150_0002
A solution of Int. 156 (5.64 g, 16.2 mmol) and Pd/C (10 %) (0.56 g) as a catalyst in MeOH (100 mL) was hydrogenated under t¾ atmosphere overnight at room
temperature. The reaction mixture was filtered through a pad of Celite® and the filtrate concentrated. Yield: 4.2 g of Int. 157 as a clear oil (100 %).
Example Al l
a) Preparation of Int. 63
Figure imgf000151_0001
Diisopropylazodicarboxylate (3.5 mL; 18 mmol) was added dropwise to a stirred solution of Boc-D-prolinol (3 g; 15 mmol), phtalimide (2.6 g; 18 mmol) and PPh3 (6 g; 18 mmol) in THF (40 mL) at 0-5 °C. The reaction mixture was stirred at room temperature for 12 h. Water was added and this mixture was extracted twice with DCM. The separated organic layer was dried over MgS04, filtered and evaporated. The residue was crystallised from Et20. The solid was filtered off and the filtrate was evaporated. The residue was purified by preparative liquid chromatography (Irregular SiOH 20-45 μιη 450 g MATREX). Mobile phase (75 % heptane, 25% EtOAc). The pure fractions were combined and the solvent was evaporated. Yield: 4.6 g of Int. 63 (93 %).
b) Preparation of Int. 64
Figure imgf000151_0002
HC1 salt
Int. 63 (830 mg; 2.5 mmol) in HC1 5 M (10 mL; aqueous) was stirred at room temperature for 24 h. Subsequently, the reaction mixture was diluted with Et20. The precipitate was filtered off and dried. Yield: 494 mg of Int. 64. c) Preparation of Int. 65
Figure imgf000152_0001
Int. 4 (224 mg, 0.45 mmol), Int. 64 (301 mg) and Na2C03 (239 mg; 2.3 mmol) in DMSO (0.8 mL) were stirred at 130 °C for 18 h. Water was added. The solid was filtered off and taken up into DCM. The organic layer was dried with MgS04, filtered and evaporated. The residue was purified by preparative LC on (Sunfire Silica 5μιη 150x30.0 mm). Mobile phase (Gradient from 71 % heptane, 1 % MeOH, 28 % EtOAc to 0 % Heptane, 20 % MeOH, 80 % EtOAc). The pure fractions were combined and the solvent was evaporated. Yield: 128 mg of Int. 65.
d) Preparation of Int. 66
Figure imgf000152_0002
Hydrazine monohydrate (180 μί, 3.7 mmol) was added to a suspension of a mixture of Int. 65 (128 mg, 0.19 mmol) in EtOH (3 ml) and 1,4-dioxane (2 ml). The reaction mixture was heated at reflux for 4 h. Water was added and the organic solvent was evaporated. The aqueous mixture was extracted twice with DCM. The organic layer was dried (MgS04), filtered and evaporated. Yield: 83 mg of Int. 66 (80 %). e) Preparation of Int. 67
Figure imgf000153_0001
HC1 (37 % in H20) (62 pL, 0.74 mmol) and distilled water (0.8 ml) were added to a solution of Int. 66 (83 mg, 0.15 mmol) in 1,4-dioxane (3 ml). The reaction mixture was stirred at 100 °C for 12 h. The solution was evaporated under reduced pressure and the residue was co-evaporated twice with toluene. Yield: 91 mg of Int. 67 as a yellow foam, used as such without further purification in the next reaction step (the synthesis of compound 26).
Example A12
a) Preparation of Int. 177
Figure imgf000153_0002
2-Piperazinone (2.5 g; 24.97 mmol) was dissolved in DCM ( 55 ml ). A solution of tert- butyloxycarbonyl anhydride (5.45g, 24.97mmol) in DCM (20 ml) was added dropwise. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated to dryness and dried under high vacuum, at room temperature. The residue containing Int. 177 (5.1 g) was used as such in the next reaction step.
b) Preparation of Int. 178
Figure imgf000153_0003
NaH (60 % in mineral oil) (0.24 g; 5.99mmol) was added to a solution of Int. 177 (1 g; 4.99 mmol) in DMF (8 ml) and cooled to 0 °C under N2-gas atmosphere. The mixture was stirred at this temperature for 10 min. Methyl bromoacetate (0.522 mL; 5.49 mmol) was added. The cooling bath was removed and the reaction stirred overnight. Subsequently, the reaction was quenched with H20 (2 ml ). A saturated NaCl aqueous solution (20 ml) was added and the mixture was extracted with EtOAc (14 ml ). The organic layer was dried over MgS04, filtered and concentrated to dryness. The residue was purified by chromatography over silica gel eluting with a gradient from 100 % DCM to 40 % DCM and 60 % DCM/MeOH 9/1, v/v. The desired fractions were collected and the solvent was evaporated. Yield: 1.14 g of Int. 178 (84 %).
c) Preparation of Int. 179
Figure imgf000154_0001
Int. 178 (1.14 g; 4.19mmol) was dissolved in HC1 4 M in 1,4-dioxane (10.5 mL; 41.9 mmol) and stirred at room temperature overnight. Diethyl ether was added and the mixture was stirred for 30 min. The mixture was filtered. The solid product was dried under high vacuum, at room temperature. The residue was suspended in DCM.
Amberlyst A-26 (OH) ion exchange resin (q.s.) was added until basic pH and the mixture was shaken for 20 min.The mixture was filtered and the ion exchange resin washed alternating with DCM (3x 5 ml) and MeOH (2x 5 ml). The combined solutions were evaporated to give 0.498 g of Int. 179 (69 %).
Example A13
a) Preparation of Int. 182
Figure imgf000154_0002
,N3-dimethyl-l,3-propanediamine (9.05 g; 88.55 mmol) was added to Int. 80 (5.54 g; 17.71 mmol). The reaction mixture was heated at 110 °C for 5 h. The reaction mixture was concentrated to dryness. The residue was stirred with 1 M NaOH (25 ml) for 1 h. The solid product was filtered off, washed with H20 (50 ml ) and dried under high vacuum, at room temperature to give 5.95 g of Int. 182 (89 %).
b) Pre aration of Int. 183
Figure imgf000155_0001
Int. 182 (0.7 g; 1.85 mmol) was suspended in a mixture of CH3CN (6 mL) and DMF (2 mL). K2CO3 (0.282 g; 2.04 mmol) and methyl bromoacetate (0.176 mL; 1.85mmol) were added successively. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (30 mL) and washed with H20 (15 mL). The aqueous layer was again extracted with EtOAc (30 mL). The combined organic layers were dried over MgS04, filtered and concentrated to dryness. The residue was purified by column chromatography over silica gel eluting with a gradient of 100 % DCM to 30 % DCM and 70 % DCM/MeOH 9/1, v/v. The desired fractions were collected and the solvent was evaporated. Yield: 0.512 g of Int. 183 (61 %). Example A14
a Preparation of Int. 186
Figure imgf000155_0002
Pd(OAc)2 (3.52 g) and PPh3 (3.93 g) were added to a mixture of (2-chloropyrimidin-5- yl)boronic acid (47.5 g; 300 mmol), 2,4-dichloropyrimidine (49.16 g; 330 mmol), K2C03 (124.2 g), THF (720 mL) and H20 (750 mL) under N2-gas atmosphere. The mixture was heated to reflux for 4 h. The reaction mixture was cooled to 50 °C. The organic layer was separated at 50 °C. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Yield: 30 g of Int. 186 (44 %). b) Preparation of Int. 187
Figure imgf000156_0001
N,N'-dimethyl-l,3-propanediamine (0.512 mL; 4.096 mmol) was added dropwise to Int. 186 (500 mg; 2.202 mmol) in DCM (10 ml) at 0 °C and the reaction was stirred for lh. Subsequently, DCM (10 mL) was added to the reaction mixture. Then di-tert-butyl dicarbonate (1.6 g; 7.331 mmol) was added to the reaction mixture at 0 °C and the reaction mixture was stirred for 1 h. The solvent was evaporated under reduced pressure. The residue was triturated with diispropyl ether and filtered. The filtrate was evaporated under reduced pressure to yield a yellow translucent oil. The crude oil was purified using normal phase flash column chromatography on silica gel SF25-60g; eluent 2 % MeOH in DCM. The desired fractions were collected and the solvent was evaporated under reduced pressure. Yield: 808 mg of Int. 187 as a pale yellow translucent (93 %).
c) Preparation of Int. 188
Figure imgf000156_0002
LiHMDS (1 M in THF) (0.2 mL; 0.2 mmol) was added to a solution of tert- butyldimethylsilyl 3-aminobenzyl ether (30 mg; 0.126 mmol) in THF (2.5 mL) at 0 °C and the reaction was stirred for lOmin. Subsequently, Int. 187 (24 mg; 0.0611 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was poured in acidic water and extracted with EtOAc. The organic layers were concentrated under reduced pressure and the residue was co-evaporated twice with toluene. Yield: 50 mg of Int. 188 as dark red oil which used as such in the next reaction step. d) Preparation of Int. 189
Figure imgf000157_0001
Acetic acid was added to a solution of Int. 188 (50 mg; 0.053 mmol) in a mixture of water (0.45 mL) and THF (0.45 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1 M NaOH aqueous solution. EtOAc and water were added to the mixture. The layers were separated and the aqueous layer was extracted with EtOAc (3x 20 mL). The combined organic layers were dried over Na2S04, filtered and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase high performance chromatography on Hyperprep C18 HS BDS, pore size 100 A, particle size 8 μιη (Shandon). Mobile phase: Gradient from 80 % ammoniumbicarbonate in H20 (0.25 %) and 20 % acetonitrile, to 40% ammoniumbicarbonate in H20 (0.25 %) and 60% acetonitrile in 40 min. The desired fractions were collected and the solvent was evaporated. Yield: 71 mg of Int. 189 as a yellow solid.
e Preparation of Int. 190
Figure imgf000157_0002
Methanesulfonyl chloride (0.0573 mL; 0.74 mmol) was added drop wise to a stirred solution of Int. 189 (71 mg; 0.148 mmol) and Et3N (0.123 mL; 0.888 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 18 h. Subsequently, the mixture was quenched by the addition of water. The product was extracted twice with DCM. The organic layer was washed with water, dried with MgS04, filtered and the filtrate was evaporated. Yield: 10 mg of Int. 190 (9 %). Int. 190 was obtained together with a derivative wherein the chloro moiety is replaced by a mesylate moiety. Int. 190 was used as a mixture (not quantified) in the next reaction step. f Preparation of Int. 191
Figure imgf000158_0001
A solution of piperazine-1 -acetic acid tert-butyl ester (10 mg; 0.0137 mmol) and Int. 190 (11.277 mg; 0.0546 mmol) and Et3N (0.00228 mL; 0.0164 mmol) in DMF (0.13 mL) was stirred at 70 °C for 1 h. The reaction mixture was quenched by the addition of water. The product was extracted twice with DCM. The organic layer was washed with water, dried with MgS04, filtered and the filtrate was evaporated. Yield: 10 mg of Int. 191.
Example A15
a) Pre aration of Int. 192
Figure imgf000158_0002
Methanesulfonyl chloride (0.575 ml; 7.423 mmol) was added dropwise to a stirred solution of Int. 122 ( 1.91 g; 3.711 mmol) in DCM (50 mL) and Et3N (5.159 mL; 37.115 mmol). The reaction mixture was stirred at room temperature for 4 h.
Subsequently, Int. 142 (2.828 g) was added and the reaction mixture was stirred at room temperature for 18 h. Then water was added, and the product was extracted twice with DCM. The combined organic layers were washed with water, dried (MgS04), filtered, and the solvent was evaporated. The residue was used in the next reaction step without further purification. Yield: 3.05 g of Int. 192.
b) Pre aration of Int. 193
Figure imgf000159_0001
LiBH4 (1.422 mL; 2.844 mmol) was added to a solution of Int. 192 (2 g; 1.422 mmol) in THF (30 mL) at room temperature. The reaction mixture was stirred at reflux temperature for 18 h, and then cooled to room temperature. Subsequently MeOH (10 mL) and water (10 mL) were added and the product was extracted with DCM. The combined organic layers were washed with water, brine, dried (MgS04), filtered and the solvent was evaporated. The residue was dissolved in DCM and purified over a S1O2 column (Grace Reveleris SRC, 80 g, Si 40) on an Armen Spot II Ultimate purification system using DCM and MeOH as eluents, gradient: from 100 % DCM to 95 % DCM / 5 % MeOH. The desired fractions were collected and the solvent was evaporated. Yield: 316 mg of crude Int. 193 (used as such in the next reaction step without further purification).
c) Preparation of Int. 194
Figure imgf000159_0002
Tert-butyl bromoacetate (0.0474 mL; 0.321 mmol) was added dropwise to a stirred solution of Int. 193 (0.316 g) and Na2C03 (0.034 g; 0.321 mmol) in DMF (134.933 mL) at room temperature. The reaction mixture was stirred at 80 °C for 18 h.
Subsequently, water was added and the product was extracted twice with DCM. The organic layer was washed with water, dried (MgS04), filtered and the solvent was evaporated. The residue was dissolved in DCM and purified over a Si02 column(Grace Reveleris SRC, 80 g, Si 40) on an Armen Spot II Ultimate purification system using DCM and MeOH as eluens, gradient: from 100 % DCM to 95 % DCM / 5 % MeOH. The desired fractions were collected and the solvent was evaporated. Yield: 46 mg of Int. 194.
d) Preparation of Int. 195
Figure imgf000160_0001
HCl salt
HCl (4 M in 1,4-dioxane; 0.144 mL; 0.574 mmol) was added to a stirred solution of Int.
194 (46 mg; 0.0574 mmol) in 1,4-dioxane (5 mL) at room temperature. The reaction mixture was stirred at 80 °C for 2 h. The solvent was evaporated. Yield: 57 mg of Int.
195 (used without further purification for the preparation of Co. 63).
Example A16
a) Preparation of Int. 201
Figure imgf000160_0002
Phenylformate (10.56 mL; 96.86 mmol) was added to 3-aminobenzaldehyde ethylene acetal (8 g; 48.43 mmol) solution in DCM (5 mL) at room temperature. The reaction mixture was stirred for 40 minutes. The solvent was evaporated and the residue was purified by preparative LC (Irregular SiOH 20-45 μιη 400 g MATREX, mobile phase: 90 % Heptane, 10 % EtOAc). The pure fractions were collected and the solvent evaporated. Yield: 9.3 g of Int. 201.
b) Preparation of Int. 202
Figure imgf000161_0001
NaH (60 % in oil) (955 mg; 23.887 mmol) was added portionwise to a solution of Int. 201 (3.85 g;19.906 mmol) in DMF (70 mL) at room temperature. The reaction mixture was stirred for 30 min. Then 2-chloro-4-(6-chloro-3-pyridinyl)-pyrimidine (4.5 g; 19.906 mmol) was added .The reaction mixture was stirred overnight at room temperature. Then 22.2 mL of a 2 N NaOH solution in H20 and 30 mL of MeOH were added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water, extracted twice with DCM, dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative LC on Irregular SiOH 20-45μιη 450g MATREX: Mobile phase 50 % heptane, 50 % EtOAc. The pure fractions were collected and the solvent was evaporated. Yield: 4.06 g of Int. 202 (58 %).
c) Preparation of Int. 203
Figure imgf000161_0002
Ammonia (50 mL; condensed at -78 °C) was added to Int. 202 (4 g; 11.274 mmol) in THF (35 mL) in a sealed vessel. The mixture was stirred at 150 °C for 15 h, under a pressure of 82 bars. A precipitate was filtered off and dried to give 2.4 g of Int. 203 as a brown solid (64 %). The filtrate was evaporated and the residue was purified by preparative LC on irregular SiOH 15-40 μιη 300 g MERCK. Mobile phase: NH4OH, DCM, MeOH 0.1/97/3. The desired fractions were collected and the solvent was evaporated. Yield: 1.2 g of Int. 203 (32 %).
d) Preparation of Int. 204
Figure imgf000162_0001
A solution of Int. 203 (3.3 g; 8.561 mmol) and p-toluenesulfonic acid (1.68 g; 8.561 mmol) in acetone (50 mL) and water (10 mL ) was stirred at room temperature for 12 h. The mixture was diluted with DCM and K2CO3 10 % in H20. The organic layer was decanted, dried over MgS04 , filtered and the solvent was evaporated. Yield: 2.5 g of Int. 204 (100 %).
e) Pre aration of Int. 205
Figure imgf000162_0002
A solution of Int. 204 (2.5 g; 8.582 mmol), N-[(l,l-dimethylethoxy)carbonyl]-P- alanine, (4.9 g; 25.746 mmol), HATU (9.8g; 25.746 mmol ), and Et3N (8.4 mL; 60.073 mmol) in THF (100 mL) was stirred at reflux for 14 h. The mixture was diluted with EtOAc and H20. The organic layer was decanted, dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative LC on irregular SiOH 15-40 μιη 300 g MERCK. Mobile phase: 98 % DCM, 2 % MeOH. The desired fractions were collected and the solvent was evaporated to give 6 g of Int. 205 (100 %). f) Pre aration of Int. 206
Figure imgf000162_0003
The reaction was performed in a microwave-apparatus (Biotage) in a sealed tube, (monomode 400 W). Sodium triacetoxyborohydride (1.7 g, 7.823 mmol) was added to a stirred solution of Int. 205 (3.6 g, 5.215 mmol) and piperazine-1 -acetic acid tert-butyl ester (2.1 g, 10.43 mmol) in DCE (16 mL) and DIPEA (1.8 mL, 10.43 mmol). The mixture was stirred at 120 °C for 20 minutes . Water, K2C03 10 % in H20 and DCM were added. The reaction mixture was extracted with DCM (3x). The organic layer was separated, dried over MgS04, filtered and the solvent was evaporated.The residue was purified by preparative LC on irregular SiOH 15-40μιη 300g MERCK. Mobile phase: NH4OH, DCM, MeOH 0.5/96/4. The desired fractions were collected and the solvent was evaporated. Yield: 285 mg of Int. 206.
g) Preparation of Int. 207
Figure imgf000163_0001
TFA (6.6 mL; 85.864 mmol) was added to a solution of Int. 206 (270 mg; 0.417 mmol) in DCM (8 mL) at room temperature. The reaction mixture was stirred for 5 h at room temperature. The solvent was evaporated to give Int. 207 as a brown oil which was used as such in the next reaction step without further purification.
Example A17
a) Preparation of Int. 208
Figure imgf000163_0002
Phenyl formate (10.6 mL; 96.876 mmol) was added to a solution of 3-[[(ter- butyldimethylsilyl)oxy]methyl]aniline (Journal of Medicinal Chemistry (2009), 52(23), 7503-7511) (11.5 g; 48.438 mmol) in DCM (10 mL) at room temperature. The reaction mixture was stirred for 40 minutes at room temperature. The solvent was evaporated. The residue was purified by preparative liquid chromatography on Irregular SiOH 15- 40 μιη 330 g. Mobile phase: 80 % Heptane, 20 % EtOAc. The pure fractions were collected and the solvent removed in vacuo. Yield: 2.7 g (21 %) of Int. 208, and 18.7 g of impure material. The impure material was purified by preparative liquid chromatography on Irregular SiOH 20-45 μιη 45 Og MATREX. Mobile phase: 75 % Heptane, 25 % EtOAc. The pure fractions were collected and the solvent removed in vacuo. Yield: 9.4 g (73 %) of Int. 208.
b) Preparation of Int. 209
Figure imgf000164_0001
The reaction was conducted 5 times on similar quantities of Int. 208 (10 g; 37.675 mmol). NaH (60 % dispersion in mineral oil) (9 g; 226.05 mmol) was added to a solution of Int. 208 (50 g; 188.375 mmol) in DMF (600 mL) at room temperature. The reaction mixture was stirred for 30 minutes and then 2-chloro-4-(6-Chloropyridin-3- yl)pyrimidine (Journal of Organic Chemistry (2002), 67(21), 7541-7543) (42.6 g; 188.375 mmol) was added. The reaction mixture was stirred at room temperature overnight. NaOH 2 N solution in water (60 ml) and MeOH (80 mL) were added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The organic layer was washed with water, dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on Irregular SiOH 20-45 μιη 1000 g DAVISIL. Mobile phase: 70% heptane, 30 % EtOAc). The solvent was evaporated. Yield: 61.7 g of Int. 209 (77 %).
c) Preparation of Int. 311
Figure imgf000164_0002
A mixture of Int. 209 (10 g; 23.42 mmol) and N,N'-dimethyl-l,3-propane diamine
(11.8 mL; 93.67 mmol) was stirred at 135 °C for 1 h. The mixture was evaporated. The residue was purified by preparative liquid chromatography on Irregular SiOH 20-45 μιη 450 g MATREX. Mobile phase: NH4OH, DCM, MeOH 1/90/10. The pure fractions were combined and the solvent evaporated yielding 9.58 g of Int. 311.
Example A18
a) Preparation of Int. 210
Figure imgf000165_0001
A solution of chloroacetyl chloride (1 mL; 12.74 mmol) in ACN (8 mL) was added dropwise to stirred solution of tert-butyl (2R)-2-(2-aminoethyl)-l- pyrrolidinecarboxylate (2.1 g; 9.80 mmol) and Et3N (2.7 mL; 19.60 mmol) in ACN (24 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature. 1-Benzylpiperazine (5.1 mL; 29.40 mmol) was added and the reaction mixture was stirred at 60 °C for 2 h. Water was added and the mixture was extracted with DCM. The organic layer was dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on Irregular SiOH 20-45 μιη 450 g MATREX. Mobile phase: NH4OH, DCM, MeOH 0.5/95/5 The desired fractions were collected and the solvent was evaporated. The oily residue (brown) was purified by preparative liquid chromatography on Irregular SiOH 20-45 μιη 450 g MATREX. Mobile phase: NH4OH, DCM, MeOH 0.5/95/5. The desired fractions were collected and solvent was evaporated. Yield: 3.2 g of Int. 210 (76 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 210:
Figure imgf000166_0001
b) Preparation of Int. 211
Figure imgf000167_0001
TFA (11 mL; 145.85 mmol) was added to a solution of Int. 210 (3.14 g; 7.29 mmol) in DCM (50 mL) at 0-5 °C. The reaction mixture was stirred at room temperature for 4 h. Additional TFA (30 eq.; 16.3 mL; 218.77 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Water and solid K2CO3 were added. The mixture was extracted with DCM, the organic layer was separated, dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on Silica 15-40 μιη, 80 g. Mobile phase: Gradient from DCM, MeOH, NH4OH 95/5/0.1 to DCM, MeOH, NH4OH 90/10/0.1. The desired fractions were collected and the solvent was evaporated. Yield: 1.9 g of Int. 211 (79 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 211 :
Figure imgf000167_0002
c) Preparation of Int. 212
Figure imgf000168_0001
A solution of Int. 209 (500 mg; 1.17 mmol), Int. 211 (697 mg; 2.11 mmol) and K2C03 (809 mg; 5.86 mmol) in DMF (800 μΐ,) were stirred at 100 °C for 18 h. Water and DCM were added. The organic layer was separated dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on irregular SiOH 15-40 μιη 300 g MERCK. Mobile phase: 40 % heptane, 10 % MeOH, 50 % EtOAc. The solvent was evaporated and the residue was purified by preparative liquid chromatography on irregular SiOH 15-40 μιη 300 g MERCK.
Mobile phase: 40 % heptane, 10 % MeOH, 50 % EtOAc. The desired fractions were collected and the solvent was evaporated. Yield: 637 mg of Int. 212 (75 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 212:
Figure imgf000169_0001
d-1) Pre aration of Int. 213
Figure imgf000169_0002
A suspension of Int. 212 (633 mg; 0.88 mmol), tert-butyloxycarbonyl anhydride (230 mg; 1.05 mmol) and Pd/C (10 %) as a catalyst (63 mg) in MeOH (6.5 mL) was hydrogenated under ¾ atmosphere of 5 bars at 50 °C in a sealed vessel for 12 h. The catalyst was filtered off on a pad of Celite®. The Celite® was washed with a mixture of DCM/MeOH (3x). The filtrate was evaporated. The residue was purified by preparative liquid chromatography on Silica 15-40 μιη, 30 g. Mobile phase: Gradient from DCM, MeOH, NH4OH 99/1/0.1 to DCM, MeOH, NH4OH 97/3/0.1. The pure fractions were collected and the solvent was evaporated. Yield: 298 mg of Int. 213 as a yellow oil (46 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 213:
Figure imgf000170_0001
d-2) Preparation of Int. 282
Figure imgf000171_0001
A suspension of Int. 281 (520 mg; 0.72 mmol) and Pd/C (10 %) as a catalyst (50 mg) in MeOH (10 mL) was hydrogenated at 50 °C under 5 bar of t¾ atmosphere in a sealed vessel for 12 h. The catalyst was filtered off on a pad of Celite®. Celite® was washed with a mixture of DCM/MeOH (3x). The filtrate was evaporated to give 472 mg of Int. 282 (oily).
e) Preparation of Int. 214
Figure imgf000171_0002
Tetrabutylammonium fluoride 1M (0.80 mL; 0.80 mmol) was added dropwise to a solution of Int. 213 (292 mg; 0.40 mmol) in THF (5.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. Water was added and the organic solvent was evaporated. The mixture was extracted with DCM. The organic layer was washed with water, dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on irregular
SiOH 15-40 μιη 24 g. Mobile phase: from DCM, MeOH, NH4OH 98/2/0.1 to DCM, MeOH, NH4OH 96/4/0.1). The pure fractions were collected and the solvent was evaporated. Yield: 191 mg of Int. 214 as a yellow oil (78 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 214:
Figure imgf000172_0001
Figure imgf000173_0001
Int. 283 (from Int. 282; used for Int. 284)
f) Preparation of Int. 215
Figure imgf000173_0002
Methanesulfonyl chloride (117 μί; 1.52 mmol) was added dropwise to a solution of Int. 214 (187 mg; 0.30 mmol) and DIPEA (265 μΐ,; 1.52 mmol) in DCM (7.3 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight. Water was added. The mixture was extracted with DCM (2x). The organic layer was dried over MgS04, filtered and the solvent was evaporated. Yield: 303 mg of Int. 215 as an orange oil which was used as such without any purification in the next reaction step.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 215:
Figure imgf000174_0001
Int. 215, 222, 251, 277 and 265 were obtained together with a derivative of these compounds wherein the chloro moiety is replaced by a mesylate moiety. These intermediates were used as mixtures (not quantified) in the next reaction step. g-1) Preparation of Int. 216
Figure imgf000175_0001
Trifluoroacetic acid (3 mL) was added dropwise to a solution of Int. 215 (303 mg; crude) in DCM (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated. The residue was taken up into DCM and the solvent was evaporated (repeated 3 x). Yield: 600 mg of Int. 216 as a yellow oil which used as such without any purification in the next reaction step (synthesis compound 86).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 216:
Figure imgf000175_0002
. 223 (from Int. 222; used for Co. 88)
TFA salt
TFA Int. 278 (from Int. 277; used for compound
93)
salt
Int. 266 (from Int. 265; used for Int. 267)
-2) Preparation of Int. 284
Figure imgf000176_0001
Thionyl chloride (1.65 mL; 22.55 mmol) was added dropwise to a stirred solution of Int. 283 (233 mg; 0.45 mmol) in DCE (54 mL) at room temperature. The reaction mixture was stirred at 60 °C for 18 h. The solvent was evaporated to dryness to give 387 mg of Int. 284 (used for the synthesis of compound 87).
Example A19
a) Preparation of Int. 224
Figure imgf000177_0001
A suspension of 1,1-dimethylethyl (2S,4S)-2-(cyanomethyl)-4-[[(l,l- dimethylethyl)dimethylsilyl]oxy]-l-pyrrolidinecarboxylate (WO/2009026197) (4.59 g; 13.48 mmol), Raney nickel as a catalyst (4.8 g) and Et3N (3.75 mL; 26.96 mmol) in MeOH (25 mL) was hydrogenated overnight under a ¾ atmosphere of 3.5 bar at room temperature in a sealed vessel The catalyst was filtered off on a pad of Celite®. The Celite® was washed with DCM and MeOH (3x). The filtrate was evaporated. The residue was purified by preparative liquid chromatography on Irregular SiOH 20-45 μιη 450 g MATREX. Mobile phaseNH4OH, DCM, MeOH 0.6/90/10. The desired fractions were collected and the solvent was evaporated. Yield: 2.65 g of Int. 224 (57
%).
b) Preparation of Int. 225
See in the table of Example A18.a
c) Preparation of Int. 226
Figure imgf000177_0002
A suspension of Int. 225 (2.47 g; 4.404 mmol) in HC1 5 M (17.6 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with diisopropylether. The precipitate (brownish) was filtered off and was dissolved in a DCM/MeOH mixture. The solution was evaporated (35 °C) to give 2 g of Int. 226.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 226:
Figure imgf000178_0001
d) Preparation of Int. 227
Figure imgf000178_0002
A suspension of Int. 226 (1.9 g; 5.045 mmol), Na2C03 (1.7g; 16.144 mmol) in DMSO (3.8 mL) was stirred at room temperature for 40 minutes. Then Int. 209 (862 mg; 2.018 mmol) was added to the reaction mixture. The solution was stirred at 130 °C for 18 h. Water was added and the mixture was extracted twice with DCM, dried over MgS04, filtered and evaporated. The residue was purified by preparative liquid chromatography on irregular SiOH 15-40 μιη 300 g MERCK. Mobile phase: NH4OH, DCM, MeOH 0.5/95/5. The desired fractions were collected and the solvent was evaporated to give 1 g of Int. 227 (67 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 227: . 239 (from Int. 238; used for Int. 240)
Figure imgf000179_0001
. 247 (from Int. 246; used for Int. 248)
Figure imgf000179_0002
. 261 (from Int. 259; used for Int. 262)
e) Preparation of Int. 228
Figure imgf000179_0003
Acetic anhydride (192 μΐ,; 2 mmol) was added to a solution of Int. 227 (1 g; 1.4 mmol), pyridine (164 μΐ.; 2 mmol) and 4-dimethylaminopyridine (17 mg; 0.14 mmol) in DCM (2.6 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 h. Water was added and the mixture was extracted with DCM (2 x). The organic layer was dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on (Stability Silica 5μιη 150 x 30.0 mm). Mobile phase: Gradient from NH4OH, DCM, MeOH 0/100/0 to NH4OH, DCM, MeOH 0.5/95/5. The pure fractions were combined and the solvent was evaporated. Yield: 492 mg of Int. 228 (46 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 228:
Figure imgf000180_0001
f) Preparation of Int. 229
Figure imgf000181_0001
Tetrabutylammonium fluoride 1M (1.3 mL; 1.3 mmol) was added dropwise to a solution of Int 228 (492 mg; 0.63 mmol) in THF (8 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes and was then stirred at room temperature for 2 h. Water and 10 % NH4C1 aqueous solution were added. The mixture was extracted with DCM. The organic layer was washed with water, dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on Stability Silica 5μιη 150 x 30.0mm. Mobile phase: Gradient from NH4OH, DCM, MeOH 0/100/0 to % NH4OH, DCM, MeOH 0.7/90/10. The desired fractions were collected and the solvent was evaporated. Yield: 476 mg of Int. 229.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 229:
Figure imgf000181_0002
Int. 241 (from Int. 240; used for Int. 242) g) Preparation of Int. 230
Figure imgf000182_0001
A suspension of Int. 229 (476 mg; 0.72 mmol) and Pd/C (10 %) as a catalyst (50 mg) in MeOH (15 mL) was hydrogenated under ¾ atmosphere of 4 bars at 30 °C in a sealed vessel for 12 h. The catalyst was filtered off on a pad of Celite®. The Celite® was washed with a mixture of DCM/MeOH (3x). The filtrate was evaporated. Yield: 398 mg of Int. 230.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 230:
Figure imgf000182_0002
Int. 242 (from Int. 241; used for Int. 243) h) Preparation of Int. 231
Figure imgf000183_0001
Thionyl chloride (2 mL; 28 mmol) was added dropwise to a stirred solution of Int. 230 (350 mg; 0.56 mmol) in DCE (80 mL) at room temperature. The reaction mixture was stirred at 65 °C for 2 h. The solvent was evaporated to dryness. Yield: 393 mg of Int. 231 which was used as such without any purification for the next reaction step.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 231 :
Figure imgf000183_0002
HC1
salt
Int. 243 (from Int. 242; used for Int. 244) i) Pre aration of Int. 232
Figure imgf000184_0001
K2C03 (1.7 g; 12 mmol) was added to a solution of Int. 231 (393 mg) in DMF (130 mL) at room temperature. The reaction mixture was stirred at 50 °C for 18 h. The solvent was evaporated. The residue was taken up into water, extracted twice with DCM, dried over MgS04, filtered and evaporated. The residue was purified by preparative liquid chromatography on irregular 15-40 μιη 30 g Merck. Mobile phase: NH4OH/DCM/MeOH 0.3/97/3. The pure fractions were combined and the solvent was evaporated. Yield: 110 mg of Int. 232.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 232:
Figure imgf000184_0002
Figure imgf000185_0001
Int. 267 (from Int. 266; used for Co. 96)
Example A20
a-1) Preparation of Int. 260
Figure imgf000185_0002
Lithium borohydride (69 mL; 138 mmol; 2 M in THF) was added to a stirred solution of (2S,4S)-4-[[(l , 1 -dimethylethyl)dimethylsilyl]oxy]- 1 ,2-pyrrolidinedicarboxylic acid, l-(l,l-dimethylethyl) 2-methyl ester (32 g, 89 mmol) in THF (58 mL) at 0-5 °C under N2 atmosphere. The reaction mixture was stirred for 12 hours. Ice was added and the mixture was extracted with EtOAc (2 x). The combined organic layers were washed with a 10 % NH4C1 aqueous solution, dried (MgS04), filtered, and the solvent was evaporated. The residue (29.8 g) was dissolved in DMSO (27 mL) and DCM (123 mL) at 0 °C under N2 atmosphere. Et3N (21.5 mL; 154.59 mmol) and then pyridine sulphur trioxide (48-50 %) (19.7 g; 123.67 mmol) were added to the stirred solution under N2 atmosphere. The reaction mixture was stirred at 0 °C for 2 h. EtOAc was added. The mixture was first washed with HC1 0. 5 N and then with brine. Subsequently, the mixture was evaporated. The residue was taken up in Et20/heptane 70/30, washed successively with HC1 1 M and brine, dried (MgS04), filtered and the solvent was evaporated. Yield: 9.76 g of Int. 260 as a colourless oil which was used as such in the next reaction step (preparation of Int. 254).
a-2) Preparation of Int. 233
Figure imgf000186_0001
Et3N (1.9 mL; 13.4 mmol) was added dropwise to a stirred solution of (2i?,4i?)-4-[[(l,l- dimethylethyl)dimethylsilyl]oxy]-2-formyl- 1 -pyrrolidinecarboxylic acid, 1,1- dimethylethyl ester (4.4 g; 13.4 mmol) (Bioorganic & Medicinal Chemistry 10 (2002) 1595-1610) in nitromethane (22 mL) at 0 °C under N2 atmosphere. The reaction mixture was stirred at room temperature for 14 h. The mixture was concentrated and the residue was dissolved in toluene and evaporated three times to give 5.2 g of int. 233 which was used as such without any purification for the next reaction step.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 233:
Figure imgf000186_0002
Int. 254 (from Int. 260; used for Int. 255) b) Preparation of Int. 234
Figure imgf000187_0001
A solution of S0C12(1.3 mL; 17 mmol) in DCM (20 mL) was added dropwise to a stirred solution of Int. 233 (5.2 g) and Et3N (7.4 mL; 53 mmol) in DCM (65 mL) at -78 °C over a period of 10 minutes. The reaction mixture was then stirred for an additional 15 minutes. The solvent was evaporated. The residue was taken up into Heptane/EtOAc (70/30). The precipitate was filtered off and the filtrate was evaporated. The residue was purified by preparative liquid chromatography on Irregular SiOH 20-45 μιη 450 g MATREX). Mobile phase: 70 % Heptane, 30 % EtOAc. The pure fractions were combined and the solvent was evaporated to give 3.1 g of Int. 234.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 234:
Figure imgf000187_0002
Int. 255 (from Int. 254; used for Int. 256) c) Preparation of Int. 235
Figure imgf000188_0001
Distilled water (25 mL) was added to a suspension of NaBH4 (1.6 g; 41.6 mmol) in THF (150 mL) at -20 °C under N2 atmospere. A solution of Int. 234 (3.1 g; 8.3 mmol) in THF (26 mL) was added dropwise at -20 °C over 30 minutes. After an additional 30 minutes, the cold reaction was carefully quenched with HC1 1 N in H20 (30 mL). The reaction mixture was then diluted with EtOAc. The solution was purified by preparative liquid chromatography on irregular SiOH 15-40 μιη 300 g MERCK. Mobile phase: 85 % heptane, 15 % EtOAc). The pure fractions were combined and the solvent was evaporated to give 2.4 g of Int. 235 (77 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 235:
Figure imgf000188_0002
Int. 256 (from Int. 255; used for Int. 257) d) Preparation of Int. 236
Figure imgf000189_0001
A suspension of Int. 235 (2.4 g; 6.4 mmol) and Raney nickel as a catalyst (2.2 g) in EtOH (22 ml) was hydrogenated under t¾ atmosphere of 3.5 bars at room temperature in a sealed vessel The reaction mixture was stirred for 3 h. The catalyst was filtered off on a pad of Celite®. Celite® was washed with DCM and MeOH. The filtrate was evaporated to give 2.28 g of Int. 236.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 236:
Figure imgf000189_0002
Int. 257 (from Int. 256; used for Int. 258)
Example A21
a) Preparation of Int. 268
Figure imgf000190_0001
Benzyl bromide (2.8 mL; 23.61 mmol) was added dropwise to a suspension of 1,4- bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (3 g; 9.08 mmol) and K2CO3 (1.63 g; 11.81 mmol) in DMF (30 mL) at 0 °C under N2 atmosphere. The reaction mixture was stirred at room temperature for 18 h. A portion of the reaction was quenched with water and EtOAc was added. The organic layer was washed with brine, dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative LC (Stability Silica 30-45 μιη, 10 g). Mobile phase: Gradient from 90 % heptane, 10 % EtOAc to 80 % heptane, 20 % EtOAc. The pure fractions were collected and the solvent was evaporated until dryness to give 112 mg of Int. 268 (3 %). Water and EtOAc were added to the remaining reaction mixture. The mixture was extracted with EtOAc (3x). The organic layer was washed with brine, dried over MgS04, filtered and the solvent was evaporated. The residue was taken up in ACN. The precipitate was filtered, washed with ACN and dried to give 2.05 g of Int. 268 (54 %). The filtrate was evaporated and the residue was purified by preparative LC (Stability Silica 30-45 μιη, 10 g. Mobile phase: Gradient from 90 % heptane, 10 % EtOAc to 80 % heptane, 20 % EtOAc. The pure fractions were collected and the solvent was evaporated until dryness to give 1.34 g of a Int. 268 (35 %).
b) Preparation of Int. 269
Figure imgf000190_0002
TFA (6.15 mL; 80.38 mmol) was added to a solution of Int. 268 (3.38 g; 8.04 mmol) in DCM (16 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. A solution of K2CO3 10 % in H20 and DCM were added. The mixture was extracted with DCM (3x). The organic layer was dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative LC on irregular SiOH 15-40 μιη 300 g (MERCK). Mobile phase: Gradient from heptane, MeOH, EtOAc 40/10/50 to NH4OH, DCM, MeOH 0.5/95/5. The desired fractions were collected and the solvent was evaporated. Yield: 315 mg of Int. 269 (12 %).
c) Preparation of Int. 270
Figure imgf000191_0001
A solution of chloroacetyl chloride (85 μί; 1.07 mmol) in ACN (0.8 mL) was added dropwise to a solution of Int. 311 (404 mg; 0.82 mmol) and Et3N (228 μί; 1.64 mmol) in ACN (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 11 h. Int. 269 (315 mg; 0.98 mmol) was added and the reaction mixture was stirred at 60 °C for 13 h. Water was added and the mixture was extracted with
DCM. The organic layer was separated, dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on Stability Silica 5 μιη 150x30.0 mm. Mobile phase: Gradient from NH4OH, DCM, MeOH 0.2/98/2 to NH4OH, DCM, MeOH 1/90/10. The desired fractions were collected and the solvent was evaporated. Yield: 242 mg of Int. 270 (35 %).
d) Preparation of Int. 271
Figure imgf000191_0002
Tetrabutylammonium fluoride 1M (302 μΐ,; 0.30 mmol) was added dropwise to a solution of Int. 270 (234 mg; 0.27 mmol) in THF (2.9 mL) at room temperature. The reaction mixture stirred at room temperature for 3 h. Water was added. THF was evaporated. The mixture was extracted with DCM. The organic layer was washed with water, dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on Stability Silica 5 μιη 150x30.0 mm. Mobile phase: Gradient from NH4OH, DCM, MeOH 0.2/98/2 to NH4OH, DCM, MeOH 1/90/10. The desired fractions were collected and the solvent was evaporated. Yield: 138 mg of Int. 271 (68 %).
e) Preparation of Int. 272
Figure imgf000192_0001
HC1 (4 M in dioxane) (149 μΐ.; 0.60 mmol) was added to a solution of Int. 271 (110 mg; 0.15 mmol) in dioxane (330 μί). The reaction mixture was stirred at 80 °C for 4 h. Water and a solution of K2CO3 10 % in H20 were added. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and the solvent was evaporated. Yield: 86 mg of Int. 272 which was used as such without purification for the next reaction step.
f) Preparation of Int. 273
Figure imgf000192_0002
Thionyl Chloride (491 μί; 6.73 mmol) was added dropwise to a stirred solution of Int. 272 (86 mg) in DCE (16 mL) at room temperature. The reaction mixture was stirred at 60 °C for 4 h. The solvent was evaporated to dryness to give 113 mg of Int. 273 which was used as such without purification for the next reaction step (synthesis of compound
92).
Example A22
a) Preparation of Int. 274
Figure imgf000193_0001
A solution of chloroacetyl chloride (199 μί; 2.50 mmol) in ACN (1.75 mL) was added dropwise to a solution of Int. 311 (949 mg; 1.93 mmol) and Et3N (536 μί; 3.85 mmol) in THF (4.75 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. 4-N-Boc-2-hydroxymethylpiperazine (500 mg; 3.85 mmol) was added and the reaction mixture was stirred at 60 °C for 6 h. Water and a solution of
K2CO3 10 % in H20 were added and the mixture was extracted with DCM. The organic layer was dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on irregular SiOH 15-40 μιη 300 g MERCK. Mobile phase: NH4OH, DCM, MeOH 0.5/95/5. The desired fractions were collected and the solvent was evaporated, yielding Int. 274 in a 68 % yield.
b) Preparation of Int. 275
Figure imgf000193_0002
Acetic anhydride (189 μί; 2 mmol) was added to a solution of Int. 274 (1 g; 1.34 mmol), pyridine (161 μί; 2 mmol) and 4-dimethylaminopyridine (16.3 mg; 0.13 mmol) in DCM (2.6 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 h. Water was added and the mixture was extracted with DCM (2x). The organic layer was dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on Irregular SiOH 20-45 μιη 450 g MATREX. Mobile phase: NH4OH, DCM, MeOH 0.1/97/3. The desired fractions were collected and the solvent was evaporated. Yield: 780 mg Int. 275 as a brown foam (74 %).
Example A23
a) Pre aration of Int. 285
Figure imgf000194_0001
138 mg (3.46 mmol) of a 60 % NaH dispersion in mineral oil was added to a solution of 1.7 g of compound 51 (3.29 mmol) in DMF (25.5 mL) at room temperature under flow of N2-gas. The reaction mixture was stirred for 1 h at room temperature. 2- (Trimethylsylil)ethoxymethyl chloride (611 μί; 3.46 mmol) was added. The reaction mixture was stirred for 1 h at room temperature. Water was added. The precipitate was filtered off, washed with water and dried to give 1.55 g of Int. 285 as an orange solid which was used as such without further purification for the next reaction step. b) Preparation of Int. 286
Figure imgf000195_0001
A 60 %NaH dispersion in mineral oil (65 mg; 1.62 mmol) was added to a solution of Int. 285 (300 mg; 0.46 mmol) in DMF (4.5 mL) at room temperature under N2 gas flow. The reaction mixture was stirred at room temperature for 1 h. Iodomethane (92 μί; 1.48 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water. The precipitate was filtered off, taken up into DCM, dried over MgS04, filtered and the solvent was evaporated to yield 335 mg of Int. 286.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 286:
Figure imgf000195_0002
Int. 287 (from Int. 285 and 4-(2- iodoethyl)morpholine; used for Co. 98) Int. 288 (from Int. 285 and 2-bromoethyl methyl ether; used for Co. 101)
Figure imgf000196_0001
Example A24
a) Preparation of Int.
Figure imgf000196_0002
Methane sulfonyl chloride (121 μΐ,; 1.6 mmol) was added dropwise to a solution of compound 103 (175 mg; 0.3 mmol) and DIPEA (273 μΕ; 1.6 mmol) in DCM (7.6 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Water was added. The mixture was extracted twice with DCM. The organic layer was dried over MgS04, filtered and the solvent was evaporated. Yield: 200 mg of Int. 291 which was used as such without any purification in the preparation of compound 106 (Int. 291 was obtained together with a derivative of the compound wherein the mesylate moiety is replaced by a chloro moiety. Int. 291 was used as a mixture (not quantified) in the next reaction step.) Example A25
a-1) Preparation of Int. 292
Figure imgf000197_0001
A solution of lithium diisopropylamide was freshly prepared via dropwise addition of n-butyllithium (1.6 M solution in hex a ties; 22.7 niL; 36.3 mmol ) to a cold solution of diisopropylamine (5. 1 niL; 36.3 mmol ) in THF (37 ml. ) under N2 atmosphere. This solution was added dropwise to a cold suspension of [(3-nitrophenyl)methyl]triphenyl- phosphonium chloride ( 10.5 g; 24.2 mmol ) in THF (extra dry; 60 ml . ) under N2 atmosphere. The reaction mixture was stirred at room temperature for 45 minutes and then at 50 °C for 30 minutes. The reaction mixture was cooled to 0 °C. A solution of N- benzyl-4-piperidone (4.5 niL; 24.2 mmol ) in THF (extra dry; 23 ml_ ) was added dropwise to this mixture. The reaction mixture was re fluxed for 5 h and was then concentrated to dryness. The residue was purified by chromatography over silica gel eluting with a gradient of EtOAc in heptane from 0 to 60 %. The desired fractions were collected and the solvent was evaporated. Yield: 1 .95 g of Int. 292 (26 %).
a-2) Preparation of Int. 298
Figure imgf000197_0002
7¾/ -butyi dicarbonate (2.24 g; 10.26 mmol ) and 4-( Λ ,Λ'-d i methy lam i no )pyrid i ne (0.125 g; 1 .03 mmol ) were added to a mixture of l-(3-nitrophenyl)-piperazine monohydrochloride (2.5 g; 1 0.26 mmol ) solution in DCM (40 niL) and sodium carbonate 1 M solution in water (20 niL ). The mixture was stirred at room temperature. The organic layer was separated and concentrated and the residue purified by column chromatography cluting with a gradient from 100 % DCM to 100 % DCM/MeOH 9/1. The desired fractions were collected and the solvent was evaporated. Yield: 2.644 g of Int. 298 (84 %).
b) Preparation of Int. 293
Figure imgf000198_0001
Int. 292 (1 g; 3.24 mmol) was dissolved in MeOH (3 mL) and cooled to 0 °C (ice-bath) under N2 atmosphere. Palladium on activated carbon 10 wt. % as a catalyst (0.2 g) was added. The reaction mixture was hydrogenated at room temperature under H2 atmosphere overnight. The suspension was filtered through a pad of Celite® and washed with MeOH. The solvent was evaporated under reduced pressure. The residue was used as such in the next reaction step. Yield: 0.604 g of Int. 293 (98 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 293 :
Figure imgf000198_0002
Int. 299 (from Int. 298; used for Int. 300) c) Preparation of Int. 294
Figure imgf000198_0003
Int. 293 (0.74 g; 3.9 mmol) was dissolved in ACN (10 mL). K2C03 (1.08 g; 7.8 mmol) was added followed by methyl bromoacetate (0.37 mL; 3.9 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by chromatography over silica gel eluting with a gradient from 100 % DCM to 40 % DCM and 60 %
(DCM/MeOH 9/1 v/v). The desired fractions were collected and the solvent was evaporated. Yield: 0.449 g of int 294 (44 %).
d) Preparation of Int. 295
Figure imgf000199_0001
2-Chloro-4-(6-chloro-3-pyridinyl)-pyrimidine (WO 2009112439) (0.773 g; 3.42 mmol), Int. 294 (0.449 g; 1.71 mmol) and p-toluenesulfonic acid monohydrate (0.325 g; 1.71 mmol) were dissolved in a mixture of 1 ,4-dioxane (20 mL) and 2-propanol (5 mL). The reaction mixture was heated at 100 °C overnight. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM/MeOH 10/1 v/v (20 ml) and washed with 1 M NaOH aqueous solution (10 ml). The aqueous phase was extracted again with DCM/MeOH 10/1 v/v ( 20 ml). The combined organic solutions were dried over MgS04, filtered and concentrated to dryness.
The residue was purified by column chromatography over silica gel eluting with a gradient from 100 % DCM to 100 % DCM/MeOH 9/1 v/v. The desired fractions were collected and the solvent was evaporated. Yield: 0.232 g of Int. 295 (15 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 295 :
Figure imgf000199_0002
e) Preparation of Int. 296
Figure imgf000200_0001
N,N -dimethyl- 1, 3 -propanediamine (0.5 mL) was added to Int. 295 (0.232 g; 0.51 mmol). The reaction mixture was heated at 110 °C for 4 h and was then concentrated to dryness. The residue was purified by chromatography over silica gel eluting with DCM/MeOH 5/1, v/v in DCM from 0 to 100%. Yield: 0.162 g Int. 296 (61 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 296:
Figure imgf000200_0002
Int. 301 (from Int. 300 and N,N -dimethyl-1,3- propanediamine; used for Int. 302)
Figure imgf000201_0001
f) Preparation of Int. 302
Figure imgf000201_0002
Sodium bicarbonate saturated solution in water (4 mL) was added to a suspension of Int. 301 ( 0.31 g; 0.58 mmol) in DCM (12 ml) and the mixture was cooled to 0-5 °C in an ice/water bath. A solution of acetyl chloride (0.684 mL; 9.4 mmol) in DCM (5 ml ) was added dropwise over 10 minutes. The mixture was allowed to warm up to room temperature and stirred for 1 h. Water was added and the product was extracted with DCM. The organic layer was separated, dried over MgS04, filtered and concentrated to dryness. Yield: 0.317 g of Int. 302 (60 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 302:
Figure imgf000202_0001
Int. 307 (from Int. 306; used for Int. 308) g) Preparation of Int. 303
Figure imgf000202_0002
A mixture of Int. 302 (0.317 g; 0.55 mmol) in HCl 4 N solution in 1,4-dioxane (5 mL) was stirred at room temperature for 1 h. The crude was concentrated and then dried under high vacuum. NaOH 1 N solution in water was added and the product was extracted with DCM. The organic layer was separated, dried over MgS04, filtered and concentrated to dryness. Yield: 0.262 g of Int. 303 (100 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 303 :
Figure imgf000203_0001
HC1 salt
Int. 308 (from Int. 306; used for Int. 309); mixture was not
basified with a NaOH solution. h) Preparation of Int. 304
Figure imgf000203_0002
Methyl bromoacetate (0.063 mL; 0.66 mmol) and K2C03 (0.084 g; 0.61 mmol) were added to a solution of Int. 303 (0.262 g, 0.55 mmol) in ACN (12 mL) and DMF (2 mL). The reaction mixture was stirred at room temperature. Water was added. The product was extracted with EtOAc. The organic layer was separated, dried over MgS04, filtered, concentrated and purified by column chromatography eluting with a gradient from 100 % DCM to 100 % DCM/MeOH 9/1. The desired fractions were collected and the solvent was evaporated. Yield: 0.298 g of Int. 304 (99 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 304:
Figure imgf000204_0001
i) Preparation of Int. 297
Figure imgf000204_0002
Int. 296 (0.162 g) was dissolved in a mixture of NaOH 1 M solution in water (3 mL), MeOH (0.5 mL) and THF (0.5 mL). The reaction mixture was stirred at room temperature overnight and was then acidified to pH 6.0 by the addition of HC1 1 M solution in water. The reaction mixture was concentrated to dryness. The residue was dried under high vacuum, at room temperature to give 0.312 g of Int. 297 which was used as such in the next reaction step.
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 297:
HC1 salt
HC1 salt Int. 310 (from Int. 309; used for Co. 111)
Int. 305 (from Int. 304; used for Co. 110)
Example A26
a) Preparation of Int. 314
Figure imgf000205_0001
Int. 209 (4.3 g; 10.1 mmol) and 1,3 diaminopropane (7.5 g; lOlmmol) were stirred at 110 °C until complete conversion. NaOH 1 M and H20 were added. The product was filtered and dried to give 3.182 g of Int. 314 (68 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 314:
Figure imgf000206_0001
) Preparation of Int. 315
Figure imgf000206_0002
Int. 314 (3.18 g; 6.85 mmol) and DIPEA(2.5 mL; 13.7 mmol) were added to DCM (40 mL). The mixture was stirred at 0 °C under N2 atmosphere. Then 2- nitrobenzene sulfonyl chloride (1.88 g; 8.22 mmol) was added dropwise and the mixture was allowed to reach room temperature. The reaction mixture was washed with Na2C03 1 M and the water layer was extracted with DCM. The combined organic layers were dried over MgS04, filtered, concentrated and purified by column chromatography over silica gel eluting with a gradient from 100 % DCM to 30 % DCM and 70 %
DCM/MeOH (9/1). The pure fractions were combined and solvent evaporated to yield 2.516 g of Int. 315 (57 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 315:
Figure imgf000207_0001
) Preparation of Int. 316
Figure imgf000207_0002
Methyl bromoacetate (0.483 ml; 5 mmol) was added to a mixture of Int. 315 (2.516 g; 3.87 mmol) and cesium carbonate (2.52 g; 7.74 mmol) in DMF (40 mL). The mixture was stirred at room temperature for 2 h. Then thiophenol (0.593 ml; 5.81 mmol) was added and the reaction mixture was stirred for an additional 30 min. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine and concentrated to dryness. The residue was purified by column chromatography over silica gel eluting with a gradient of MeOH in DCM from 0 to 10 %. The pure fractions were combined and solvent evaporated to yield 1.412 g of Int. 316 (68 %). The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 316:
Figure imgf000208_0001
Int. 323 (from Int. 322; used for Int. 324) d) Preparation of Int. 317
Figure imgf000208_0002
Tert- butyloxycarbonyl anhydride (0.574 g; 2.63 mmol) and DMAP (0.032 g; 0.26 mmol) were added to mixture of Int. 316 (1.412 g; 2.63 mmol) in DCM (25 mL). The mixture was stirred at room temperature until complete conversion. The reaction mixture was concentrated and purified by column chromatography over silica gel eluting with a gradient of 100 % DCM to DCM/MeOH 9/1. The pure fractions were combined and solvent evaporated to yield 1.552 g of Int. 317 (93 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 317:
Int. 324 (from Int. 323; used for Int. 325) e) Preparation of Int. 318
Figure imgf000209_0001
Int. 317 (1.552 g; 2.44 mmol) was dissolved in THF (25 mL).
Tetrabutylammoniumfluoride trihydrate (1.54 g; 4.88 mmol) was added. The reaction mixture was stirred at room temperature for 5 h and was concentrated to dryness. The residue was taken up into water and was extracted with EtOAc. The organic layer was washed with H20 and then with saturated NaCl. The organic layer was dried over MgSC"4, filtered and concentrated to dryness. The residue was purified by
chromatography over silica gel eluting with a gradient from 100 % DCM to 30 % DCM and 70 % DCM/MeOH 9/1, v/v. The pure fractions were combined and solvent evaporated to yield 0.941 g of Int. 318 (74 %). The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 318:
Figure imgf000210_0001
Int. 325 (from Int. 324; used for Int. 326) f) Preparation of Int. 319
Figure imgf000210_0002
Methane sulfonyl chloride (0.3 ml; 3.5 mmol) was added in two portions to a solution Int. 318 (0.941 g; 1.8 mmol) and DIPEA (1.6 ml; 9 mmol) in DMF (15 ml). The reaction mixture was stirred for 30 min. 1-Piperazinecarboxylic acid, 1,1-dimethylethyl ester (0.7 g; 3.6 mmol) was added and the reaction mixture was stirred for 1 h at room temperature and then heated at 80 °C for 1 h. The reaction mixture was concentrated. The reaction mixture was taken up into EtOAc and the organic solution was washed with 1 M Na2C03, brine, dried over MgS04, filtered and concentrated. The residue was purified by column chromatography eluting with a gradient from 100 % DCM to 30 % DCM and 70 % DCM/MeOH (9/1). The pure fractions were combined and solvent evaporated to yield 1.14 g of Int. 319 (92 %).
The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 319:
Figure imgf000211_0001
butyloxycarbonylpiperazine)
Int. 326 (from Int. 325; used for Int. 327) g) Preparation of Int. 320
Figure imgf000211_0002
Int. 319 (1.14 g ; 1.65 mmol) was dissolved in a mixture of NaOH 1 N (17 ml; 16.5 mmol) and THF (4 mL). The reaction mixture was stirred overnight at room temperature. HCl (10 mL; 37 %) was added. The reaction mixture was heated at 40 °C overnight. The reaction mixture was concentrated to dryness and dried under high vacuum, at room temperature. The residue was used as such in the next reaction step. Yield: 0.786 g of Int. 320. The intermediates in the table below were prepared according to an analogous reaction protocol as used for Int. 320:
Figure imgf000212_0001
Example A27
a) Preparation of Int. 328
Figure imgf000212_0002
A saturated sodium hydrogenocarbonate solution in water (30 mL) and tert- butoxycarbonyl anhydride (1.28 g; 5.85 mmol) were added succesively to a solution of 4-(4-nitrobenzylidene)piperidine (WO 2011051282) (1.35 g; 5.32 mmol) in DCM. The mixture was stirred for 1 h and then the phases were separated. The organic layer was dried over MgS04, filtered and concentrated. The residue was purified by
chromatography over silica gel eluting with a gradient of EtOAc in heptane from 0 % to 25 %). The solvent was evaporated to yield 1.358 g of Int. 328 (80 %).
b) Preparation of Int. 329
Figure imgf000213_0001
m-Chloroperoxybenzoic acid (0.81 g; 4.69 mmol) was added to an ice cooled solution of Int. 328 (1.358 g; 4.26 mmol) in chloroform (40 mL). The mixture was stirred overnight at room temperature. DCM was added and the solution was washed with 1 M Na2C03. The organic layer was dried over MgS04, filtered and concentrated. The residue was purified by chromatography over silica gel eluting with a gradient of EtOAc in heptane from 0 % to 35 %. The solvent was evaporated to give 0.72 g of Int. 329 (53 %).
c) Preparation of Int. 330
Figure imgf000213_0002
Palladium (0.25 g) as a catalyst was added to a solution of Int. 329 (0.5 g; 1.49 mmol) was dissolved in MeOH at 0 °C. The reaction mixture was hydrogenated at room temperature under H2 gas atmosphere for 6 h. The catalyst was filtered off through a pad of Celite®. The filtrate was concentrated to an oil and dried under vacuum to yield
0.315 g of Int. 330 (69 %).
d) Preparation of Int. 331
Figure imgf000214_0001
A solution of 2-chloro-4-(6-chloro-3-pyridinyl)-pyrimidine (WO 2009112439) (0.233 g; 1.03 mmol), Int. 330 (0.315 g; 1.03 mmol) and 4-toluenesulfonic acid (0.04 g; 0.206 mmol) were refluxed (110 °C) in 1,4-dioxane (10 mL) for 16 h. The reaction mixture was concentrated, the residue was dissolved in EtOAc and washed with 1 M Na2C03. The organic layer was dried over MgS04, filtered and concentrated. The crude was purified by column chromatography eluting with a gradient of EtOAc in Heptane from 0 % to 50 %. The desired fractions were collected and the solvent was evaporated to give 0.21 g of Int. 331 (41 %).
e) Preparation of Int. 332
Figure imgf000214_0002
A solution of Int. 331 (0.21 g 0.42 mmol) in N,N'-dimethylpropanediamine (0.25 g; 2.12 mmol) was heated at 100 °C for 3 h. The solvent was evaporated and the residue was purified by column chromatography eluting with a gradient from 100 % DCM to 100 % DCM/MeOH (5/1). The desired fractions were collected and the solvent was evaporated to give 0.237 g of Int. 332 (100 %).
f) Preparation of Int. 333
Figure imgf000215_0001
Acetyl chloride (0.035 mL; 0.5 mmol) was added to a solution of Int. 332 (0.23 g; 0.41 mmol) and Et3N (0.14 mL; 1 mmol) in DCM (15 mL). After 2 h the reaction was quenched by addition of 1 M Na2C03 (10 mL). The recation mixture was extracted with DCM (2 x 20 mL). The organic phase was dried over MgS04, filtered and concentrated to dryness. The residue was purified by column chromatography over silica gel eluting with a gradient of MeOH in DCM from 0 to 5 %. The desired fractions were collected and the solvent was evaporated to give 0.179 g of Int. 333 (72 %).
g) Preparation of Int. 334
Figure imgf000215_0002
A suspension of Int. 333 (0.179 g; 0.296 mmol) was taken in 4 N HCl in dioxane (4 mL) and stirred overnight. The mixture was concentrated and the crude Int. 334 was used as such in the next step.
h) Preparation of Int. 335
Figure imgf000216_0001
Int. 334 (crude) was suspended in 4 N HC1 in dioxane (4 mL). Potassium carbonate (0.082 g; 0.5992 mmol) and methyl bromoacetate (0.029 mL; 0.296 mmol) were added and the suspension was stirred overnight. The reaction mixture was concentrated to dryness and the residue was purified by flash column chromatography over silica gel eluting with a gradient of MeOH in DCM from 0 to 10 %. The desired fractions were collected and the solvent was evaporated to yield 0.165 g of Int. 335.
i) Preparation of Int. 336
Figure imgf000216_0002
1 M NaOH (5 mL; 5 mmol) was added to a solution of Int. 335 (0.163 g; 0.283 mmol) in MeOH (1 mL) and THF (1 mL). The mixture stirred for 2 h at room temperature. HC1 (37 %) (1 mL) was added and the mixture was heated at 100 °C for 36 h. The mixture was concentrated to dryness and the crude Int. 336 was used as such in next reaction step.
Example A28
a) Preparation of Int. 337
Figure imgf000217_0001
A mixture of Int. 295 (1.76 g; 3.89 mmol) and 1,3-propanediamine (3.27 mL; 38.9 mmol ) was heated at 100 °C overnight. The reaction mixture was concentrated to dryness. The residue was dried under high vacuum to give 4.34 g of Int. 337 which used as such in the next reaction step.
b) Preparation of Int. 338
Figure imgf000217_0002
A solution of Int. 337 (4.34 g) in HC1 (37 %) (20 mL) was refluxed for 5 days. The reaction mixture was concentrated to dryness. The residue was purified by reverse phase chromatography [ start ( 90 % H20 - 10 % CH3CN - CH3OH ) - end ( 54 % H20 - 46 % CH3CN - CH3OH)] - [H20: 25 mM NH4HC03]. The desired fractions were collected and the solvent was evaporated to give 0.458 g Int. 338 (used in the preparation of compound 115). Example A29
a) Preparation of Int. 380
Figure imgf000217_0003
Methanesulfonyl chloride (1.9 mL; 23.98 mmol) was added dropwise to a solution of Int. 80 (1.5 g; 4.80 mmol), DIPEA (4.2 mL; 23.98 mmol) in DCM (118 mL) at 5°C under N2 flow. The reaction mixture was stirred at 5°C for 15 min. Water and K2CO3 were added. The mixture was extracted with DCM (2x). The organic layer was dried over MgS04, filtered and the solvent was evaporated. The residue was dissolved in DMF (7.6 mL) and was added dropwise to a suspension of 2-methyl-l- piperazinecarboxylic acid, 1,1-dimethylethyl ester (1.22 g; 6.08 mmol) and K2CO3 (2.8 g; 20.26 mmol) in DMF (5.5 mL). The mixture was stirred at r.t. for 30 min. Water and EtOAc were added. The mixture was extracted with EtOAc (3x). The organic layer was dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative LC on (irregular SiOH 15-40μιη 300g Merck). Mobile phase (60%
Heptane, 3% MeOH, 37% EtOAc). The desired fractions were collected and the solvent was evaporated, yielding 1.9 g of Int. 380 as a yellow foam (61 %).
b) Preparation of Int. 381
Figure imgf000218_0001
TFA (4.6 mL; 61.41 mmol) was added to a solution of Int. 380 (1.9 g; 3.07 mmol) in DCM (21 mL) at 0-5°C. The reaction mixture was stirred at r.t. for 4 h. More TFA ( 6.9 mL; 92.12 mmol) was added. The reaction mixture was stirred at r.t. for 2 h The solvent was evaporated. The residue was purified by preparative LC on (Irregular SiOH 20-45μιη 450g MATREX). Mobile phase NH4OH, DCM, MeOH 0.5/93/7. The desired fractions were collected and the solvent was evaporated, yielding 1.22 g of Int. 381 (78 %).
c) Preparation of Int. 382
Figure imgf000218_0002
Et3N ( 327μί; 2.355 mmol) was added portionwise to a stirred solution of Int. 381 (620 mg; 1.57 mmol ) in DCM ( 4.3 mL; 67.51 mmol ) at r.t. The r.m. was stirred for 45 min and was then cooled down to 0-5°C. Tert-butyl bromoacetate (299 μί; 2.041 mmol ) was added and the reaction mixture was stirred at r.t. for 5 h and was then poured into water and extracted with DCM. The organic layer was dried, filtered and evaporated. The residue was purified by preparative LC on (irregular SiOH 15-40μιη 30g
MERCK). Mobile phase: pure DCM to DCM, MeOH, NH4OH 97/3/0.3). The desired fractions were collected and the solvent was evaporated to give 650 mg of Int. 382. d) Preparation of Int. 383
Figure imgf000219_0001
A mixture of Int. 382 (0.63 g; 1.238 mmol) and 1,3-diaminopropane (0.42 mL; 4.95 mmol) in NMP (1.3 mL) in a sealed tube was heated at 110°C using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 90 min [fixed hold time]. The mixture was evaporated to dryness. The residue was purified by preparative LC on (irregular SiOH 15-40μιη 300g MERCK). Mobile phase NH4OH, DCM, MeOH 1/83/17. The desired fractions were collected and the solvent was evaporated to give 270 mg of Int. 383 (40 %).
e) Preparation of Int. 384
Figure imgf000219_0002
HC1 salt
HC1 (37% in H20) (206 μί; 2.469 mmol) and water (0.72 mL) were added to a solution of Int. 383 (270 mg; 0.494 mmol) in 1,4-dioxane (7.2 mL). The reaction mixture was stirred at 100 °C for 3 h .The solution was evaporated under reduced pressure and the residue was used without any further purification for the next reaction step. B. Preparation of the final compounds
Example B 1
a) Preparation of Compound 1
Figure imgf000220_0001
Diethyl cyanophosphonate (0.751 mL, 4.519 mmol) was added to a stirred solution of Int. 11 (1.6 g) and Et3N (6.281 mL, 45.186 mmol) in DMF (100 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was flushed with N2-gas for 15 minutes and then a saturated aqueous NaHC03 solution (q.s.) was added. This mixture was stirred for 10 minutes and then diluted with water and a mixture of 10 % MeOH and 90 % DCM. The organic layer was separated. The water layer was extracted twice with a mixture of 10 % MeOH and 90 % DCM. The combined organic layers were washed with water, dried with MgS04, filtered and the filtrate was evaporated. Yield: 0.92 g of compound 1.
b) Preparation of Compound 14
Figure imgf000220_0002
Diethyl cyanophosphonate (0.185 mL, 1.237 mmol) was added to a solution of Int. 47 (330 mg) and Et3N (0.172 mL, 1.237 mmol) in DMF (45 ml) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure. The residue was stirred in 0.1 M aqueous NaHC03 (50 ml) at room temperature for 2 h. The aqueous layer was decanted. The residue was crystallized from MeOH. The precipitate was filtered off and dried. Yield: 182 mg of compound 14.
c) Preparation of Compound 16
Figure imgf000221_0001
Diethyl cyanophosphonate (0.208 mL, 1.392 mmol) was added to a solution of Int. 49 (251.99 mg) and Et3N (0.194 mL, 1.392 mmol) in DMF (71 ml) at room temperature. The solution was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure. The residue was stirred in 0.1 M aqueous NaHC03 (50 ml) at room temperature for 2 h. The aqueous layer was concentrated to a volume of approximately 10 mL. The solution was purified by Preparative HPLC (Uptisphere CI 8 ODB - 10 μπι, 200 g, 5 cm). Mobile phase (0.25% NH4HC03 solution in water, MeOH). The desired fractions were collected and the solvent was evaporated.
Subsequently, the residue was dissolved in DCM/MeOH and the solvent was evaporated. The residue was dried under vacuum. Yield: 36 mg of compound 16.
Example B2
a) Preparation of Compound 30
Figure imgf000221_0002
Diethylcyanophosphonate (215 μΐ, 1.439 mmol) was added to a solution of Int. 84 (600 mg) and DIPEA (1240 μΐ, 7.197 mmol) in DMF. After addition, the reaction mixture was stirred at 60 °C for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of DCM/MeOH 95/5 and washed with a saturated bicarbonate solution and water. The organic layer was dried with MgS04, filtered and evaporated to dryness. The residue was purified by preparative liquid chromatography on (Stability Silica 5 μιη 150 x 30.0 mm). Mobile phase (Gradient from NH4OH, DCM, MeOH 0.2/98/2 to NH4OH, DCM, MeOH 0.8/92/8). The desired fractions were collected and the solvent was evaporated. Yield: 24 mg of compound 30. Intermediate 379 was prepared according to an analogous protocol as compound 30, starting from Int. 363:
Figure imgf000222_0001
Example B3
a) Preparation of Compound 32
Figure imgf000222_0002
Diethylcyanophosphonate (0.064 mL; 0.43 mmol) in DMF (10 mL) was added dropwise to a solution of Int. 95 (105 mg) and DIPEA (0.25 mL; 1.4 mmol in DMF (110 mL). After addition, the reaction mixture was heated at 100 °C for 4 h. The solvent was evaporated. The residue was purified by chromatography over silica gel [(Irregular SiOH, 20-45μιη, 40g). Mobile phase: gradient from DCM, MeOH, NH4OH 100/0/0 to DCM, MeOH, NH4OH 80/20/0.1. The desired fractions were collected and the solvent as evaporated until dryness to give 90 mg of compound 32.
Example B4
a) Preparation of Compound 34
Figure imgf000222_0003
Diethyl cyanophosphonate (4.377 ml, 29.279 mmol) was added to a solution of Int. 109 (4.495 g) and Et3N (4.075 ml, 29.279 mmol) in DMF (434.8 ml) at room temperature. The reaction mixture was stirred at room temperature for 16 h and was then
concentrated under reduced pressure. The residue was dissolved in water (500 ml). The water layer was basified with a saturated NaHC03 solution (100 ml). The water layer was stirred 1 h at room temperature and was then concentrated under reduced pressure. The residue was co-evaporated with MeOH (2x 150 ml). The residue was purified by flash chromatography on silica gel : eluens DCM/MeOH(NH3) // from 100/0 to 95/5. The pure fractions were collected and concentrated under reduced pressure. The residue was dried under vacuum at 50°C for 16 h. Yield: 3.128 g of compound 34.
Example B5
a) Preparation of Compound 46
Figure imgf000223_0001
Diethyl cyanophosphonate (382 μί; 2.55 mmol) was added drop wise to a solution of Int. 114 (624 mg) and DIPEA (1.47 mL; 8.51 mmol) in DMF (384 mL). After addition, the reaction mixture was heated at 100 °C for 4 h. DMF was evaporated to give 1.34 g of a brown oil. The residue was purified by preparative LC (Irregular SiOH 20-45 μιη 450 g MATREX). Mobile phase: NH4OH, DCM, MeOH 1/93/7. The desired fractions were collected and the solvent was evaporated. Yield: 285 mg of compound 46 as a yellow oil.
Example B6
a) Preparation of Compound 85
Figure imgf000223_0002
Diethyl cyanophosphonate (321 μΕ; 2.147 mmol) was added slowly to a solution of Int. 207 (450 mg; 0.716 mmol) and DIPEA (1.2 mL; 7.155 mmol)in DMF (80 mL).The reaction mixture was stirred at 100 °C for 4 h . The solvent was evaporated. The residue was purified by preparative LC on irregular SiOH 15-40 μιη 300 g MERCK). Mobile phase: NH4OH, DCM, MeOH 0.5/93/7. The desired fractions were collected and the product was further purified by preparative LC on irregular 15-40 μιη 50 g Merck. Mobile phase: NH4OH, DCM, MeOH 0.5/95/5. The desired fractions were collected and the solvent was evaporated. Yield: 21 mg of compound 85 (6 %). Example B7
a) Preparation of Compound 86
Figure imgf000224_0001
K2C03 (1.41 g; 10.17 mmol) was added to a solution of Int. 216 (600 mg) in DMF (55 mL) at room temperature. The reaction mixture was stirred at 50 °C for 3 h. Water and DCM were added. The water layer was separated and extracted with DCM (3x). The combined organic solutions were dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on irregular 15-40 μιη 30 g Merck. Mobile phase: NH4OH, DCM, MeOH 0.5/93/7. The desired fractions were collected and the solvent was evaporated. Yield: 70 mg of a colorless oil. The oil was freeze-dried with water-ACN to give 56 mg of compound 86.
Example B8
a) Pre aration of Compound 97
Figure imgf000224_0002
HC1 (2 N; 4.9 mL, 9.7 mmol) was added to a solution of Int. 286 (335 mg; 0.51 mmol) in EtOH (4.9 mL). The reaction mixture was stirred at 50 °C for 5 h. A solution of aqueous K2C03 10 % and DCM were added. The mixture was extracted twice with DCM. The organic layer was dried with MgS04, filtered and the solvent was evaporated. The residue was purified by preparative LC on silica gel (irregular 15-40 μιη 30 g Merck). Mobile phase: NH4OH, DCM, MeOH 0.1/97/3. The pure fractions were combined and the solvent was evaporated. The residue was crystallised from ACN. The precipitate was filtered off, washed with Et20 and air dried to give 80 mg of compound 97.
Example B9
a) Pre aration of Compound 109
Figure imgf000225_0001
A mixture of Int. 297 (0.312 g; 0.313 mmol) and DIPEA (0.16 mL; 0.94 mmol) dissolved in N,N-dimethylformamide (10 mL) was added dropwise to a solution of 1- [bis(dimethylamino)methylene]-lH-Benzotriazolium-3 -oxide (0.356 g; 0.939 mmol) and DIPEA (0.16 mL; 0.94 mmol) in DMF (20 mL). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc (20 mL) and washed with a Na2C03 1 M solution in water (2 x 10 ml). The organic layer was separated and washed once more with a saturated NaCl solution in water (10 mL). The organic layer was dried over MgS04, filtered and concentrated to dryness. The residue was purified by chromatography over silica gel eluting with a gradient from 100 % DCM to 100 % (DCM/MeOH 9/1 , v/v). The desired fractions were collected and the solvent was evaporated. The residue was crystallized from ACN to give 0.054 g of compound 109 (36 %) as a white solid.
Co. I l l was prepared according to an analogous reaction protocol as B9, but
Amberlyst A-26 (OH) ion exchange resin was used in the work-up procedure.
Example B10
a) Preparation of Compound 112
Figure imgf000226_0001
A solution of DIPEA (0.88 ml; 4.95 mmol) and Int. 320 (0;786 g) in DMF (30 mL) was added dropwise to a solution of HBTU (1.91 g; 4.95 mmol) and DIPEA (0.59 ml; 3.3 mmol) in DMF (30 mL). The mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and taken up into EtOAc and the organic layer was washed with 1 M Na2C03. The organic layer was dried over MgS04, concentrated and purified by column chromatography eluting over silica gel with a gradient from 100 % DCM to 100 % of DCM/MeOH (9/1). The pure fractions were combined and the solvent was evaporated. The product was crystallized from CH3CN to give 0.023 g of compound 112 as a brown solid.
Example B 11
a) Preparation of Compound 114
Figure imgf000226_0002
1 - [Bis(dimethylamino)methylene] - 1 H-benzotriazolium hexafluorophosphate( 1 -) 3 - oxide (0.3 mL) was added to a solution of Int. 336 (0.283 mmol) in DMF (10 mL) and stirred for 15 min at room temperature. The mixture was filtered and the filtrate was added dropwise over 15 min to a solution of of l-[bis(dimethylamino)methylene]-lH- benzotriazolium hexafluorophosphate(l-) 3 -oxide and N-ethyldiisopropylamine (0.2 mL) in DMF (10 mL). The mixture was stirred for 1 h and concentrated to dryness. The residue was partitioned between EtOAc (20 mL) and 1 M Na2C03 (20 mL). The aqueous phase was extracted once more with EtOAc (20 mL). The combined organic layers were dried over MgS04, filtered and concentrated. The residue was purified by chromatography over silica gel eluting with a gradient of MeOH in DCM from 0 to 20 %. The product was recrystallized from hot ACN (4 mL) to give 0.035 g of compound 114.
Co. 115 was prepared according to an analogous reaction protocol as Bl 1, but
Amberlyst A-26 (OH) ion exchange resin was used in the work-up procedure.
Example B12
a) Preparation of Compound 131
Figure imgf000227_0001
Int. 379 (0.13 g; 0.224 mmol) was taken up in TFA (2.5 ml) and stirred at 100 °C for 4 h. The reaction mixture was concentrated to dryness. The residue was taken up in toluene (30 ml) and concentrated again. The residue was partitioned between DCM (20 ml) and saturated NaHCOs (20 ml). The aqueous phase was extracted once more with DCM (20 ml). The combine organic layers were dried over MgS04, filtered and concetrated. The residue was purified by column chromatography over silica gel eluting with a gradient of MeOH in DCM from 0 to 10 %. The desired fractions were collected and evaporated.
Yield: 0.077 g of Compound 131 (70%).
Example B13
a) Preparation of Compounds 68 and 69
Figure imgf000228_0001
Compound 68 Compound 69
A solution of Int. 152 (1.76 g) and DIPEA (8.52 mmol, 1.45 ml ) dissolved in DMF (40 mL) was added dropwise to a solution of HBTU (1.62 g 4.26 mmol) and DIPEA (4.26 mmol, 0.72 ml ) dissolved in DMF (90 ml). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated to dryness. The residue was dissolved in
DCM/MeOH, 7/1, v/v, (2x 50 ml) and washed with 1 M Na2C03 (30 ml). The organic layer was separated, dried over MgS04, filtered and concentrated to dryness. The residue was purified over silica gel eluting with a gradient of from 100 % DCM to 40 % DCM and 60 % DCM/NH3 3.5 N in MeOH, 9/1, v/v. The desired fractions were collected and the solvent was evaporated. The residue was crystallized from MeOH to give a white solid. The residue was purified by reverse phase chromatography [start (72 % H20 - 28 % CH3CN-MeOH) - end ( 36 % H20 - 64%)]-[ H20: 65 mM NH4OAc + CH3CN(90:10)]. Two different product fractions were obtained. The solvent of each fraction was evaporated. Both residues were crystallized from CH3CN. Yield: 0.065 g of Co. 68; and 0.058 g of Co. 69.
Co. 72 was prepared according to an analogous reaction protocol as B13, but
Amberlyst A-26 (OH) ion exchange resin was used in the work-up procedure.
Example B14
a) Preparation of Compound 76
Figure imgf000228_0002
A solution of carbonochloridic acid, 4-nitrophenyl ester (0.068 g, 0.326 mmol) in 1,4 dioxane (25ml) was added to a solution of Int. 165 (0.485 g; 1.086 mmol) and DIPEA (0.58 mL, 3.26 mmol) in 1,4 dioxane (25 ml) at 80 °C. The reaction mixture was heated to reflux (110 °C). 1 M NaOH in H20 (15 ml) was added. The aqueous mixture was extracted with EtOAc (50 ml), dried over MgS04, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel eluting with a gradient from DCM 100 % to 50 % DCM and 50 % (MeOH/DCM 9/1). The desired fraction were collected and the solvent was evaporated. Yield: 0.09 g of compound 76 (2 %).
Compound 130 was prepared by using successively analogous reaction protocols as used for Int. 164, Int. 165 and compound 76, starting from Int. 85 instead of Int. 122 (which was used for the synthesis of Int. 164).
Example B15
a) Preparation of Compound 84
Figure imgf000229_0001
HC1 (4 M in dioxane) (0.0212 mL; 0.0846 mmol) was added to a stirred solution of Int. 191 (10 mg; 0.00846 mmol) in 1,4-dioxane (0.31 mL) at room temperature. The reaction mixture was stirred at 60 °C for 2 h. The solvent was evaporated. DMF (1 mL), Et3N (23.522 μί; 0.169 mmol) and diethylcyanophosphonate (2.811 μ 0.0169 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of water. The product was extracted twice with DCM. The organic layer was washed with water, dried with MgS04, filtered and the filtrate was evaporated. Yield: 29 mg of compound 84.
Example B16
a) Preparation of Compound 89
Figure imgf000230_0001
K2CO3 (82 mg; 0.59 mmol) was added to a suspension of Int. 232 (110 mg; 0.2 mmol) in MeOH (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 h. Water and DCM were added. The mixture was extracted with DCM/MeOH (95/5) (3x). The organic layer was dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on Stability Silica 5 μιη 150x30.0 mm). Mobile phase: Gradient from NH4OH, DCM, MeOH 0.2/98/2 to NH4OH, DCM, MeOH 1.3/87/13. The pure fractions were combined and the solvent was evaporated. The residue was freeze-dried with water/ ACN. Yield: 56 mg of compound 89 (55 %).
Example B17
a) Preparation of Compounds 93 a and 93
Figure imgf000230_0002
Compound 93a Compound 93
K2CO3 (2 g; 14.79 mmol) was added to a solution of int. 278 (1.26 g) in DMF (156 mL) at room temperature. The reaction mixture was stirred at 50 °C for 12 h. Water and DCM were added. The organic layer was separated and washed with water, dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on irregular 15-40 μιη 90 g Merck. Mobile phase: NH4OH, DCM, MeOH 0.1/96/4. The desired fractions were collected and the solvent was evaporated. Yield: 275 mg of compound 93a and 40 mg of compound 93. Example B 18
Figure imgf000231_0001
A mixture of Int. 291 (182 mg; 0.29 mmol) and 1-methylpiperazine (0.43 g; 4.3 mmol) in THF (2.4 mL) in a sealed tube was heated at 90°C using one single mode microwave (Biotage Initiator EXP 60 ) with a power output ranging from 0 to 400 W for 60 min. Subsequently, the solvent was evaporated. The residue was purified by preparative LC on Stability Silica 5μιη 150x30.0mm. Mobile phase: Gradient from NH4OH, DCM, MeOH 0.2/98/2 to NH4OH, DCM, MeOH 1.3/87/13. The pure fractions were combined and the solvent was evaporated. The residue was purified by achiral SFC on 2- ethylpyridine 6 μιη 150 x 21.2mm. Mobile phase: isopropylamine, C02, MeOH.
0.3/85/15. The pure fractions were combined, the solvent was evaporated and the residue was freeze-dried with ACN/water 20/80 to give 52 mg of compound 106.
Co. 107 was prepared according to an analogous reaction protocol as B18, starting from Int. 291 and anhydrous piperazine.
Co. 108 was prepared according to an analogous reaction protocol as B18, starting from Int. 291 and dimethylamine.
Example B19
a) Preparation of Compound 135
Figure imgf000232_0001
Diethyl cyanophosphonate (222 iiL; 1.485 mmol ) was added slowly to a solution of Int. 384 (300 mg) and DIPEA (853 iiL; 4.95 1 mmol ) in DMF (60 mL ). After the addition, the reaction mixture was heated at 100 °C for 4 h .The r.m. was evaporated and the residue was purified by preparative LC on (Stability Silica 5iim 1 50x30.0mm ). Mobile phase (Gradient from NH OH, DCM, MeOH 0.2/98/2 to Η ,ΟΗ, DCM, MeOH 1.3/87/13). The desired fractions were collected and the solvent was evaporated, yielding 72 mg of compound 135.
C. Conversion reactions
Example C I
a) Preparation of Compound 11
Figure imgf000232_0002
Compound 10 (150 mg, 0.164 mmol) was stirred in HC1 (4 M in dioxane) (10.606 mL, 42.422 mmol) at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was co-evaporated twice with 1,4-dioxane (2x50 ml). The residue was stirred in 0.1 M aqueous NaHC03 (50 ml) at room temperature for 2 h. The solution was concentrated to ±10ml volume. The concentrate was purified by Prep HPLC on (RP Vydac Denali C18 - 10 μπι, 200 g, 5 cm). Mobile phase (0.25 %
NH4HC03 solution in water, CH3CN). The desired fractions were collected, evaporated, dissolved in MeOH and evaporated again. Yield: 62 mg of compound 11
(71 %).
Example C2
a) Preparation of Compound 35
Figure imgf000233_0001
Cyclopropylmethyl bromide (0.0318 g, 0.236 mmol) dissolved in 3 ml DMF was added dropwise to compound 34 (0.108 g, 0.236 mmol) and Et3N (0.162 ml, 0.942 mmol) in DMF (15 ml) at 50 °C over 30 min. The reaction mixture was stirred at 70 °C for 16 h and was then concentrated. The residue was purified by Prep HPLC (RP SunFire Prep C18 OBD-10 μιη,30χ150 mm). Mobile phase (0.25% NH4HCO3 solution in water, CH3CN). The desired fractions were collected, evaporated, dissolved in MeOH and evaporated again. Yield: 50 mg of compound 35 (41.4 %).
The compounds in the table below were prepared according to an analogous reaction protocol as used for compound 35, but wherein cyclopropylmethyl bromide is replaced by another startin material (as indicated):
Figure imgf000233_0002
Co. 37 (using homoallyl bromide)
Co. 36 (using propargyl bromide)
Figure imgf000233_0003
Co. 38 (using 2-methylpropyl bromide) Co. 39 (using (tetrahydropyran-4-yl)methyl bromide)
Figure imgf000234_0001
Co. 41 (using 5-chloro-l,l,l-trifluoro-3- (using (RS)-tetrahydrofurfuryl oxapentane)
bromide)
Figure imgf000234_0002
Co. 43 (using 1 -propyl bromide) (using methoxy ethyl chloride)
Figure imgf000234_0003
o. 45 (using allyl bromide) b) Preparation of Com ound 44
Figure imgf000235_0001
Cyclopropanecarbonyl chloride (13.678 mg; 0.131 mmol) was added to compound 34 (50 mg; 0.109 mmol) and DIPEA (0.0752 ml; 0.436 mmol) in DMF (3.5 ml) at room temperature. The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated. The residue was purified by Prep HPLC on (RP SunFire Prep CI 8 OBD-ΙΟμιη, 30x150 mm). Mobile phase (0.25% NH4HCO3 solution in water, CH3CN) The desired fractions were collected and the solvent was evaporated, yielding
Compound 44 (42 mg; 73. 14 %).
The compounds in the table below were prepared according to an analogous reaction protocol as used for compound 44, but wherein cyclopropanecarbonyl chloride is replaced by another starting material (as indicated):
Figure imgf000235_0002
c) Preparation of Compound 134
Figure imgf000236_0001
Sulfamide (157 mg; 163.4 mmol) was added to Compound 34 (50 mg; 0.1 lmmol) in dioxane (3 ml) at room temperature. The reaction mixture was stirred at 80 °C for 4 days. The reaction mixture was concentrated and the residue was purified by Prep
HPLC on (RP Vydac Denali CI 8 - ΙΟμπι, 200g, 5cm). Mobile phase (0.25% NH4HCO3 solution in water, CH3CN), yielding Compound 134 (41 mg; 70%).
Example C3
a) Preparation of Compound 71
Figure imgf000236_0002
Sodium cyanoborohydride (0.087 g, 1.32 mmol) was added to a solution of compound 70 (0.401 g; 0.875 mmol) and formol (0.04 g; 1.32 mmol) in MeOH (15 mL). The mixture was stirred at room temperature until complete conversion. Subsequently, NaOH 1 M in H20 and DCM were added. The organic layer was separated, dried over MgS04, concentrated and purified by column chromatography over silica gel eluting with a gradient of DCM/MeOH (5/1, v/v)/ DCM from 0 % to 100 %. The desired fraction were collected and the solvent was evaporated. The residue was crystallized from CH3CN. Yield: 0.120 g of Compound 71 (29 %).
Compound 129 was prepared according to an analogous reaction protocol as used for Compound 71, starting from compound 128.
Example C4
a) Preparation of Compounds 93, 94 and 95 mixture)
Figure imgf000237_0001
K2CO3 (191 mg; 1.38 mmol) was added to a suspension of compound 93a (257 mg; 0.46 mmol) in MeOH (3.6 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. Water and DCM were added. The mixture was extracted with DCM/MeOH (95/5) (3x). The organic layer was dried over MgS04, filtered and the solvent was evaporated. The residue was purified by preparative liquid chromatography on Stability Silica 5 μιη 150x30.0 mm. Mobile phase: Gradient from NH4OH, DCM, MeOH 0.3/97/3 to NH4OH, DCM, MeOH 1.3/87/13. The desired fractions were collected and the solvent was evaporated. The residue was purified by chiral SFC on CHIRALPAK AD-H 5 μιη 250x20 mm. Mobile phase: isopropylamine, C02, MeOH 0.3/45/55. The desired fractions were collected and the solvent was evaporated, yielding 38 mg of crude compound 94 and 37 mg of crude compound 95. Crude compound 94 was freeze-dried with water/ ACN to give 34 mg of compound 94 (14 %). Crude compound 95 was freeze-dried with water/ ACN to give 20 mg of compound 95 (8 %).
Example C5
a) Preparation of Compounds 24 and 25
Figure imgf000237_0002
Compound 24 Compound 25
Compound 23 (0.3 g; 0.63 mmol) was purified by chiral SFC (CHIRALPAK AD-H 5 μιη 250x20 mm). Mobile phase: iPrNH2, C02, iPrOH 0.3/55/45. The desired fractions were combined and evaporated untill dryness to give 120 mg of compound 25 (40 %; R or S) and 160 mg of a second residue which was taken up into DCM (20 mL) and MeOH (7 mL). Tris-(2-aminoethyl)amine resin was added to the second residue and the mixture was stirred for 12 h. The resin was filtered off. The filtrate was evaporated untill dryness to give 139 mg of residue which was purified by preparative LC
(Stability Silica 5 μιη 150 x 30.0 mm, mobile phase gradient from 95% DCM, 5% MeOH to 90% DCM, 10% MeOH ). The desired fractions were collected and the solvent was evaporated. Yield: 77 mg of compound 24 (25 %).
b) Preparation of Compounds 47 and 48
Figure imgf000238_0001
Compound 47 Compound 48
Compound 46 was purified by chiral SFC (CHIRALPAK AD-H 5 μιη 250x20 mm). Mobile phase: iPrNH2, C02, iPrOH 0.3/55/45. The pure fractions were collected and the solvent was evaporated. Yield: 41 mg of compound 47 (43 %) and 41 mg of compound 48 (43 %).
c) Preparation of Compounds 61 and 62
Figure imgf000238_0002
Compound 61
Compound 60 (229 mg; 0.49 mmol) was purified by chiral SFC (CHIRALPAK AD-H 5μιη 250x20 mm). Mobile phase: iPrNH2, C02, iPrOH 0.3/53/47). The pure fractions were collected and the solvent was evaporated. Yield: 88 mg of an orange oil which was freeze-dried with water/ ACN to give 85 mg of compound 62 as a white powder (37 %); and 102 mg of an orange oil which was freeze-dried with water/ ACN to give 93 mg of a white powder which was taken up in an aqueous K2CO3 solution (10 %) and EtOAc mixture. This mixture was extracted with EtOAc (3 x) and the solvent was evaporated. The residue was freeze-dried with water/ ACN to give 86 mg of compound 61 (37 %).
d) Preparation of Compounds 99 and 100
Figure imgf000239_0001
Compound 98 (70 mg, 0.111 mol) was purified by preparative SFC on Chiralcel Diacel OD 20 x 250 mm. Mobile phase: C02, MeOH with 0.2 % iPrNH2. The desired fractions were collected and the solvent was evaporated. Yield: 32 mg of compound 99 and 32 mg of compound 100.
e) Preparation of Compounds 104 and 105
Figure imgf000239_0002
Compound 103 (170 mg) was purified by preparative SFC on Chiralcel Diacel OD 20 x 250 mm. Mobile phase: C02, MeOH with 0.2 % iPrNH2. The desired fractions were collected and the solvent was evaporated. Yield: 34 mg of compound 104 and 35 mg of compound 105. f) Preparation of Compounds 136 and 137
Figure imgf000240_0001
Compound 136 Compound 137
Compound 135 (72 mg) was purified by chiral SFC on Chiralpak AD-H 5 iim
250x20mm. Mobile phase iPrNH2, C02, EtOH 0.3/50/50. The desired fractions were collected and the solvent was evaporated. The two enantiomers were freeze-dried with water-AC yielding 18mg of Compound 136 and 24mg of Compound 137.
Example C6
a) Preparation of Compound 54
Figure imgf000240_0002
NaH (60 % dispersion in mineral oil) (4.912 mg; 0.123mmol) was added to a solution of Co. 46 (20 mg; 0.0409 mmol) in DMF (1 mL) at room temperature under N2-gas atmosphere. The mixture was stirred for 30 min at room temperature. Then 3- bromopropionitrile (4.088 μί; 0.0491 mmol) was added dropwise. After addition the reaction mixture was stirred for 1 h.
The reaction was quenched by the addition of water. The product was extracted twice with DCM. The organic layer was washed with water, dried with MgS04, filtered and the solvents were evaporated The residue was purified by Prep HPLC on (RP SunFire Prep CI 8 OBD-10 μαι, 30x 150 mm). Mobile phase (0.25 % NH4HCO3 solution in water, ACN). The pure fractions were combined and the solvent was evaporated yielding 7 mg of compound 54.
Analytical Part and Compound Tables
LCMS General procedure The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).
Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time. ..) in order to obtain ions allow ing the identification of the compound's nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental retention times (R,) and ions. If not speci fied differently in the table of data, the reported molecular ion corresponds to the [M+H j (protonated molecule) and/or [M-H]~ (deprotonated molecule ). In case the compound was not directly ionizable the type of adduct is specified ( i.e. [M+NH4]+, [M+HCOO]", etc .). For molecules with multiple isotopic patterns (Br, CI...), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.
Hereinafter, "SQD" means Single Quadrupole Detector, "MSD" Mass Selective Detector, "RT" room temperature, "BEH" bridged ethylsi loxane/si 1 ica hybrid, "DAD" Diode Array Detector, "ELSD" Evaporative Light Scanning Detector.
Table 1 : LCMS Method codes ( Flow expressed in mL/min; column temperature (T) in °C; Run time in minutes).
Figure imgf000241_0001
Figure imgf000242_0001
By using analogous reaction protocols as described in the foregoing examples, the compounds listed in the Tables below have been prepared.
'Co. No.' means compound number.
'Method' refers to the Example number in analogy to which protocol the compound was synthesized. In case no specific stereochemistry is indicated for a stereocenter of a compound, this means that the compound was obtained as a mixture of the R and the S enantiomers.
The values of salt stoichiometry or acid content in the compounds as provided herein, are those obtained experimentally and may vary dependent on the analytical method used (for the compounds in Table 2, Ή NMR and/or elemental analysis was used). In case no salt form is indicated, the compound was obtained as a free base.
Table 2: compounds and physico-chemical data (Co. No. means compound number)
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Melting points (m.p.)
For compound 80, the m.p. was determined with a DSC 1 STAR6 System from Mettler Toledo. The melting point was measured with a temperature gradient of 30°C/minute up to 300 °C. The melting point is given as a peak value: 291.27 °C.
For a number of compounds, melting points were obtained with a Kofler hot bench, consisting of a heated plate with linear temperature gradient, a sliding pointer and a temperature scale in degrees Celsius:
Figure imgf000271_0001
Optical Rotation (OR)
Compound 24: +41.14° (589 nm; 20 °C; 0.333 w/v %; DMF)
Compound 25: -41.56° (589 nm; 20 °C; 0.4115 w/v %; DMF)
Compound 47: +79.35° (589 nm; 20 °C; 0.247 w/v %; DMF)
Compound 48: -81.7° (589 nm; 20 °C; 0.235 w/v %; DMF)
Compound 52: -89.94° (589 nm; 20 °C; 0.218 w/v %; DMF)
Compound 53: +73.77° (589 nm; 20 °C; 0.183 w/v %; DMF)
Compound 61 : -92.16° (589 nm; 20 °C; 0.204 w/v %; DMF)
Compound 62: +95.63° (589 nm; 20 °C; 0.252 w/v %; DMF)
Compound 89: -141.15° (589 nm; 20 °C; 0.2345 w/v %; DMF)
Compound 90: -120.00° (589 nm; 20 °C; 0.265 w/v %; DMF)
Compound 91 : +141.95° (589 nm; 20 °C; 0.174 w/v %; DMF)
Compound 96: +117.91° (589 nm; 20 °C; 0.2205 w/v %; DMF)
SFC-MS
For SFC-MS, an analytical SFC system from Berger Instruments (Newark, DE, USA) was used comprising a dual pump control module (FCM-1200) for delivery of C02 and modifier, a thermal control module for column heating (TCM2100) with temperature control in the range 1-150 °C and column selection valves (Valco, VICI, Houston, TX, USA) for 6 different columns. The photodiode array detector (Agilent 1100,
Waldbronn, Germany) is equipped with a high-pressure flow cell (up to 400 bar) and configured with a CTC LC Mini PAL auto sampler (Leap Technologies, Carrboro, NC , USA). A ZQ mass spectrometer (Waters, Milford, MA, USA) with an orthogonal Z-electrospray interface is coupled with the SFC-system. Instrument control, data collection and processing were performed with an integrated platform consisting of the SFC ProNTo software and Masslynx software.
Co. No. 99-100: SFC-MS was carried out on a OD-H column (250 x 4.6 mm) (Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min. Two mobile phases (mobile phase A: C02; mobile phase B: MeOH containing 0.2 % isopropylamine (iPrNH2)) were employed. 45 % B was hold for 15 min. Column temperature was set at 30°C. Under these conditions, Co. No. 99 had a shorter Rt on the column than Co. No. 100. The measurement was compared against the mixture of the compounds.
Co. No. 94-95: SFC-MS was carried out on a AD-H column (250 x 4.6 mm) (Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min. Two mobile phases (mobile phase A: C02; mobile phase B: MeOH containing 0.3 % iPrNH2) were employed. 60 % B was hold for 11 min. Column temperature was set at 35 °C. Under these conditions, Co. No. 94 had a shorter Rt on the column than Co. No. 95. The measurement was compared against the mixture of the compounds.
Co. No. 136-137: SFC-MS was carried out on a AD-H column (250 x 4.6 mm) (Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min. Two mobile phases (mobile phase A: C02; mobile phase B: EtOH containing 0.3 % iPrNH2) were employed. 60 % B was hold for 7 min. Column temperature was set at 35 °C. Under these conditions, Co. No 136 had a shorter Rt on the column than Co. No 137. The measurement was compared against the mixture of the compounds.
Co. No. 104-105: SFC-MS was carried out on a OD-H column (250 x 4.6 mm) (Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min. Two mobile phases (mobile phase A: C02; mobile phase B: MeOH containing 0.2 % iPrNH2) were employed. 45 % B was hold for 15 min. Column temperature was set at 30°C. Under these conditions, Co. No. 104 had a shorter Rt on the column than Co. No. 105. The measurement was compared against the mixture of the compounds.
NMR
For a number of compounds, 1H NMR spectra were recorded on a Bruker Avance III with a 300 MHz Ultrashield magnet, on a Bruker DPX-400 spectrometer operating at 400 MHz, on a Bruker DPX-360 operating at 360 MHz, on a Bruker Avance 600 spectrometer operating at 600 MHz, or a Bruker Avance 500 III operating at 500 MHz using internal deuterium lock. As solvents CHLOROFORM-<i (deuterated chloroform, CDCI3) or OMSO-d (deuterated DMSO, dimethyl-d6 sulfoxide) were used. Chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as internal standard.
Compound 1
1H NMR (600 MHz, CHLOROFORM- ) δ ppm 1.76 - 1.88 (m, 2 H) 2.66 (br. s., 8 H) 3.10 (s, 3 H) 3.13 - 3.18 (m, 2 H) 3.19 (s, 2 H) 3.25 (s, 3 H) 3.51 (s, 2 H) 3.59 - 3.73 (m, 2 H) 6.41 (d, J=8.8 Hz, 1 H) 6.85 - 6.91 (m, 1 H) 7.02 (d, J=5.3 Hz, 1 H) 7.09 (s, 1 H) 7.11 - 7.16 (m, 1 H) 7.27 - 7.33 (m, 1 H) 7.99 (s, 1 H) 8.08 - 8.16 (m, 1 H) 8.32 (d, J=5.3 Hz, 1 H) 8.91 (br. s., 1 H) + minor rotamer Compound 87
1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (br. s., 1 H) 1.74 - 2.15 (m, 5 H) 2.50 - 2.81 (m, 8 H-partially obscured by solvent peak) 2.88 (d, J=15.4 Hz, 1 H) 2.99 (d, J=15.4 Hz, 1 H) 3.06 - 3.17 (m, 1 H) 3.19 - 3.31 (m, 1 H) 3.34 - 4.15 (m, 5 H-partially obscured by solvent peak) 6.42 (d, J=8.9 Hz, 1 H) 6.98 (d, J=7.6 Hz, 1 H) 7.01 (d, J=7.6 Hz, 1 H) 7.18 - 7.37 (m, 2 H) 7.52 - 8.32 (m, 3 H) 8.38 (d, J=5.4 Hz, 1 H) 8.89 (br. s., 1 H) 9.42 (s, 1 H)
Compound 62
1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (d, J=5.7 Hz, 3 H) 1.50 - 1.69 (m, 2 H) 2.04 - 2.25 (m, 2 H) 2.43 (t, J=10.1 Hz, 1 H) 2.49 - 2.57 (m, 1 H-partially obscured by solvent peak) 2.65 - 2.95 (m, 5 H) 2.98 - 3.14 (m, 3 H) 3.37 - 3.47 (m, 2 H-partially obscured by solvent peak) 4.04 (d, J=l 1.7 Hz, 1 H) 6.45 (d, J=8.8 Hz, 1 H) 6.93 (d, J=7.4 Hz, 1 H) 7.00 (d, J=7.4 Hz, 1 H) 7.16 (d, J=5.0 Hz, 1 H) 7.19 - 7.26 (m, 2 H) 7.64 - 7.78 (m, 1 H) 7.93 -8.07 (m, 2 H) 8.37 (d, J=5.4 Hz, 1 H) 8.95 (br. s., 1 H) 9.41 (s, 1 H)
Compound 53
1H NMR (500 MHz, DMSO-d6) δ ppm 1.53 - 2.21 (m, 4 H) 2.38 - 2.45 (m, 1 H) 2.58 - 3.30 (m, 13 H) 3.34 - 4.17 (m, 7 H-partially obscured by solvent peak) 4.38 - 4.68 (m, 1 H) 6.42 - 7.04 (m, 3 H) 7.11 - 7.32 (m, 2 H) 7.85 - 8.55 (m, 3 H) 8.84 - 9.21 (m, 1 H) 9.38 - 9.54 (m, 1 H)
Compound 47
1H NMR (500 MHz, DMSO-d6) δ ppm 1.48 - 1.81 (m, 2 H) 2.04 - 2.15 (m, 1 H) 2.26 (t, J=9.9 Hz, 1 H) 2.42 - 2.50 (m, 2 H-partially obscured by solvent peak) 2.61 - 2.79 (m, 2 H) 2.85 - 2.99 (m, 3 H) 3.01 - 3.12 (m, 2 H) 3.27 - 3.42 (m, 3 H-partially obscured by solvent peak) 3.49 - 3.55 (m, 1 H) 3.78 - 3.87 (m, 1 H) 4.14 (d, J=12.0 Hz, 1 H) 4.62 (t, J=5.2 Hz, 1 H) 6.45 (d, J=9.1 Hz, 1 H) 6.95 (d, J=7.6 Hz, 1 H) 6.98 (d, J=7.6 Hz, 1 H) 7.16 (d, J=5.4 Hz, 1 H) 7.20 - 7.27 (m, 2 H) 7.66 - 7.83 (m, 1 H) 7.88 - 8.06 (m, 2 H) 8.37 (d, J=5.4 Hz, 1 H) 8.95 (s, 1 H) 9.41 (s, 1 H)
Compound 14
1H NMR (400 MHz, DMSO-d6) δ ppm 1.60 - 1.70 (m, 2 H) 2.54 - 2.61 (m, 4 H) 2.68 - 2.77 (m, 4 H) 2.92 (s, 2 H) 3.20 - 3.28 (m, 2 H) 3.41 - 3.50 (m, 2 H) 3.53 (s, 2 H) 6.50 (d, J=8.9 Hz, 1 H) 6.99 (t, J=6.1 Hz, 1 H) 7.19 (dd, J=8.5, 2.0 Hz, 1 H) 7.23 (d, J=5.2 Hz, 1 H) 7.55 (t, J=5.9 Hz, 1 H) 7.63 (d, J=8.1 Hz, 1 H) 7.97 (dd, J=8.9, 2.4 Hz, 1 H) 8.40 (d, J=2.0 Hz, 1 H) 8.43 (d, J=5.7 Hz, 1 H) 9.00 (d, J=2.0 Hz, 1 H) 9.69 (br. s., 1 H)
Compound 88 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (br. s., 1 H) 1.74 - 2.15 (m, 5 H) 2.50 - 2.81 (m, 8 H-partially obscured by solvent peak) 2.88 (d, J=15.4 Hz, 1 H) 2.99 (d, J=15.4 Hz, 1 H) 3.06 - 3.17 (m, 1 H) 3.19 - 3.31 (m, 1 H) 3.34 - 4.15 (m, 5 H-partially obscured by solvent peak) 6.42 (d, J=8.9 Hz, 1 H) 6.98 (d, J=7.6 Hz, 1 H) 7.01 (d, J=7.6 Hz, 1 H) 7.18 - 7.37 (m, 2 H) 7.52 - 8.32 (m, 3 H) 8.38 (d, J=5.4 Hz, 1 H) 8.89 (br. s., 1 H) 9.42 (s, 1 H)
Compound 91
1H NMR (500 MHz, DMSO-d6) δ ppm 1.20 - 1.41 (m, 1 H) 1.90 - 2.13 (m, 4 H) 2.30 - 2.81 (m, 8 H-partially obscured by solvent peak) 2.88 (d, J=15.4 Hz, 1 H) 2.98 (d, J=15.4 Hz, 1 H) 3.06 - 3.18 (m, 1 H) 3.24 - 3.33 (m, 2 H-partially obscured by solvent peak) 3.44 - 3.54 (m, 1 H) 3.58 - 3.64 (m, 1 H) 3.68 - 4.32 (m, 1 H) 4.36 - 4.47 (m, 1 H) 4.99 (d, J=3.5 Hz, 1 H) 6.42 (d, J=8.8 Hz, 1 H) 6.98 (d, J=7.6 Hz, 1 H) 7.01 (d, J=7.6 Hz, 1 H) 7.16 - 7.41 (m, 2 H) 7.60 - 8.28 (m, 3 H) 8.38 (d, J=5.0 Hz, 1 H) 8.88 (br. s., 1 H) 9.42 (s, 1 H)
Compound 96
1H NMR (500 MHz, DMSO-d6) 5 ppm 1.88 - 2.18 (m, 4 H) 2.31 - 2.81 (m, 8 H- partially obscured by solvent peak) 2.86 (d, J=15.4 Hz, 1 H) 2.99 (d, J=15.4 Hz, 1 H) 3.08 - 3.18 (m, 1 H) 3.20 - 3.30 (m, 1 H) 3.35 - 3.36 (m, 1 H-partially obscured by solvent peak) 3.36 - 3.84 (m, 4 H) 4.39 (br. s., 1 H) 5.05 (br. s., 1 H) 6.42 (d, J=9.1 Hz, 1 H) 6.97 (d, J=7.6 Hz, 1 H) 7.01 (d, J=7.6 Hz, 1 H) 7.21 - 7.32 (m, 2 H) 7.93 (br. s, 1 H) 8.06 - 8.34 (m, 2 H) 8.38 (d, J=5.4 Hz, 1 H) 8.88 (br. s., 1 H) 9.42 (s, 1 H)
Compound 4
1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 - 1.77 (m, 2 H) 2.81 (br. s., 8 H) 3.10 (s, 2 H) 3.19 - 3.28 (m, 2 H) 3.32 - 3.40 (m, 2 H) 3.81 (s, 2 H) 6.42 (d, J=8.9 Hz, 1 H) 7.01 (d, J=5.2 Hz, 1 H) 7.13 (t, J=7.7 Hz, 1 H) 7.16 - 7.23 (m, 1 H) 7.30 - 7.39 (m, 1 H) 7.46 (br. s., 1 H) 7.79 (dd, J=8.9, 2.4 Hz, 1 H) 8.30 (d, J=5.2 Hz, 1 H) 8.56 (d, J=2.0 Hz, 1 H)
Compound 45
1H NMR (360 MHz, DMSO-d6) δ ppm 2.53 - 2.60 (m, 8 H) 2.60 - 2.66 (m, 2 H) 2.96 (s, 2 H) 3.10 (d, J=6.2 Hz, 2 H) 3.23 - 3.33 (m, 2 H) 3.38 (s, 2 H) 3.75 (s, 2 H) 5.14 (dd, J=10.2, 1.8 Hz, 1 H) 5.22 (dd, J=17.2, 1.8 Hz, 1 H) 5.77 - 5.89 (m, 1 H) 6.95 - 7.02 (m, 1 H) 7.02 - 7.09 (m, 1 H) 7.26 (t, J=7.7 Hz, 1 H) 7.51 (d, J=5.1 Hz, 1 H) 7.61 (t, J=4.9 Hz, 1 H) 7.65 (d, J=8.1 Hz, 1 H) 8.12 (t, J=1.5 Hz, 1 H) 8.53 - 8.63 (m, 2 H) 9.20 (d, J=1.8 Hz, 1 H) 9.70 (s, 1 H)
Compound 35
1H NMR (360 MHz, DMSO-d6) δ ppm -0.05 - 0.03 (m, 2 H) 0.29 - 0.38 (m, 2 H) 0.72 - 0.86 (m, 1 H) 2.26 (d, J=7.0 Hz, 2 H) 2.48 - 2.63 (m, 8 H) 2.66 - 2.75 (m, 2 H) 2.92 (s, 2 H) 3.24 - 3.28 (m, 2 H) 3.32 (s, 2 H) 3.73 (s, 2 H) 6.95 (d, J=7.7 Hz, 1 H) 6.97 - 7.03 (m, 1 H) 7.21 (t, J=7.7 Hz, 1 H) 7.46 (d, J=5.1 Hz, 1 H) 7.56 - 7.65 (m, 2 H) 8.06 (t, J=1.6 Hz, 1 H) 8.52 (d, J=5.1 Hz, 1 H) 8.56 (dd, J=8.4, 2.2 Hz, 1 H) 9.13 (d, J=1.8 Hz, 1 H) 9.65 (s, 1 H)
Compound.43
1H NMR (360 MHz, DMSO-d6) δ ppm 0.80 (t, J=7.3 Hz, 3 H) 1.37 (sxt, J=7.2 Hz, 2 H) 2.38 (t, J=7.0 Hz, 2 H) 2.52 - 2.60 (m, 8 H) 2.60 - 2.65 (m, 2 H) 2.96 (s, 2 H) 3.27 - 3.33 (m, 2 H) 3.35 (s, 2 H) 3.70 (s, 2 H) 6.94 - 7.02 (m, 1 H) 7.03 - 7.10 (m, 1 H) 7.22 - 7.31 (m, 1 H) 7.51 (d, J=5.1 Hz, 1 H) 7.56 - 7.67 (m, 2 H) 8.12 (s, 1 H) 8.53 - 8.63 (m, 2 H) 9.19 (d, J=1.8 Hz, 1 H) 9.71 (s, 1 H)
Compound 2
1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 - 1.70 (m, 2 H) 2.52 - 2.60 (m, 4 H) 2.64 - 2.72 (m, 4 H) 2.90 (s, 2 H) 3.17 - 3.24 (m, 2 H) 3.37 - 3.45 (m, 2 H) 3.46 (s, 2 H) 6.47 (d, J=8.9 Hz, 1 H) 6.93 (t, J=6.1 Hz, 1 H) 7.03 (t, J=8.9 Hz, 1 H) 7.06 - 7.10 (m, 1 H) 7.11 (d, J=5.2 Hz, 1 H) 7.54 (t, J=5.9 Hz, 1 H) 7.95 (dd, J=8.9, 2.4 Hz, 1 H) 8.12 (dd, J=6.9, 2.8 Hz, 1 H) 8.35 (d, J=5.2 Hz, 1 H) 8.95 (d, J=2.4 Hz, 1 H) 9.11 (s, 1 H)
Pharmacology
Biochemical EF2 lysate-based kinase assay
LN-229 cells were purchased from ATCC (CRL-2611); these are glioblastoma cells. Cell lysates from LN229 were used in this kinase assay to provide both the kinase and the substrate (EF2). The AlphaLISA p-eEF2 (Thr56) detection assay was developed using a sandwich assay format with two specific antibodies recognizing different epitopes of the target, including one antibody against the phosphorylation site of interest. One anti-eEF2 antibody was conjugated onto AlphaLISA Acceptor beads, while the second antibody was biotinylated and captured by streptavidin coated Donor beads.
Compound was mixed with LN-229 cell lysates in the presence of a kinase buffer (e.g.
2_|_
HEPES) at a pH of 6.6, containing 10 mM Mg (e.g. magnesium acetate) and 10 mM adenosine-tri-phosphate (ATP) and incubated at room temperature for 15 minutes. The kinase reaction was stopped with excess ethylenediaminetetraacetic acid disodium salt and the biotinylated -anti phospho eEF2 antibody (3nM) was added for 1 hour. Then the anti-EF2 acceptor beads (10 μg/ml) as well as the streptavidin coated donor beads (20 μg/ml ) were added for 1 hour, and the AlphaLISA signal was measured in an Envision instrument once, left overnight, and measured again for the final read. EF2 cell-based assay
In this assay, 2.5 mM 2-deoxyglucose was used to deplete intracellular ATP and activate 5' adenosine monophosphate- activated protein kinase (AMPK) in the immortalized epithelial breast cell lines, MCFIOA. MCF 10A cells were purchased from ATCC (CRL-10317). This resulted in a rapid activation of eEF2K and an increase in phosphorylation of EF2 at Thr 56, which was determined using a phospho-specific ELISA (AlphaLISA) as described above in the lysate-based EF2k kinase assay.
MCFIOA cells are seeded at a density of 1.25 x 10 5 Cells/ ml at 100 μΐ /well in a 96- well plate and incubated for 24 hours (37 °C, 5 % C02). Compound is added for 1 hour, and cell are stimulated with 2.5 mM of 2-deoxy-glucose for 4 hours. Medium is then removed, and cells are lysed in an ice-cold buffer M-PER (Thermo Scientific, 78501), containing protease and phosphatase inhibitors. P-EF2 levels are determined in these lysates using the P-EF2 AlphaLISA described above.
Biochemical Vps34 lipid kinase assay
A non-radiometric kinase assay (ADP-Glo™ Assay, Promega, Madison, Wi, USA) was used for measuring the kinase activity of the PIK3C3 lipid kinase. All kinase assays were performed in 96-well half-area microtiter plates in a 25 μΐ reaction volume. The reaction cocktail was pipetted in 3 steps in the following order:
10 μΐ of ATP solution (in assay buffer, see below)
5 μΐ of test sample in 5% DMSO 10 μΐ of enzyme/substrate mixture
All lipid kinase assays contained 50 mM HEPES (4-(2-hydroxyethyl)-l- pi perazi neethanesu 1 ton ic acid ) - NaOH, pH 7.5, 1 mM EGTA ((ethylene glycol tetraacetic acid ), 1 00 mM NaCl, 0.03 % CHAPS ( 3 - [ ( 3 -C h o I a m i d o p ro p y I ) dimethylammonio]-l- prapanesulfonate), 2 mM DTT ( Dithiothreitol ), 20 iiM ATP (corresponding to the apparent ATP-Km), kinase (7.6 iiM ) and substrate (50 uM ). The assay for PI 3C3 additionally contained 3 mM MnCl2.
The reaction cocktails were incubated at 30° C for 60 minutes. The reaction was stopped with 25 μΐ ADP-Glo™ reagent per well. Plates were incubated for 40 minutes at room temperature, followed by addition of 50 μΐ kinase detection reagent per well and incubation for 60 minutes at room temperature. Signal was determined with a microplate luminescence reader (Victor, Perkin Elmer). The assay was either performed using a single dose of compound (1 μΜ final concentration in the assay reaction) with resulting data expressed as residual activity compared to control (DMSO), or using a serial (half-log) dilution of compounds starting at 10 μΜ and down to 0.3 nM (final concentrations in the assay) with data expressed as the pIC50.
The results of the above described assays are shown in tabic 3 :
(pIC5o is -logIC5o where IC5o represents the concentration expressed in M at which the test compound gives 50% inhibition) eEF2K C alphalisa eEF2K C PThr56 VPS34 ImicroM VPS34
Comp No. pIC50 pIC50 % of cntrl pIC50
1 7.12 5.53 5.81
131 6.34 5.12 17.31 6.76
81 5.62 4.74 26.39 6.05
109 5.87 <4.52 14.67 6.54
74 4.69 20.73 6.32
31 6.97 -5.4 8.47 7.06
75 <4.52 <4.52 22.86 5.86
82 6.47 <4.52 10.75 6.39
114 5.35 4.63 30.76
83 5.75 <4.52 3.25 7.16
68 4.70 28.43 6.11
119 6.10 5.30 15.68 6.77
21 5.96 5.06 23.59 6.30
69 <4.52 22.76 5.65
30 4.83 59.71
121 4.75 34.10
79 <4.52 <4.52 24.30 6.22
22 5.14 <4.52 17.27 5.21
128 5.74 4.58 5.81 6.99
110 5.83 <4.52 7.68 6.46
77 5.68 <4.52 6.27 6.89
78 5.92 <4.52 7.48 6.88
125 4.80 <4.52 28.36 6.47
113 5.55 5.35 7.65 6.78
129 6.02 5.03 9.26 6.33
127 5.43 <4.52 19.23 6.45
111 5.35 <4.52 1.43 6.77
70 5.22 <4.52 7.38 7.92
112 5.41 5.13 6.25 7.22
71 5.12 <4.52 11.99 7.76
73 5.74 <4.52 19.57 6.39
72 5.42 <4.52 11.46 6.52
124 <4.52 <4.52 53.23
115 6.67 <4.52 6.01 6.82
76 6.63 8.71 6.46
130 <4.52 <4.52 21.02 6.62 eEF2K C alphalisa eEF2K C PThr56 VPS34 ImicroM VPS34
Comp No. pIC50 pIC50 % of cntrl pIC50
123 5.06 <4.52 23.62 5.41
23 6.30 4.65 7.45 6.82
120 6.76 4.84 7.29 6.92
29 4.76 <4.52 5.67 6.70
118 5.10 <4.52 8.10 6.85
28 -7.26 <4.52 45.63
117 6.46 <4.52 11.72 6.70
67 6.89 5.41 32.12
64 6.14 4.58 64.60
80 6.76 5.26 63.22
20 5.74 <4.52 8.85 6.79
60 6.75 5.56 6.55 7.19
33 6.18 4.67 23.91 6.13
32 6.93 5.29 11.13 6.84
34 6.28 -5.14 6.08
126 6.76 <4.52 4.95 7.12
46 6.78 5.31 3.73 7.57
27 5.53 <4.52 50.67
116 5.11 <4.52 14.00 6.35
85 5.57 <4.52 47.64
56 5.39 5.35 3.19 7.90
7 4.86 <4.52 15.08 6.80
7a 4.86 <4.52 15.08 6.80
9 -5.22 <4.52 8.43 7.01
9a -5.22 <4.52 8.43 7.01
8 4.85 <4.52 41.08
8a 4.85 <4.52 41.08
5 6.12 4.60 7.30 7.16
6 6.18 4.61 17.37 6.60
49 6.41 5.63 37.40
59 6.24 <4.52 3.56 7.41
25 5.54 <4.52 6.36 7.11
24 -6.19 4.96 10.54 6.91
57 5.59 <4.52 6.53
58 6.93 5.68 15.91 6.37
51 6.81 4.81 14.59 6.32
84 6.54 5.06 30.59
54 6.04 <4.52 4.02 7.07
50 6.95 5.31 12.43 6.40
87 7.40 5.70 5.21 6.72
10 6.44 4.89 10.75 6.54
15 6.22 4.56 1.07 7.30
13 6.40 5.17 9.00 7.06
18 5.72 <4.52 23.39 6.04 eEF2K C alphalisa eEF2K C PThr56 VPS34 ImicroM VPS34
Comp No. pIC50 pIC50 % of cntrl pIC50
17 5.96 <4.52 39.48
12 6.68 4.98 7.68 6.36
66 7.11 5.38 6.72 6.85
65 6.78 5.25 10.79 6.48
62 7.11 5.69 166.89
61 5.88 <4.52 6.78 7.35
52 6.04 <4.52 12.80 6.40
53 7.47 <4.52 13.15 6.56
63 6.62 <4.52 16.43 6.49
16 5.69 <4.52 15.94 6.44
19 -5.8 <4.52 87.11
11 6.34 <4.52 33.33
26 4.83 <4.52 5.23 6.99
92 7.05 <4.52 38.27
47 >7.52 5.34 7.88 7.08
48 5.26 <4.52 3.34 7.37
55 6.84 <4.52 6.05
101 6.77 4.69 29.36 6.11
97 6.82 4.65 24.62 6.27
102 7.09 4.83 26.45 6.07
14 7.15 5.12 3.37 6.98
94 7.17 -4.89 14.26 6.48
95 6.08 <4.52 18.78 6.46
136 6.84 -5.07 3.08 7.78
137 5.71 <4.52 8.17 7.09
88 8.11 6.02 17.99 6.19
86 5.31 <4.52 7.25 7.11
98 6.83 4.56 33.92
103 6.71 4.73 28.28 6.17
108 6.68 4.61 25.46 6.28
132 7.16 5.40 7.12 6.72
106 6.52 4.78 36.34
107 6.49 <4.52 32.68
89 -5.2 <4.52 13.56 7.33
91 7.93 5.85 5.29
90 5.03 <4.52 15.81 6.68
96 8.17 5.90 6.88
4 7.08 5.06 29.31 6.32
3 5.78 <4.52 4.43 7.17
2 7.20 5.24 4.44 7.00
104 4.75 <4.52 25.12 6.52
105 7.06 4.75 28.59 6.01
99 5.62 <4.52 5.82
100 7.19 4.83 43.01 eEF2K C alphalisa eEF2K C PThr56 VPS34 ImicroM VPS34
Comp No. pIC50 pIC50 % of cntrl pIC50
45 8.10 6.66 6.78
133 5.59 <5 14.64 6.83
35 8.03 6.88 7.11
36 7.36 5.88 16.04 6.47
37 8.12 6.74 7.02
41 -6.35 5.75 30.81
42 7.49 6.37 10.21 6.52
134 5.89 <5 4.78 7.19
38 8.05 6.73 7.11
39 5.92 5.51 30.67
40 6.87 -6.09 17.70 6.65
43 8.21 6.72 4.32 6.97
44 7.07 5.62 10.20 6.52
Composition examples
"Active ingredient" (a.i.) as used throughout these examples relates to a compound of Formula (I), including any tautomer or stereoisomeric form thereof, or a
pharmaceutically acceptable addition salt or a solvate thereof; in particular to any one of the exemplified compounds.
Typical examples of recipes for the formulation of the invention are as follows:
1. Tablets
Active ingredient 5 to 50 mg
Di-calcium phosphate 20 mg
Lactose 30 mg
Talcum 10 mg
Magnesium stearate 5 mg
Potato starch ad 200 mg
2. Suspension
An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.
3. Injectable
A parenteral composition is prepared by stirring 1.5 % (weight/volume) of active ingredient in 0.9 % NaCl solution or in 10 % by volume propylene glycol in water.
4. Ointment
Active ingredient 5 to 1000 mg
Stearyl alcohol 3 g Lanoline 5 g
White petroleum 15 g
Water ad 100 g
In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.

Claims

Claims
1. A compound of Formula ( I )
Figure imgf000282_0001
a tautomer or a stereoisomeric form thereof, wherein
Xa, Xb and Xc each independently represent CH or N;
-Xi- represents -(CHRi2)s-NRi-Xe-Ci_4alkanediyl-(S02)P3- or
-(CH2)s-0-Xe-Ci_4alkanediyl-(S02)p3-; wherein each of said Ci_4alkanediyl moieties are optionally substituted with hydroxyl or hydroxyCi_4alkyl;
-Xe- represents -C(R2)2- or -C(=0)-;
a represents -NR4-C(=0)-[C(R5b)2]r- or -NR4-C(R5b)2-C(=0)- or -C(=0)-NR4-
C(R5b)2-;
b represents
Figure imgf000282_0002
, wherein said b ring may contain extra bonds to form a bridj ring system selected from 2,5-diazabicyclo[2.2.2]octanyl, 3,8- diazabicyclo[3.2.1 Joctanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,9- diazabicyclo[3.3.1 ]nonyl;
Xdi represents CH or N;
Xd2 represents CH2 or NH;
provided that at least one of Xdi and Xd2 represents nitrogen;
c represents a bond, -[C(R5a)2]m-, -C(=0)-, -0-, -NR5a-, -S02-, or -SO-; A ring represents phenyl or pyridyl;
Ri represents hydrogen, Ci_4alkyl, C2-4alkenyl, C2_4alkynyl, cyanoCi_4alkyl,
-C(=0)-Ci_4alkyl, -C(=0)-haloCi_4alkyl, hydro xyCi_4alkyl, haloCi_4alkyl,
Ci_4alkyloxyCi_4alkyl, haloCi_4alkyloxyCi_4alkyl, -C(=0)NR7R8, -S02-NR7R8, -S02-R9, Rii, Ci_4alkyl substituted with Rn, -C(=0)-Rn, or -C(=0)-Ci_4alkyl-Rn;
each R2 independently represents hydrogen, Ci_4alkyl, Ci_4alkyl substituted with C3_6cycloalkyl, hydroxyCi_4alkyl, Ci_4alkyloxyCi_4alkyl, carboxyl, -C(=0)-0-Ci_4alkyl wherein Ci_4alkyl is optionally substituted with Ci_4alkyloxy, -C(=0)-NH2, -C(=0)- NH(Ci_4alkyl) wherein Ci_4alkyl is optionally substituted with Ci_4alkyloxy, or -C(=0)- N(Ci_4alkyl)2 wherein each Ci_4alkyl is optionally substituted with Ci_4alkyloxy;
or Ri and one R2 are taken together to form Ci_4alkanediyl or C2_4alkenediyl, each of said Ci_4alkanediyl and C2_4alkenediyl optionally being substituted with 1 to 4 substituents each independently selected from hydroxyl, oxo, halo, cyano, N3, hydroxyCi_4alkyl, -NR7R8, -S02-NR7R8, -NH-S02-NR7R8, -C(=0)-NR7R8, or -NH- C(=0)-NR7R8;
or Ri and Ri2 are taken together to form Ci_4alkanediyl or C2_4alkenediyl, each of said Ci_4alkanediyl and C2_4alkenediyl optionally being substituted with 1 to 4 substituents each independently selected from hydroxyl, oxo, halo, cyano, N3, hydroxyCi_4alkyl, -NR7R8, -S02-NR7R8, -NH-S02-NR7R8, -C(=0)-NR7R8, or -NH-C(=0)-NR7R8;
each R3 independently represents hydrogen; oxo; hydroxyl; carboxyl; -NR3aR3b;
-C(=0)-NR3aR3b; hydroxyCi_4alkyl; haloCi_4alkyl; -(C=0)-Ci_4alkyl; -C(=0)-0-Ci_ 4alkyl wherein said Ci_4alkyl may optionally be substituted with phenyl; Ci_4alkyl optionally substituted with cyano, carboxyl, Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, -O- C(=0)-C1_4alkyl, -NR3eR3f, -C(=0)-NR3eR3f, -S02-NR3eR3f, Q, -C(=0)-Q, or -S02-Q; hydroxyCi_4alkyloxyCi_4alkyl; Ci_4alkyloxyhydroxyCi_4alkyl;
hydroxyCi_4alkyloxyhydroxyCi_4alkyl; or Ci_4alkyloxyCi_4alkyl optionally substituted with cyano, carboxyl, Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, -0-C(=0)-Ci_4alkyl, -NR3eR3f, -C(=0)-NR3eR3f, -S02-NR3eR3f, Rio, -C(=O)-R10, or -SO2-R10;
or two R3 substituents attached to the same carbon atom are taken together to form C2_5alkanediyl or -(CH2)p-0-(CH2)p-;
each R3a and R3b independently represent hydrogen; -(C=0)-Ci_4alkyl; -S02-NR3cR3d; or Ci_4alkyl optionally substituted with Ci_4alkyloxy; or R3a and R3b are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 or 2 further heteroatoms selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
each R c and R3d independently represent hydrogen, Ci_4alkyl or -(C=0)-Ci_4alkyl; or R3c and R3d are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 or 2 further heteroatoms selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
each R e and R3f independently represent hydrogen, Ci_4alkyl optionally substituted with Ci_4alkyloxy, -(C=0)-Ci_4alkyl, or -S02-NR3cR3d;
R4 represents hydrogen, Ci_4alkyl or Ci_4alkyloxyCi_4alkyl;
each R5a independently represents hydrogen or Ci_4alkyl; or
two R5a substituents attached to the same carbon atom are taken together to form C2_5alkanediyl or -(CH2)p-0-(CH2)p-;
R5a' represents hydrogen or Ci_4alkyl;
each R5b independently represents hydrogen; Ci_4alkyl; Ci_4alkyl substituted with NR5biR5b2; Ci_4alkyloxyCi_4alkyl; hydroxyCi_4alkyl; hydroxyl; C3_6cycloalkyl; or phenyl optionally substituted with Ci_4alkyl, halo, hydroxyl or Ci_4alkyloxy; or two Rsb substituents attached to the same carbon atom are taken together to form C2_5alkanediyl or -(CH2)p-0-(CH2)p-;
R5bi and R5b2 independently represent hydrogen, Ci_4alkyl optionally substituted with Ci_4alkyloxy, -(C=0)-Ci_4alkyl, or -S02-NR5b R5b4;
R5b3 and R5b4 independently represent hydrogen, Ci_4alkyl or -(C=0)-Ci_4alkyl; or R5b3 and Rsb4 are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 or 2 further heteroatoms selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
each Re independently represents hydrogen, halo, hydroxyl, carboxyl, cyano, Ci_4alkyl, Ci_4alkyloxyCi_4alkyl, hydroxyCi_4alkyl, haloCi_4alkyl, C2_4alkenyl, C2_4alkynyl, -NR6aR6b, or -C(=0)NR6aR6b;
each R6a and R6b independently represent hydrogen or Ci_4alkyl;
each R7 and Rg independently represent hydrogen, Ci_4alkyl, haloCi_4alkyl, or
C3_6cycloalkyl; or R7 and R8 are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 further heteroatom selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
Rg represents Ci_4alkyl, haloCi_4alkyl, or C3_6cycloalkyl;
each Rio independently represents a 4 to 7 membered saturated monocyclic
heterocyclic ring containing up to 2 heteroatoms selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each
independently selected from Ci_4alkyl, halo, hydroxyl or haloCi_4alkyl;
each Rii independently represents C3_6cycloalkyl, phenyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
each Ri2 independently represents hydrogen or Ci_4alkyl;
Q represents a 4 to 7 membered saturated monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl or haloCi_4alkyl;
n represents an integer of value 1 or 2;
m represents an integer of value 1 or 2 ;
p represents an integer of value 1 or 2;
pi represents an integer of value 1 or 2;
each p2 independently represents an integer of value 0, 1 or 2;
r represents an integer of value 0, 1 or 2;
each p3 independently represents an integer of value 0 or 1 ;
each s independently represents an integer of value 0, 1 or 2;
or a N -oxide, a pharmaceutically acceptable addition salt or a solvate thereof.
2. The compound according to claim 1 , wherein
Xa, Xb and Xc each independently represent CH or N;
-Xi- represents -(CHRi2)s-NRi-Xe-Ci_4alkanediyl-(S02)P3- or
-(CH2)s-0-Xe-Ci_4alkanediyl-(S02)P3-; wherein each of said Ci_4alkanediyl moieties are optionally substituted with hydroxyl or hydroxyCi_4alkyl;
-Xe- represents -C(R2)2- or -C(=0)-;
a represents -NR4-C(=0)-[C(R5b)2]r- or -NR4-C(R5b)2-C(=0)-; b represents
Figure imgf000286_0001
Xdi represents CH or N; Xd2 represents NH;
c represents a bond, -[C(R5a)2]m-, -C(=0)-, -S02
ring
Figure imgf000286_0002
phenyl or pyridyl;
Ri represents hydrogen, Ci_4alkyl, C2_4alkenyl, C2_4alkynyl, cyanoCi_4alkyl,
-C(=0)-Ci_4alkyl, -C(=0)-haloCi_4alkyl, hydro xyCi_4alkyl, haloCi_4alkyl,
Ci_4alkyloxyCi_4alkyl, haloCi_4alkyloxyCi_4alkyl, -C(=0)NR7R8, -S02-NR7R8, -S02-R9, Rii, Ci_4alkyl substituted with Rn, -C(=0)-Rn, or -C(=0)-Ci_4alkyl-Rn;
R2 is hydrogen;
or Ri and one R2 are taken together to form Ci_4alkanediyl or C2_4alkenediyl, each of said Ci_4alkanediyl and C2_4alkenediyl optionally being substituted with 1 to 4 hydroxyl substituents;
each R3 independently represents hydrogen; oxo; hydroxyl; carboxyl; -NR3aR3b;
-C(=0)-NR3aR3b; hydroxyCi_4alkyl; haloCi_4alkyl; -(C=0)-Ci_4alkyl;
-C(=0)-0-Ci_4alkyl wherein said Ci_4alkyl may optionally be substituted with phenyl;
Ci_4alkyl optionally substituted with cyano, carboxyl, Ci_4alkyloxy,
-C(=0)-0-Ci_4alkyl, -0-C(=0)-Ci_4alkyl, -NR3eR3f, -C(=0)-NR3eR3f, or -S02-NR3eR3f; hydroxyC i_4alkyloxyC i_4alkyl; C i_4alkyloxyhydroxyCi_4alkyl;
hydroxyCi_4alkyloxyhydroxyCi_4alkyl; or
Ci_4alkyloxyCi_4alkyl optionally substituted with cyano, carboxyl, Ci_4alkyloxy,
-C(=0)-0-Ci_4alkyl, -0-C(=0)-Ci_4alkyl, -NR3eR3f, -C(=0)-NR3eR3f, -S02-NR3eR3f,
Rio, -C(=0)-Rio, or -SO2-Ri0;
each R3a and R3b independently represent hydrogen;
each R3e and R3f independently represent hydrogen, Ci_4alkyl optionally substituted with Ci_4alkyloxy, or -(C=0)-Ci_4alkyl;
R4 represents hydrogen, Ci_4alkyl or Ci_4alkyloxyCi_4alkyl;
each R5a independently represents hydrogen; each R5b independently represents hydrogen; Ci_4alkyl; Ci_4alkyloxyCi_4alkyl;
hydroxyCi_4alkyl; hydroxyl; C3_6cycloalkyl; or phenyl optionally substituted with Ci_4alkyl, halo, hydroxyl or Ci_4alkyloxy;
each Re independently represents hydrogen, halo, hydroxyl, carboxyl, cyano, Ci_4alkyl, Ci_4alkyloxyCi_4alkyl, hydroxyCi_4alkyl, haloCi_4alkyl, C2-4alkenyl, C2_4alkynyl, -NRea sb, or -C(=0)NR6aR6b;
each R6a and R6b independently represent hydrogen or Ci_4alkyl;
each R7 and Rg independently represent hydrogen; or
R7 and Rg are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 further heteroatom selected from N, O or S02, said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
R represents Ci_4alkyl or haloCi_4alkyl;
each Rio independently represents a 4 to 7 membered saturated monocyclic
heterocyclic ring containing up to 2 heteroatoms selected from N or O, said
heterocyclic ring being optionally substituted with 1 to 4 substituents each
independently selected from Ci_4alkyl, halo, hydroxyl or haloCi_4alkyl;
each R11 independently represents C3_6cycloalkyl, phenyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 to 4 substituents each
independently selected from Ci_4alkyl, halo, hydroxyl, or haloCi_4alkyl;
each Ri2 independently represents hydrogen;
n represents an integer of value 1 or 2;
m represents an integer of value 1 or 2 ;
pi represents an integer of value 1 or 2;
each p2 independently represents an integer of value 0, 1 or 2;
r represents an integer of value 1 ;
each p3 independently represents an integer of value 0 or 1 ;
each s independently represents an integer of value 0, 1 or 2.
3. The compound according to claim 1, wherein
Xa is CH or N;
Xb and Xc represent CH;
-Xi- represents -(CHRi2)s-NRi-Xe-Ci_4alkanediyl-(S02)P3- or
-(CH2)s-0-Xe-Ci_4alkanediyl-(S02)P3-; wherein each of said Ci_4alkanediyl moieties are optionally substituted with hydroxyl; -Xe- represents -C(R2)2- or -C(=0)-;
a represents -NR4-C(=0)-[C(R5b)2]r- or -NR4-C(R5b)2-C(=0)-;
b represents
Figure imgf000288_0001
Xdi represents CH or N;
Xd2 represents CH2 or NH;
provided that at least one of Xdi and Xd2 represents nitrogen;
c represents a bond, -[C(R5a)2]m-, -C(=0)-, or -S02-;
ring
Figure imgf000288_0002
phenyl or pyridyl;
Ri represents hydrogen, Ci_4alkyl, C2_4alkenyl, C2_4alkynyl, cyanoCi_4alkyl, -C(=0)- haloCi_4alkyl, Ci_4alkyloxyCi_4alkyl, haloCi_4alkyloxyCi_4alkyl, -S02-NR7R8, -S02-R9, Ci_4alkyl substituted with Rn, or -C(=0)-Rn;
each R2 independently represents hydrogen;
or Ri and one R2 are taken together to form Ci_4alkanediyl optionally being substituted with 1 hydroxyl substituent;
each R3 independently represents hydrogen; oxo; hydroxyl; -C(=0)-NR3aR3b;
hydroxyCi_4alkyl; haloCi_4alkyl; -C(=0)-0-Ci_4alkyl wherein said Ci_4alkyl may optionally be substituted with phenyl; Ci_4alkyl optionally substituted with -0-C(=0)-
Ci_4alkyl; hydroxyCi_4alkyloxyCi_4alkyl; or Ci_4alkyloxyCi_4alkyl optionally substituted with cyano, Ci_4alkyloxy, -NR3eR3f, or Rio;
R3a and R3b represent hydrogen;
R3e and R3f represent Ci_4alkyl;
R4 represents hydrogen, Ci_4alkyl or Ci_4alkyloxyCi_4alkyl;
R5a represents hydrogen;
each R5b independently represents hydrogen; Ci_4alkyl; Ci_4alkyloxyCi_4alkyl;
hydroxyCi_4alkyl; or phenyl;
each ¾ independently represents hydrogen, halo, hydroxyl, carboxyl, cyano, Ci_4alkyl,
Figure imgf000288_0003
each R6a and R6b independently represent hydrogen or Ci_4alkyl; R7 and Rg represent hydrogen;
R9 represents Ci_4alkyl;
each Rio independently represents a 4 to 7 membered saturated monocyclic heterocyclic ring containing up to 2 heteroatoms selected from N or O, said heterocyclic ring being optionally substituted with 1 Ci_4alkyl substituent;
each R11 independently represents C3_6cycloalkyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 oxygen atoms;
each R12 independently represents hydrogen;
n represents an integer of value 1 ;
m represents an integer of value 1 or 2 ;
pi represents an integer of value 1;
each p2 independently represents an integer of value 1 or 2;
r represents an integer of value 0 or 1 ;
each p3 independently represents an integer of value 0;
each s independently represents an integer of value 0 or 1.
4. The compound according to claim 1 , wherein
Xa, Xb and Xc represent CH;
-Xi- represents -(CHRi2)s-NRi-Xe-Ci_4alkanediyl-;
-Xe- represents -C(R2)2-;
a represents -NR4-C(=0)-[C(R5b)2]r- or -NR4-C(R5b)2-C(=0)- b represents
Figure imgf000289_0001
, provided that the linker with the 'a substituent' is present on
Xd2 or is present on a carbon atom in the alpha position of X,
c represents CH2 or a bond.
5. The compound according to claim 1 , wherein
Figure imgf000289_0002
-Xi- represents -CH2-NRi-CH2-Ci_4alkanediyl-, -NRi-CH2-C2-4alkanediyl-, or -Xi- represents one of the following groups wherein -(CH2)2- is attached to 'variable a':
Figure imgf000290_0001
Ri represents Ci_4alkyl, C2-4alkenyl, C2-4alkynyl, Ci_4alkyloxyCi_4alkyl;
a represents -NR4-C(=0)-CH2-;
b represents
Figure imgf000290_0002
;
pi is 1;
R3 represents hydrogen; Ci_4alkyloxyCi_4alkyl optionally substituted with cyano; or hydroxyC i_4alkyloxyC i_4alkyl;
c is CH2; and
R6 represents H.
6. The compound according to claim 1 , wherein if Ri is taken together with one R2, the bond towards the second R2 substituent is oriented as shown hereunder:
Figure imgf000290_0003
7. The compound according to claim 1 , wherein b represents
Figure imgf000290_0004
8. The compound according to claim 1 , wherein
Ri represents hydrogen, Ci_4alkyl, C2-4alkenyl, C2-4alkynyl, cyanoCi_4alkyl,
-C(=0)-Ci_4alkyl, -C(=0)-haloCi_4alkyl, hydro xyCi_4alkyl, haloCi_4alkyl,
Ci_4alkyloxyCi_4alkyl, haloCi_4alkyloxyCi_4alkyl, -C(=0)NR7R8, -S02-NR7R8, -S02-R9, Rii, Ci_4alkyl substituted with Rn, -C(=0)-Rn, or -C(=0)-Ci_4alkyl-Rn;
R2 is hydrogen;
or Ri and one R2 are taken together to form C3_4alkanediyl or C3_4alkenediyl, each of said C3_4alkanediyl and C3_4alkenediyl optionally being substituted with 1 to 4 hydroxyl substituents.
9. The compound according to claim 1 , wherein
a represents - R -C( O )-[C( R5b )?],-·
10. The compound according to claim 1 wherein c is CH2.
1 1. The compound according to any one of claims 1 - 10, wherein Xa, X(, and Xc represent CH.
12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 1 1 .
13. A compound as defined in any one of claims 1 to 1 1 for use as a medicament .
14. A compound as defined in any one of claims 1 to 1 1 for use in the treatment or prevention of a disease or condition selected from cancer, depression, and memory and learning disorders.
15. The compound according to claim 14 wherein the disease or condition is selected from glioblastoma, medulloblastoma, prostate cancer, breast cancer, ovarian cancer and colorectal cancer.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017140843A1 (en) 2016-02-19 2017-08-24 Sprint Bioscience Ab 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes
WO2017140841A1 (en) 2016-02-19 2017-08-24 Sprint Bioscience Ab 6-aryl-4-morpholin-1-ylpyridone compounds useful for the treatment of cancer and diabetes
WO2018177889A1 (en) 2017-03-28 2018-10-04 Bayer Aktiengesellschaft Novel ptefb inhibiting macrocyclic compounds
WO2018177899A1 (en) 2017-03-28 2018-10-04 Bayer Aktiengesellschaft Novel ptefb inhibiting macrocyclic compounds
WO2019038390A1 (en) 2017-08-23 2019-02-28 Sprint Bioscience Ab Morpholinylpyridone compounds
WO2019038389A1 (en) 2017-08-23 2019-02-28 Sprint Bioscience Ab Pyridinamine-pyridone and pyrimidinamine-pyridone compounds
WO2019038384A1 (en) 2017-08-23 2019-02-28 Sprint Bioscience Ab Azaindolylpyridone and diazaindolylpyridone compounds
WO2019038387A1 (en) 2017-08-23 2019-02-28 Sprint Bioscience Ab Pyridylpyridone compounds

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115551868A (en) * 2020-02-18 2022-12-30 特修斯制药公司 Macrocyclic compounds and uses thereof
CN113735856A (en) * 2020-05-29 2021-12-03 百极弘烨(南通)医药科技有限公司 Macrocyclic JAK inhibitors and uses thereof
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WO2024078263A1 (en) * 2022-10-09 2024-04-18 药雅科技(上海)有限公司 Preparation and use of macrocyclic heterocyclic compound as egfr inhibitor

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084898A1 (en) 2003-03-24 2004-10-07 Actimis Pharmaceuticals, Inc. 2-phenoxy- and 2-phenylsulfomamide derivatives with ccr3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders
WO2004105765A1 (en) 2003-05-27 2004-12-09 Janssen Pharmaceutica N.V. Macrocyclic quinazoline derivatives as antiproliferative agents
WO2005058913A1 (en) 2003-12-18 2005-06-30 Janssen Pharmaceutica N.V. Pyrido- and pyrimidopyrimidine derivatives as anti- proliferative agents
WO2005058318A1 (en) 2003-12-18 2005-06-30 Janssen Pharmaceutica N.V. 3-cyano-quinoline derivatives with antiproliferative activity
WO2006061415A1 (en) 2004-12-08 2006-06-15 Janssen Pharmaceutica N.V. 2,4 (4,6) pyrimidine derivatives
WO2006061417A2 (en) 2004-12-08 2006-06-15 Janssen Pharmaceutica N.V. Macrocyclic quinazole derivatives and their use as mtki
WO2007003525A2 (en) 2005-06-30 2007-01-11 Janssen Pharmaceutica N.V. Cyclic anilino-pyridinotriazines as gsk-3 inhibitors
WO2008155421A2 (en) 2007-06-21 2008-12-24 Janssen Pharmaceutica Nv Indolin-2-ones and aza-indolin-2-ones
WO2009016132A1 (en) 2007-07-27 2009-02-05 Janssen Pharmaceutica Nv Pyrrolopyrimidines
WO2009026197A1 (en) 2007-08-20 2009-02-26 Glaxo Group Limited Novel cathepsin c inhibitors and their use
WO2009112439A1 (en) 2008-03-10 2009-09-17 Janssen Pharmaceutica Nv 4-aryl-2-anilino-pyrimidines as plk kinase inhibitors
WO2011008788A1 (en) 2009-07-14 2011-01-20 Dawei Zhang Fluoro-substituted compounds as kinase inhibitors and methods of use thereof
WO2011051282A1 (en) 2009-10-27 2011-05-05 N.V. Organon (1,1, 1,3, 3, 3-hexafluoro-2-hydroxypropan-2-yl) phenyl derivatives, pharmaceutical compositions thereof and their use for the treatment of atherosclerosis

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078682A2 (en) * 2003-03-05 2004-09-16 Irm Llc Cyclic compounds and compositions as protein kinase inhibitors
US8143255B2 (en) * 2005-11-16 2012-03-27 S*Bio Pte Ltd. Heteroalkyl linked pyrimidine derivatives
EP1961149B1 (en) 2005-11-24 2018-08-08 Synchronica plc Method for securely associating data with http and https sessions
KR20110031318A (en) 2008-06-13 2011-03-25 노파르티스 아게 2,4'-bipyridinyl compounds as protein kinase d inhibitors useful for the treatment of ia heart failure and cancer
BRPI1011612A2 (en) 2009-05-28 2019-09-24 Tetralogic Pharm Corp compound, pharmaceutical composition, and methods for inducing apoptosis in a cell, for treating cancer, and for treating an autoimmune disease.

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084898A1 (en) 2003-03-24 2004-10-07 Actimis Pharmaceuticals, Inc. 2-phenoxy- and 2-phenylsulfomamide derivatives with ccr3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders
WO2004105765A1 (en) 2003-05-27 2004-12-09 Janssen Pharmaceutica N.V. Macrocyclic quinazoline derivatives as antiproliferative agents
WO2005058913A1 (en) 2003-12-18 2005-06-30 Janssen Pharmaceutica N.V. Pyrido- and pyrimidopyrimidine derivatives as anti- proliferative agents
WO2005058318A1 (en) 2003-12-18 2005-06-30 Janssen Pharmaceutica N.V. 3-cyano-quinoline derivatives with antiproliferative activity
WO2006061415A1 (en) 2004-12-08 2006-06-15 Janssen Pharmaceutica N.V. 2,4 (4,6) pyrimidine derivatives
WO2006061417A2 (en) 2004-12-08 2006-06-15 Janssen Pharmaceutica N.V. Macrocyclic quinazole derivatives and their use as mtki
WO2007003525A2 (en) 2005-06-30 2007-01-11 Janssen Pharmaceutica N.V. Cyclic anilino-pyridinotriazines as gsk-3 inhibitors
WO2008155421A2 (en) 2007-06-21 2008-12-24 Janssen Pharmaceutica Nv Indolin-2-ones and aza-indolin-2-ones
WO2009016132A1 (en) 2007-07-27 2009-02-05 Janssen Pharmaceutica Nv Pyrrolopyrimidines
WO2009026197A1 (en) 2007-08-20 2009-02-26 Glaxo Group Limited Novel cathepsin c inhibitors and their use
WO2009112439A1 (en) 2008-03-10 2009-09-17 Janssen Pharmaceutica Nv 4-aryl-2-anilino-pyrimidines as plk kinase inhibitors
WO2011008788A1 (en) 2009-07-14 2011-01-20 Dawei Zhang Fluoro-substituted compounds as kinase inhibitors and methods of use thereof
WO2011051282A1 (en) 2009-10-27 2011-05-05 N.V. Organon (1,1, 1,3, 3, 3-hexafluoro-2-hydroxypropan-2-yl) phenyl derivatives, pharmaceutical compositions thereof and their use for the treatment of atherosclerosis

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
AMARAVADI ET AL., CLIN CANCER RES., vol. 17, 2011, pages 654 - 666
ANDERS POULSEN ET AL: "Structure-based design of nitrogen-linked macrocyclic kinase inhibitors leading to the clinical candidate SB1317/TG02, a potent inhibitor of cyclin dependant kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3)", JOURNAL OF MOLECULAR MODELING, SPRINGER, DE, vol. 19, no. 1, 22 July 2012 (2012-07-22), pages 119 - 130, XP035158034, ISSN: 0948-5023, DOI: 10.1007/S00894-012-1528-7 *
ASHWINI K. DEVKOTA ET AL: "Investigating the Kinetic Mechanism of Inhibition of Elongation Factor 2 Kinase by NH125: Evidence of a Common in Vitro Artifact", BIOCHEMISTRY, vol. 51, no. 10, 13 March 2012 (2012-03-13), pages 2100 - 2112, XP055121644, ISSN: 0006-2960, DOI: 10.1021/bi201787p *
BEN-ZVI ET AL., CLIN REV ALLERGY IMMUNOL., vol. 42, no. 2, 2012, pages 145 - 53
BIOORGANIC & MEDICINAL CHEMISTRY, vol. 10, 2002, pages 1595 - 1610
BROWNE ET AL., EUR J BIOCHEM., vol. 269, no. 22, 2002, pages 5360 - 5368
BURGER ET AL., MEDICINAL CHEMISTRY LETTERS, vol. 2, no. 1, 2011, pages 34 - 38
HAIT ET AL., CLIN CANCER RES., vol. 12, 2006, pages 1961 - 1965
JIN ET AL., J CELL SCI., vol. 120, no. 3, 2007, pages 379 - 83
JOURNAL OF ANTIBIOTICS, vol. 37, no. 5, 1984, pages 532 - 45
JOURNAL OF MEDICINAL CHEMISTRY, vol. 37, no. 9, 1994, pages 1362 - 70
JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, no. 23, 2009, pages 7503 - 7511
JOURNAL OF ORGANIC CHEMISTRY, vol. 67, no. 21, 2002, pages 7541 - 7543
KAVALALI ET AL., AM J PSYCHIATRY, vol. 169, no. 11, 2012, pages 1150 - 1156
LEPRIVIER ET AL., CELL, vol. 153, no. 5, 2013, pages 1064 - 1079
MAIURI ET AL., CELL DEATH DIFFER., vol. 16, no. 1, 2009, pages 87 - 93

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* Cited by examiner, † Cited by third party
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