WO2008002244A2 - Imidazol-pyrimidine derivatives for treatment of diseases related to glycogen synthase kinase (gsk3) - Google Patents

Imidazol-pyrimidine derivatives for treatment of diseases related to glycogen synthase kinase (gsk3) Download PDF

Info

Publication number
WO2008002244A2
WO2008002244A2 PCT/SE2007/000620 SE2007000620W WO2008002244A2 WO 2008002244 A2 WO2008002244 A2 WO 2008002244A2 SE 2007000620 W SE2007000620 W SE 2007000620W WO 2008002244 A2 WO2008002244 A2 WO 2008002244A2
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
imidazol
fluoro
pyrimidin
amino
Prior art date
Application number
PCT/SE2007/000620
Other languages
French (fr)
Other versions
WO2008002244A8 (en
WO2008002244A3 (en
Inventor
Jeremy Burrows
Fernando Huerta
Fredrik Lake
Torben Pedersen
Tobias Rein
Didier Rotticci
Karin Staaf
Ulrika Yngve
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=38846127&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2008002244(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to CA002655441A priority Critical patent/CA2655441A1/en
Priority to MX2008015720A priority patent/MX2008015720A/en
Priority to AU2007265731A priority patent/AU2007265731A1/en
Priority to JP2009518044A priority patent/JP2009542638A/en
Priority to EP07748281A priority patent/EP2046782A4/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to BRPI0713576-9A priority patent/BRPI0713576A2/en
Publication of WO2008002244A2 publication Critical patent/WO2008002244A2/en
Publication of WO2008002244A3 publication Critical patent/WO2008002244A3/en
Publication of WO2008002244A8 publication Critical patent/WO2008002244A8/en
Priority to IL195666A priority patent/IL195666A0/en
Priority to NO20090327A priority patent/NO20090327L/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to new compounds of formula (I), as a free base or a pharmaceutically acceptable salt thereof, to pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
  • the present invention further relates to a process for the preparation of compounds of formula (I) and to new intermediates used therein.
  • Glycogen synthase kinase 3 is a serine / threonine protein kinase composed of two isoforms ( ⁇ and ⁇ ), which are encoded by distinct genes but are highly homologous within the catalytic domain. GSK3 is highly expressed in the central and peripheral nervous system. GSK3 phosphorylates several substrates including tau, ⁇ -catenin, glycogen synthase, pyruvate dehydrogenase and elongation initiation factor 2b (eIF2b). Insulin and growth factors activate protein kinase B, which phosphorylates GSK.3 on serine 9 residue and inactivates it.
  • eIF2b elongation initiation factor 2b
  • AD dementias Alzheimer's Disease (AD) dementias, and taupathies AD is characterized by cognitive decline, cholinergic dysfunction and neuronal death, neurofibrillary tangles and senile plaques consisting of amyloid- ⁇ deposits.
  • Glycogen synthase kinase 3 ⁇ (GSK3 ⁇ ) or Tau phosphorylating kinase selectively phosphorylates the microtubule associated protein Tau in neurons at sites that are hyperphosphorylated in AD brains.
  • Hyperphosphorylated tau has lower affinity for microtubules and accumulates as paired helical filaments, which are the main components that constitute neurofibrillary tangles and neuropil threads in AD brains.
  • Neurofibrillary tangles are consistently found in diseases such as AD, amyotrophic lateral sclerosis, parkinsonism- dementia of Gaum, corticobasal degeneration, dementia pugilistica and head trauma, Down's syndrome, postencephalatic parkinsonism, progressive supranuclear palsy, Niemann-Pick's Disease and Pick's Disease.
  • GSK3 ⁇ preferentially labels neurofibrillary tangles and has been shown to be active in pre-tangle neurons in AD brains. GSK3 protein levels are also increased by 50% in brain tissue from AD patients.
  • GSK3 ⁇ phosphorylates pyruvate dehydrogenase, a key enzyme in the glycolytic pathway and prevents the conversion of pyruvate to acetyl-Co-A (Hoshi et al., PNAS 1996, 93: 2719-2723).
  • Acetyl-Co-A is critical for the synthesis of acetylcholine, a neurotransmitter with cognitive functions.
  • Accumulation of amyloid- ⁇ is an early event in AD.
  • GSK Tg mice show increased levels of amyloid- ⁇ in brain.
  • PDAPP mice fed with Lithium show decreased amyloid- ⁇ levels in hippocampus and decreased amyloid plaque area (Su et al., Biochemistry 2004, 43: 6899-6908).
  • GSK3 ⁇ inhibition may have beneficial effects in progression as well as the cognitive deficits associated with Alzheimer's disease and other above-referred to diseases.
  • GSK3 ⁇ activity is increased in cellular and animal models of neurodegeneration such as cerebral ischemia or after growth factor deprivation.
  • the active site phosphorylation was increased in neurons vulnerable to apoptosis, a type of cell death commonly thought to occur in chronic and acute degenerative diseases such as cognitive disorders, Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, Huntington's Disease and HIV dementia and traumatic brain injury; and as in ischemic stroke.
  • Lithium was neuroprotective in inhibiting apoptosis in cells and in the brain at doses that resulted in the inhibition of GSK3 ⁇ .
  • GSK3 ⁇ inhibitors could be useful in attenuating the course of neurodegenerative diseases.
  • Bipolar Disorders (BD) BD
  • Bipolar Disorders are characterised by manic episodes and depressive episodes. Lithium has been used to treat BD based on its mood stabilising effects. The disadvantage of lithium is the narrow therapeutic window and the danger of overdosing that can lead to lithium intoxication. The discovery that lithium inhibits GSK3 at therapeutic concentrations has raised the possibility that this enzyme represents a key target of lithium's action in the brain (Stambolic et al., Curr. Biol. 1996, 68(12):1664-1668, 1996; Klein and Melton; PNAS 1996, 93:8455-8459; Gould et al., Neuropsychopharmacology, 2005, 30:1223-1237).
  • GSK3 inhibitor has been shown to reduce immobilisation time in forced swim test, a model to assess on depressive behavior (O'Brien et al., J Neurosci 2004, 24(30): 6791-6798).
  • GSK3 has been associated with a polymorphism found in bipolar II disorder (Szczepankiewicz et al., Neuropsychobiology. 2006, 53: 51-56). Inhibition of GSK3 ⁇ may therefore be of therapeutic relevance in the treatment of BD as well as in AD patients that have affective disorders.
  • GSK3 is involved in signal transduction cascades of multiple cellular processes, particularly during neural development.
  • GSK3 ⁇ levels were 41% lower in the schizophrenic patients than in comparison subjects.
  • This study indicates that schizophrenia involves neurodevelopmental pathology and that abnormal GSK3 regulation could play a role in schizophrenia.
  • reduced ⁇ -catenin levels have been reported in patients exhibiting schizophrenia (Cotter et al., Neuroreport 1998, 9(7): 1379-1383).
  • Atypical antipsychotic such as olanzapine, clozapine, quetiapine, and ziprasidone, inhibits GSK3 by increasing ser9 phosphorylation suggesting that antipsychotics may exert their beneficial effects via GSK3 inhibition (Li X. et al., Int. J.of Neuropsychopharmacol, 2007, 10: 7-19, Epubl. 2006, May 4).
  • Insulin stimulates glycogen synthesis in skeletal muscles via the dephosphorylation and thus activation of glycogen synthase.
  • GSK3 phosphorylates and inactivates glycogen synthase via dephosphorylation.
  • GSK3 is also over-expressed in muscles from Type II diabetic patients (Nikoulina et al., Diabetes 2000 Feb; 49(2): 263- 71). Inhibition of GSK3 increases the activity of glycogen synthase thereby decreasing glucose levels by its conversion to glycogen.
  • GSK3 inhibitors lowered plasma glucose levels up to 50 % (Cline et al., Diabetes, 2002, 51:
  • GSK3 inhibition may therefore be of therapeutic relevance in the treatment of Type I and Type II diabetes and diabetic neuropathy.
  • GSK3 phosphorylates and degrades ⁇ -catenin.
  • ⁇ -catenin is an effector of the pathway for keratonin synthesis, ⁇ -catenin stabilisation may be lead to increase hair development.
  • Mice expressing a stabilised ⁇ -catenin by mutation of sites phosphorylated by GSK3 undergo a process resembling de novo hair morphogenesis (Gat et al., Cell, 1998, 95(5): 605-14)).
  • the new follicles formed sebaceous glands and dermal papilla, normally established only in embryogenesis.
  • GSK3 inhibition may offer treatment for baldness.
  • GSK3 inhibitors provide anti-inflammatory effects.
  • Inflammation is a common feature of a broad range of conditions including Alzheimer's Disease and mood disorders.
  • GSK3 is overexpressed in ovarian, breast and prostate cancer cells and recent data suggests that GSK3b may have a role in contributing to cell proliferation and survival pathways in several solid tumor types.
  • GSK3 plays an important role in several signal transduction systems which influence cell proliferation and survival such as WNT, PI3 Kinase and NFkB.
  • GSK3b deficient MEFs indicate a crucial role in cell survival mediated NFkB pathway (Ougolkov AV and Billadeau DD., Future Oncol. 2006 Feb; 2(1): 91-100.).
  • GSK3 inhibitors may inhibit growth and survival of solid tumors, including pancreatic, colon and prostate cancer.
  • GSK3 inhibitors could be used for treatment of bone-related disorders. This has been discussed in e.g. Tobias et al., Expert Opinion on Therapeutic Targets, Feb 2002, pp 41-56.GSK3 inhibitors could be used for treatment of bone-related disorders or other conditions, which involves a need for new and increased bone formation. Remodeling of the skeleton is a continuous process, controlled by systemic hormones such as parathyroid hormone (PTH), local factors (e.g. prostaglandin E2), cytokines and other biologically active substances. Two cell types are of key importance: osteoblasts (responsible for bone formation) and osteoclasts (responsible for bone resorption).
  • PTH parathyroid hormone
  • prostaglandin E2 local factors
  • cytokines cytokines and other biologically active substances.
  • Two cell types are of key importance: osteoblasts (responsible for bone formation) and osteoclasts (responsible for bone resorption).
  • Osteoporosis is a skeletal disorder in which low bone mass and deterioration of bone microarchitecture lead to increased bone fragility and fracture risk.
  • the two main strategies are to either inhibit bone resorption or to stimulate bone formation.
  • the majority of drugs currently on the market for the treatment of osteoporosis act to increase bone mass by inhibiting osteoclastic bone resorption. It is recognized that a drug with the capacity to increase bone formation would be of great value in the treatment of osteoporosis as well as having the potential to enhance fracture healing in patients.
  • the present invention relates to a compound of formula (I):
  • R 1 is selected from sulphamoyl, carbamoyl, a group -R 5 -R 6 and a nitrogen linked 4-7 membered saturated ring which optionally contains an additional nitrogen, oxygen or sulphur atom; wherein said ring is optionally substituted on carbon by one or more R 7 ; and wherein if said ring contains an additional nitrogen atom that nitrogen is optionally substituted by R 8 ;
  • At least one of X 1 , X 2 , X 3 and X 4 is selected from N, the other three X 1 , X 2 , X 3 or X 4 are independently selected from N or C(R 9 ), provided that not more than two of X 1 , X 2 , X 3 or X 4 are selected from N;
  • R 2 is halo or cyano
  • R 3 is methyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl, wherein the tetrahydropyranyl group is optionally substituted on carbon by one or more R 10 ;
  • R 4 is selected from hydrogen, halo, cyano and C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with one or more halo;
  • R 5 is selected from -0-, -C(O)-, -C(O)O-, -C(O)N(R 11 )-, -S(OV and -SO 2 N(R 12 )-; wherein R 11 and R 12 are independently selected from hydrogen or C 1-6 alkyl and said alkyl is optionally substituted by one or more R 13 ; and r is O, 1 or 2;
  • R 6 is selected from C 1-6 alkyl, carbocyclyl and heterocyclyl; wherein R 6 is optionally substituted on carbon by one or more R 14 ; and wherein if said heterocyclyl contains an - NH- moiety that nitrogen is optionally substituted by a group selected from R 15 ;
  • R 7 is selected from halo, cyano, hydroxy, trifluoromethoxy, C 1-3 alkoxy and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by one or more halo;
  • R 9 is selected from hydrogen, halo, cyano, hydroxy, amino, C 1-3 alkyl and C 1-3 alkoxy;
  • R 1 , R 13 and R 14 are independently selected from halo, cyano, hydroxy, amino, sulphamoyl, Ci.6alkanoylamino, N-(C 1-(5 alkyr)carbanioyl, N,N-(Ci -6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a wherein a is O to 2, iV-(C 1-6 alkyl)sulphamoyl, N,iy-(C 1-6 alkyl) 2 Sulphamoyl, C 1- ⁇ alkylsulphonylamino, carbocyclyl, heterocyclyl, carbocyclylCi-salkyl-R 16 -, heterocyclylCi-salkyl-R 17 -, carbocyclyl-R 18 - and heterocyclyl-R 19 -; wherein R 10 , R 13 and R 1 are independently of each other substituted on carbon by one or more R 20 ; and
  • R 16 , R 17 , R 18 and R 19 are independently selected from -O-, -N(R 22 )-, -C(O)-, -N(R 23 )C(O)- 5 -C(O)N(R 24 )-, -S(O)s-, -SO 2 N(R 25 )- and -N(R 26 )SO 2 -; wherein R 22 , R 23 , R 24 , R 25 and R 26 are independently selected from hydrogen and Ci -6 alkyl; and s is O, 1 or 2;
  • R 8 , R 15 and R 21 are independently selected from C 1-4 alkyl, carbocyclyl, heterocyclyl, -C 1- 4 alkylcarbocyclyl, and C 1- 4 alkoxycarbonyl; wherein R 8 , R 15 and R 21 independently of each other may be optionally substituted on carbon by one or more R 27 ; and R 20 and R 27 are independently selected from halo, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, mesyl, ethylsulphonyl and phenyl;
  • One aspect of the present invention relates to a compound of formula (I), wherein
  • R 1 is a group -R 5 -R 6 or a nitrogen linked 4-7 membered saturated ring which optionally contains an additional nitrogen, oxygen or sulphur atom; wherein said ring may be optionally substituted on carbon by one or more R 7 ; and wherein if said ring contains an additional nitrogen atom that nitrogen is optionally substituted by R 8 ; at least one of X 1 , X 2 , X 3 and X 4 is selected from N, the other three X 1 , X 2 , X 3 or X 4 are independently selected from N or C(R 9 ) provided that not more than two of X 1 , X 2 , X 3 or X 4 are selected from N;
  • R 2 is halo or cyano
  • R 3 is methyl or 4-tetrahydropyranyl, wherein said tetrahydropyranyl group is optionally substituted on carbon by one or more R 10 ;
  • R 4 is selected from hydrogen, halo, cyano and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with one or more halo;
  • R 5 is selected from -O-, -C(O)-, -C(O)O-,-C(O)N(R n )-, -S(O) 1 - and -SO 2 N(R 12 )-;
  • R 11 and R 12 are independently selected from hydrogen or C 1-6 alkyl and said alkyl is optionally substituted by one or more R 13 ; and r is O or 2;
  • R 6 is selected from carbocyclyl and heterocyclyl; wherein R 6 is optionally substituted on carbon by one or more R 14 ; and wherein if said heterocyclyl contains an -
  • R 7 is selected from halo, cyano, hydroxy, trifluoromethoxy, C 1-3 alkoxy and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by one or more halo;
  • R 9 is selected from hydrogen, halo, cyano, hydroxy, C h alky! and C 1-3 alkoxy;
  • R 10 , R 13 and R 14 are independently selected from halo, cyano, hydroxy, amino, sulphamoyl,
  • R 16 , R 17 , R 18 and R 19 are independently selected from -O-, -N(R 22 )-, -C(O)-,-N(R 23 )C(O)-, -C(O)N(R 24 )-, -S(O)s-, -SO 2 N(R 25 )- and -N(R 26 )SO 2 -; wherein R 22 , R 23 , R 24 , R 25 and R 26 are independently selected from hydrogen or C ⁇ alkyl; and s is 0, 1 or 2; R 8 , R 15 and R 21 are independently selected from C 1-4 alkyl, carbocyclyl, heterocyclyl, -C 1- 4 alkylcarbocyclyl, -Ci -4 alkylheterocyclyl, C 1-4 alkanoyl, C 1-4 alkylsulphonyl and C 1- 4 alkoxycarbonyl; wherein R 8 , R 15 and R 21 independently of each other may be optionally substitute
  • any or all of the compounds of the present invention have a potent inhibiting effect at GSK3 in addition to a selective inhibiting effect at GSK3.
  • Another aspect of the present invention relates to a compound of formula (I), wherein R 2 is halo.
  • Yet another aspect of the present invention relates to a compound of formula (I), wherein R 2 is fluoro.
  • Another aspect of the present invention relates to a compound of formula (I), wherein R 3 is 4-tetrahydropyranyl or methyl.
  • Yet another aspect of the present invention relates to a compound of formula (I), wherein R 4 is hydrogen or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with one or more halo.
  • R 4 is C 1-3 alkyl.
  • R 4 is methyl.
  • R 4 is trifluoromethyl.
  • One aspect of the present invention relates to a compound of formula (I), wherein R 5 is -C(O)-or -S(O) 1 -; and r is 0 or 2. According to one embodiment of the present invention is -C(O)-. According to one embodiment of the present invention, -S(O) 1 -; and r is 2.
  • One aspect of the present invention relates to a compound of formula (I), wherein R 5 is -O- or C(O)O-.
  • Another aspect of the present invention relates to a compound of formula (I), wherein R 5 is -C(O)N(R 1 J )- or -SO 2 N(R 12 )-; wherein R 1 ⁇ and R 12 are independently selected from hydrogen or C 1-6 alkyl.
  • Yet another aspect of the present invention relates to a compound of formula (I), wherein R 6 is C 1-6 alkyl or heterocyclyl; wherein R 6 is optionally substituted on carbon by one or more R 14 ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from R 15 .
  • said C 1-6 alkyl is methyl, ethyl, butan-2-yl, butan-3-yl, propan-2-yl or tert-butyl.
  • said heterocyclyl is selected from morpholinyl, homomorpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl, , homopiperidinyl and homopiperazinyl.
  • said heterocyclyl is selected from piperidinyl, pyrrolidinyl, azetidinyl and piperazinyl
  • R 14 is Ci -6 alkoxy, halo, C 1-6 alkyl, carbocyclyl, heterocyclyl and N,N-(C 1-6 alkyl) 2 amino; wherein R 14 is optionally substituted on carbon by one or more R 20 .
  • R is C 1-4 alkyl or carbocycle; wherein R 15 is optionally substituted on carbon by one or more R 27 .
  • R 8 is C 1- 4 alkyl, and wherein R 8 may be optionally substituted on carbon by one or more R 27 .
  • R 7 is hydroxy, halo, ethoxy, methoxy or phenyl.
  • Another aspect of the present invention relates to a compound of formula (I), wherein at least one of X 2 , X 3 and X 4 is selected from N, the other two X 2 , X 3 or X 4 are independently selected from N or C(R 9 ). According to one embodiment of the present invention, X 3 or X 4 is N.
  • R 9 is hydrogen, methyl, trifluoromethyl, trifluoromethoxy or halo.
  • R 9 is hydrogen.
  • one of R 9 is halo.
  • said halo is chloro.
  • R 10 are for example fluoro, cyano, methyl and ethyl and other sutiable values of R 11 and R 12 are for example hydrogen and C ⁇ alkyl.
  • One aspect of the present invention relates to a compound of formula (I), wherein
  • R 1 is a group -R 5 -R 6 ; at least one of X 1 , X 2 , X 3 and X 4 is selected from N, the other three X 1 , X 2 , X 3 or X 4 are independently selected from N or C(R 9 ), provided that not more than two of X 1 , X 2 , X 3 or
  • X 4 are selected from N;
  • R 2 is halo
  • R 3 is methyl or 4-tetrahydropyranyl
  • R 4 is C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with one or more halo
  • R 5 is selected from -O-, -C(O)-, -C(O)O-, -C(O)N(R 11 )-, -S(O) 1 - and -SO 2 N(R 12 )-; wherein
  • R 11 and R 12 are independently selected from hydrogen or C 1-6 alkyl and said alkyl is optionally substituted by one or more R 13 and r is 2;
  • R 6 is C 1-6 alkyl or heterocyclyl; wherein R 6 is optionally substituted on carbon by one or more R 14 ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from R 15 ;
  • R 9 is hydrogen or halo
  • R 14 is selected from halo, C 1-6 alkyl, carbocycle, N,N-(C 1-6 alkyl) 2 amino, heterocyclyl and
  • R 14 is optionally on carbon by one or more R 20 ;
  • R 15 is C 1-4 alkyl or carbocycle; wherein R 15 is optionally substituted on carbon by one or more R ; and
  • R and R are independently selected from halo, methoxy, ethoxy, and phenyl.
  • R 1 is a group -R 5 -R 6 ; at least one of X 1 , X 2 , X 3 and X 4 is selected from N, the other three X 1 , X 2 , X 3 or X 4 are independently selected from N or C(R 9 ), provided that not more than two of X 1 , X 2 , X 3 or X 4 are selected from N;
  • R 2 is halo;
  • R 3 is 4-tetrahydropyranyl;
  • R 4 is C 1-3 alkyl;
  • R 5 is -C(O) or -S(0) r - and -SO 2 N(R 12 )-; and r is 2;
  • R 6 is C 1-6 alkyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from R 15 ;
  • R 9 is hydrogen; and
  • R 15 is
  • the present invention also provides a compound selected from:
  • the present invention also provides a compound selected from:
  • the present invention also provides a compound selected from: Lithium 5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-carboxylate;
  • Said compound(s) can be used as intermediates in processes for obtaining a compound of formula (I).
  • alkyl includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only.
  • C 1-6 alkyl and “C 1-4 alkyl” include methyl, ethyl, propyl, isopropyl and t-butyl.
  • references to individual alkyl groups such as 'propyl' are specific for the straight-chained version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only.
  • halo refers to fluoro, chloro, bromo and iodo.
  • a “4-7 membered saturated heterocyclic group” is a saturated monocyclic ring containing 4-7 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)- and a sulphur atom may be optionally oxidised to form the S-oxides.
  • Examples and suitable values of the term "4-7 membered saturated heterocyclic group" are morpholino, piperidyl, 1,4-dioxanyl, 1,3-dioxolanyl, 1,2- oxathiolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, homopiperazinyl and tetrahydropyranyl.
  • a "nitrogen linked 4-7 membered saturated ring which optionally contains an additional nitrogen, oxygen or sulphur atom” is a saturated monocyclic ring containing 4-7 atoms linked to the X*-X 4 containing ring of formula (I) via a nitrogen atom contained in the ring.
  • the ring optionally contains an additional heteroatom selected from nitrogen, sulphur or oxygen, wherein a -CH 2 - group can optionally be replaced by a -C(O)-, and the optional sulphur atom may be optionally oxidised to form the S-oxides.
  • an additional heteroatom selected from nitrogen, sulphur or oxygen
  • a -CH 2 - group can optionally be replaced by a -C(O)-
  • the optional sulphur atom may be optionally oxidised to form the S-oxides.
  • Particular examples of a "nitrogen linked 4-7 membered saturated ring which optionally contains an additional nitrogen, oxygen or sulphur atom” are piperazin-1-yl and morpholino, particularly morpholino.
  • a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)-, a ring nitrogen atom may optionally bear a C 1-6 alkyl group and form a quaternary compound or a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides.
  • heterocyclyl examples and suitable values of the term "heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5- dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, iV-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-JV-oxide and quinoline-JV-oxide.
  • a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH 2 - group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides.
  • a “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH 2 - group can optionally be replaced by a -C(O)-. Particularly “carbocyclyl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms.
  • Suitable values for "carbocyclyl” include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.
  • Examples of “C 1-6 alkoxy” include methoxy, ethoxy and propoxy.
  • Examples of “Ci -6 alkanoylamino” include formamido, acetamido and propionylamino.
  • Examples of "C 1-6 alkylS(O)a wherein a is 0,1 or 2” include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.
  • Examples of “C 1-6 alkanoyl” include propionyl and acetyl.
  • Examples of "iV-(C 1-6 alkyl)amino” include methylamino and ethylamino.
  • JV,JV-(C 1-6 alkyl) 2 amino examples include di-iV-methylamino, di-(JV-ethyl)amino and N-ethyl-JV-methylamino.
  • JV-(C 1-6 alkyl)sulphamoyl examples include JV- (methyl)sulphamoyl and JV-(ethyl)sulphamoyl. are N,JV-(dimethyl)sulphamoyl and N-(methyl)-JV-(ethyl)sulphamoyl.
  • JV-(C 1 examples include di-iV-methylamino, di-(JV-ethyl)amino and N-ethyl-JV-methylamino.
  • JV-(C 1-6 alkyl)sulphamoyl examples include JV- (methyl)sulphamoyl and JV-(ethyl)sulphamoyl. are N,JV-
  • 6 alkyl)carbamoyl are methylaminocarbonyl and ethylaminocarbonyl.
  • Examples of “N,JV- (C 1-6 alkyl) 2 carbamoyl” are dimethylaminocarbonyl and methylethylaminocarbonyl.
  • Examples of "C 1-6 alkylsulphonylamino” include methylsulphonylamino, isopropylsulphonylamino and t-butylsulphonylamino.
  • Examples of “C ⁇ ealkylsulphonyl” include methylsulphonyl, isopropylsulphonyl and t-butylsulphonyl.
  • -C M alkylcarbocyclyl and “-C 1-4 alkylheterocyclyl” includes both straight and branched chain alkyl groups of between one and four carbon atoms that then link to a carbocycle or heterocycle respectively.
  • carbocycle and heterocycle are as defined above.
  • Non-limiting examples of Ci ⁇ ahkylcarbocyclyl therefore include benzyl, 2- phenylethyl, 1-phenylethyl, cyclopropylmethyl and cyclohexylethyl.
  • Non-limiting examples of C 1-4 alkylheterocyclyl include pyridin-3-ylmethyl, oxolan-2yl-methyl, 2-(4- piperidyl)ethyl and l-thiophen-2-ylethyl.
  • a suitable pharmaceutically acceptable salt of a compound of the present invention is, for example, an acid-addition salt of a compound of the present invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morphorine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation
  • a salt with methylamine, dimethylamine, trimethylamine, piperidine, morphorine or tris-(2-hydroxyethyl)amine for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morphorine or tris-(2-hydroxy
  • Some compounds of the formula (I) may have stereogenic centres and/or geometric isomeric centres (E- and Z-isomers), and it is to be understood that the present invention encompasses all such optical, diastereoisomers and geometric isomers that possess GSK3 inhibitory activity.
  • the present invention relates to any and all tautomeric forms of the compounds of the formula (I) that possess GSK3 inhibitory activity.
  • the definition of compounds of formula (I) also includes in vivo hydrolysable esters, solvates or solvates of salts thereof. It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the present invention encompasses all such solvated forms that possess GSK3 inhibitory activity.
  • the present invention also provides a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof or in vivo hydrolysable ester thereof, which process comprises: a) reacting a pyrimidine of formula (II):
  • Y is a displaceable group
  • R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 and X 4 are, unless otherwise specified, as defined in formula (I); and thereafter optionally: b) converting a compound of the formula (I) into another compound of formula (I); c) removing any protecting groups; and d) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.
  • Y is, as mentioned above, a displaceable group. Suitable values for Y are, for example, a halo (such as a chloro, bromo or iodo) or sulphonyloxy group (such as trifluoromethanesulphonyloxy group). According to one embodiment of the present invention, Y is chloro, bromo or iodo.
  • Specific reaction conditions for the above reactions are as follows: Step a): Amines of formula (II) and compounds of formula (III) may be reacted together under standard Buchwald-Hartwig conditions, (for example see J. Am. Chem. Soc, 118, 7215; J. Am. Chem. Soc, 119, 8451; J. Am. Chem.
  • a suitable solvent for example an aromatic solvent such as toluene, benzene or xylene
  • a suitable base for example an inorganic base such as caesium carbonate or an organic base such
  • R 3 has the general structure R a -CH-R b , wherein R a and R b are hydrogen or form together a tetrahydropyran ring, wherein R 4 is hydrogen or C ⁇ aHcyl, wherein said C ⁇ alkyl may optionally be substituted with one or more halo and wherein R 2 is fluoro and R x is as defined above, may be prepared according to Scheme 3, wherein,
  • a compound of formula (Ia) can be prepared by reacting an acid intermediate (VI) with primary or secondary amines as shown in Scheme 4. This reaction can be achieved by mixing the acid or carboxylate salt with a coupling agent in a polar, aprotic solvent followed by addition of the primary or secondary amine.
  • the amidation conditions involve, for example, taking a mixture of the carboxylate or acid, a coupling agent (such as HBTU or CDI), a base, such as DIPEA, together in a solvent such as DCM, N-methyl pyrrolidinone or dimethylformamide and then adding the amine at room temperature.
  • a coupling agent such as HBTU or CDI
  • DIPEA a base
  • C(O)NR 28 R 29 is defined as -R 5 -R 6 above.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halo group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group that may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on- carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a /-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a /-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well-known in the chemical art.
  • spectra were recorded at 400 MHz for proton, 376 MHz for fluorine-19 and 100 MHz for carbon-13.
  • the following reference signals were used: the middle line of DMSO-Je ⁇ 2.50 (IH), ⁇ 39.51 (13C); the middle line of CD 3 OD ⁇ 3.31 (IH) or ⁇ 49.15 (13C); CDCl 3 ⁇ 7.26 (IH) and the middle line OfCDCl 3 ⁇ 77.16 (13C) (unless otherwise indicated).
  • NMR spectra are reported either from high to low field or from low to high field.
  • Mass spectra were recorded on a Waters LCMS consisting of an Alliance 2795 (LC), Waters PDA 2996 and a ZQ single quadrupole mass spectrometer.
  • the mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode.
  • the capillary voltage was 3 kV and cone voltage was 30 V.
  • the mass spectrometer was scanned between m/z 100-700 with a scan time of 0.3s.
  • mass spectra were recorded on a Waters LCMS consisting of an Alliance 2690 Separations Module, Waters 2487 Dual 1 Absorbance Detector (220 and 254 nm) and a Waters ZQ single quadrupole mass spectrometer.
  • the mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode.
  • the capillary voltage was 3 kV and cone voltage was 30 V.
  • the mass spectrometer was scanned between m/z 97-800 with a scan time of 0.3 or 0.8 s. Separations were performed on a Chromolith Performance RP-18e (100 x 4.6 mm). A linear gradient was applied starting at 95% A (A: 0.1% HCOOH (aq.)) ending at 100% B (MeCN) in 5 minutes. Flow rate: 2.0 mL/min.
  • Microwave heating was performed in a single-mode microwave cavity producing continuous irradiation at 2450 MHz.
  • HPLC analyses were performed on a Gynkotek P580 HPG consisting of gradient pump with a Gynkotek UVD 170S UV-vis.-detector equipped with a Chromolith Performance RP column (Cl 8, 100 mm x 4.6 mm). The column temperature was set to +25 0 C. A linear gradient was applied using MeCN/0.1 trifluoroacetic acid in MiUiQ water, run from 10% to 100% MeCN in 5 minutes. Flow rate: 3 ml/min.
  • a typical workup procedure after a reaction consisted of extraction of the product with a solvent such as ethyl acetate, washing with water followed by drying of the organic phase over MgSO 4 or Na 2 SO 4 , filtration and concentration of the solution in vacuo.
  • TLC Thin layer chromatography
  • Merck TLC-plates Silica gel 60 F 254
  • Flash chromatography was performed on a Combi Flash ® CompanionTM using RediSepTM normal-phase flash columns.
  • Typical solvents used for flash chromatography were mixtures of chloroform/methanol, DCM/methanol, heptane/ethyl acetate, chloroform/methanol/ NH 3 (aq.) and DCM/methanol/NH 3 (aq.).
  • SCX ion exchange columns were performed on Isolute ® columns. Chromatography through ion exchange columns were typically performed in solvents such a methanol.
  • Preparative chromatography was run on a Waters autopurif ⁇ cation HPLC with a diode array detector. Column: XTerra MS C8, 19 x 300 mm, 10 ⁇ m. Narrow gradients with MeCN/(95:5 0.1M NH 4 OAcMeCN) were used at a flow rate of 20 ml/min. Alternatively, purification was achieved on a semi preparative Shimadzu LC-8A HPLC with a Shimadzu SPD-IOA UV-vis.-detector equipped with a Waters Symmetry ® column (C18, 5 ⁇ m, 100 mm x 19 mm).
  • Narrow gradients with MeCN/0.1% trifluoroacetic acid in MiIIiQ Water were used at a flow rate of 10 ml/min.
  • the formation of hydrochloride salts of the final products were typically performed in solvents or solvents mixtures such as diethyl ether, tetrahydrofuran, DCM/toluene, DCM/methanol, followed by addition of IM hydrogen chloride in diethyl ether.
  • PrOH propan-1-ol r.t. or RT room temperature
  • the groups R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 and Y are used independently to indicate the diversity of substitution within each structure.
  • the identity of R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 and Y will be clear to a person skilled in the art based on the starting materials and intermediates for each specific example.
  • Example 1 which refers to General method A, Al is 5-fluoro-4-[2-methyl-l-(tetrahydro- 2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine such that R 3 is 4-tetrahydropyranyl and R 4 is methyl and A2 is 2-bromo-5-(methylsulfonyl)pyridine such that X 1 is N, X 2 , X 3 and X 4 are CH and R 1 is sulphonylmethane.
  • the title compound was prepared in accordance with general method A using 5-fluoro-4- [2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine (as described in Example 6) (50 mg, 0.18 mmol) and 5-bromo-2-(methylsulfonyl)pyridine (42 mg, 0.18 mmol) to give the title compound (36 mg, 46%).
  • the title compound was prepared in accordance with general method A using 5-fluoro-4- [2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrirnidin-2-amine (as described in Example 6) (26 mg, 0.095 mmol) and l-[(5-bromopyridin-2-yl)carbonyl]-4- methylpiperazine (obtained from Example 4b) (27 mg, 0.095 mmol) to give the title compound in 61% (28 mg) yield.
  • the title compound was prepared in accordance with general method A, with the exception that a second purification on a silica gel column was necessary to obtain a pure material, using 5-fluoro-4-[2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2- amine (as described in Example 6) (36 mg, 0.13 mmol) and 2-(azetidin-l-ylcarbonyl)-5- bromopyridine (reported in WO 2005014571) (32 mg, 0.13 mmol) to give the title compound in 18% (10 mg) yield.
  • 1,2-Dimethylimidazole (0.960 g, 10.0 mmol) was diluted in dry THF (50 mL) under an argon atmosphere and the solution was cooled to -78°C.
  • tert-Butyllithium (1.7M in pentane, 6.47 mL, 11.0 mmol) was added dropwise over 5 minutes.
  • the reaction mixture was stirred for 1 h at -78 °C and then treated with a solution of trimethyltin chloride (2.2 g, 11.0 mmol) in anhydrous THF (10 mL). The mixture was stirred for 60 h from -78°C to r.t.. The solvent was then evaporated in vacuo to give the title compound (1.29 g, 50%).
  • the crude product was used in the next step without further purification.
  • the methanol was removed from the reaction mixture, and the intermediate amine was extracted with ethyl acetate (3x80 mL). The combined organic layers were dried (Na 2 SO 4 ), concentrated to dryness, dissolved in toluene and re-concentrated.
  • the crude intermediate amine was dissolved in CH 2 Cl 2 (20 mL) and pyridine (2 mL, 26 mmol) was added. The mixture was cooled to 0°C and trifluoroacetic anhydride (4.35 g, 20.7 mmol) was added dropwise. The mixture was continued stirring for 2 h at r.t. and was then washed with water and saturated NaHCO 3 .
  • Trifluoroacetic anhydride (10 mL, 71 mmol) in CH 2 Cl 2 (100 mL) was added to N,5- dimethylisoxazol-4-amine (Reiter, L.A., J. Org. Chem. 1987, 52, 2714-2726) (6.68g, 59.6 mmol) in DCM (200 mL) and pyridine (6 mL, 74 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min and at r.t. for 2 h. The reaction mixture was diluted with CH 2 Cl 2 (100 mL) and washed with H 2 O and saturated NaHCO 3 (aq).
  • the title compound was prepared in accordance with the general method A using 5-fluoro- 4-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine (as described in Example 6) (50 mg, 0.18 mmol) and 5-bromo-2-ethoxy-pyridine (36 mg, 0.18 5 mmol) to give the title compound (27 mg, 38%).
  • Examples 12-40 were prepared by the general procedure B using the appropriate starting materials which include: lithium 5-[[5-fluoro-4-[2-methyl-3-(oxan-4- yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridine-2-carboxylate (as described below) and the amine necessary to deliver the amide shown in the table below.
  • Methyl 5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-carboxylate (prepared as described in Example 41) (1.49 g, 3.61 mmol) in MeOH (70 mL) was heated at 60 0 C for 30 min. The flask was removed from the oil bath and a solution of LiOH monohydrate (167 mg, 3.97 mmol) in water (13 mL) was added dropwise during one minute. The mixture was heated at 60°C during 4h, allowed to cool and concentrated to a yellow powder which was dried under vacuum to yield 1.44 g (99%) of the title compound. The isolated material was used in amidation reactions without further purification.
  • the title compound was prepared in accordance with the general method A using 4-(l,2- dimethyl-lH-imidazol-5-yl)-5-fluoropyrimidin-2-amine (as described in Example 7) (30 mg, 0.145 mmol) and 2-(azetidin-l-ylcarbonyl)-5-bromopyridine (41 mg, 0.17 mmol) (reported in WO 2005014571) to give the title compound (22 mg, 41%).
  • the title compound was prepared in accordance with the general method A using 4-(l,2- dimethyl-lH-imidazol-5-yl)-5-fluoropyrimidin-2-amine (as described in Example 7) (40 mg, 0.193 mmol) and l-[(5-bromopyridin-2-yl)carbonyl]-4-methylpiperazine (as described in Example 4(b)) (55 mg, 0.23 mmol) to give the title compound (45 mg, 57%).
  • the title compound was prepared in accordance with the general method C using 3,5- dichloropyridine-2-carboxylic acid (500 mg, 2.6 mmol) and azetidine (150 mg, 2.6 mmol) to give the title compound (430 mg, 72%).
  • the title compound was prepared in accordance with the general method C using 3,5- dichloropyridine-2-carboxylic acid (555 mg, 2.89 mmol) and 1-methylpiperazine (320 ⁇ L, 2.89 mmol) to give the title compound (417 mg, 53 %).
  • the title compound was prepared in accordance with the general method A using 4-(l,2- dimethyl-lH " -imidazol-5-yl)-5-fluoropyrimidin-2-amine (as described in Example 7) (50 mg, 0.24 mmol) and (3,5-dichloropyridin-2-yl)-(4-methylpiperazin-l-yl)methanone (as described above) (66 mg, 0.24 mmol) to give the title compound (29 mg, 27%).
  • 3,5-Dichloro-2-pyridine carboxylic acid (1.25 g, 6.5 mmol) was suspended in thionyl chloride (10 ml). DMF (2 drops) was added and the mixture was refluxed for 15 minutes under an atmosphere of nitrogen. The solvent was evaporated. Toluene was added and the solvent was evaporated to give a solid. The solid was dissolved in DCM (8 ml) and the mixture was cooled to 0° C. Piperidine (0.64 ml, 6.5 mmol) was added dropwise followed by triethylamine (0.91 ml, 6.5 mmol). The cooling bath was removed. The mixture was stirred under nitrogen atmosphere until RT was reached and then for an additional 15 minutes.
  • a pharmaceutical0 formulation comprising the compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof, in an essentially pure and isolated form, for use in the prevention and/or treatment of conditions associated with glycogen synthase kinase-3.
  • the formulation used in accordance with the present invention may be in a form suitables for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment, patch or cream, for rectal administration as a suppository and for local administration in a body cavity or in a bone cavity.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • a sterile solution suspension or emulsion
  • topical administration as an ointment, patch or cream
  • rectal administration as a suppository and for local administration in a body cavity or in a bone cavity.
  • the formulation may be in a form suitable for oral administration, for example as a tablet, for parenteral injection as a sterile solution or suspension.
  • the above formulation may be prepared in a conventional manner using pharmaceutically carriers or diluents.
  • Suitable daily doses of the compound of formula (I) as a free base and pharmaceutically acceptable salts thereof in the treatment of a mammal, including human are approximately 0.01 to 250 mg/kg bodyweight at per oral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration.
  • the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.
  • the compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof, in an essentially pure and isolated form, may be used on its own but will usually be administered in the form of a pharmaceutical formulation in which the active ingredient is in association with pharmaceutically acceptable diluents, excipients or inert carrier.
  • the pharmaceutical formulation may comprise from 0.05 to 99 %w (per cent by weight), for example from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • a diluent or carrier includes water, aqueous poly(ethylene glycol), magnesium carbonate, magnesium stearate, talc, a sugar (such as lactose), pectin, dextrin, starch, tragacanth, microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose or cocoa butter.
  • a formulation of the present invention can be in a unit dosage form such as a tablet or an injectable solution.
  • the tablet may additionally comprise a disintegrant and/or may be coated (for example with an enteric coating or coated with a coating agent such as hydroxypropyl methylcellulose).
  • the present invention further provides a process for the preparation of a pharmaceutical formulation of the present invention which comprises mixing of the compound of formula (I) or a pharmaceutically acceptable salt thereof, a hereinbefore defined, with pharmaceutically acceptable diluents, excipients or inert carriers.
  • An example of a pharmaceutical formulations of the present invention is an injectable solution comprising the compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof, as hereinbefore defined, and sterile water, and, if necessary, either a base sodium hydroxide or an acid hydrochloric acid to bring the pH of the final formulation to about pH in the range of about 4 to 6 , particularly about 5, and optionally a surfactant to aid dissolution.
  • a suitable base is sodium hydroxide.
  • a suitable acid is hydrochloric acid.
  • a suitable pharmaceutically acceptable salt of the compound of formula (I) useful in accordance to the present invention is, for example, an acid-addition salt, which is sufficiently basic, for example an inorganic or organic acid.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention, which is sufficiently acidic is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base, which affords a physiologically-acceptable cation.
  • the compounds of formula (I) defined in the present invention are well suited for inhibiting glycogen synthase kinase-3 (GSK3). Accordingly, said compound of the present invention is expected to be useful in the prevention and/or treatment of conditions associated with glycogen synthase kinase-3 activity, i.e. the compounds may be used to produce an inhibitory effect of GSK3 in mammals, including human, in need of such prevention and/or treatment.
  • GSK3 is highly expressed in the central and peripheral nervous system and in other tissues. Thus, it is expected that compound of the present invention is well suited for the prevention and/or treatment of conditions associated with glycogen synthase kinase-3 in the central and peripheral nervous system.
  • the compound of the present invention is expected to be suitable for prevention and/or treatment of conditions associated with cognitive disorders and predemented states, especially dementia, Alzheimer's Disease (AD), Cognitive Deficit in Schizophrenia (CDS), Mild Cognitive Impairment (MCI), Age- Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD) and Cognitive Impairement No Dementia (CIND), diseases associated with neurofibrillar tangle pathologies, Frontotemporal dementia (FTD), Frontotemporal dementia Parkinson's Type (FTDP), progressive supranuclear palsy (PSP), Pick's Disease, Niemann-Pick's Disease, corticobasal degeneration (CBD), traumatic brain injury (TBI) and dementia pugilistica.
  • AD Alzheimer's Disease
  • CDS Cognitive Deficit in Schizophrenia
  • MCI Mild Cognitive Impairment
  • AAMI Age- Associated Memory Impairment
  • ARCD Age-Related Cognitive Decline
  • CIND
  • One embodiment of the present invention relates to the prevention and/or treatment of Alzheimer's Disease, especially the use in the delay of the disease progression of Alzheimer's Disease.
  • PD Parkinson's Disease
  • ALS amyotrophic lateral sclerosis
  • MND motor neuron diseases
  • ADD attention deficit hyperactivity disorder
  • ADHD attention deficit hyperactivity disorder
  • affective disorders wherein the affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, and dysthymia.
  • Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, and dysthymia.
  • MDD major depressive disorders
  • schizoaffective disorders including schizophrenia, and dysthymia.
  • Type I diabetes Type II diabetes
  • diabetic neuropathy diabetic neuropathy
  • alopecia inflammatory diseases and cancer
  • One embodiment of the present invention relates to the use of a compound of the formula (I), as defined in the present invention, in the prevention and/or treatment of bone-related disorders or conditions in mammals.
  • One aspect of the present invention is directed to the use of a compound of the formula (I) , as defined in the present invention to treat osteoporosis.
  • One aspect of the present invention is directed to the use of a compound of the formula (I), as defined in the present invention to increase and promote bone formation in mammals.
  • One aspect of the present invention is directed to the use of a compound of the formula (I), as defined in the present invention to increase bone mineral density in mammals.
  • Another aspect of the present invention is directed to the use of a compound of the formula (I), as defined in the present invention to reduce the rate of fracture and/or increase the rate of fracture healing in mammals.
  • Another aspect of the present invention is directed to the use of a compound of the formula (I), as defined in the present invention to increase cancellous bone formation and/or new bone formation in mammals.
  • Another aspect of the present invention is directed to a method of prevention and/or treatment of bone-related disorders comprising administering to a mammal in need of such prevention and/or treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.
  • Another aspect of the present invention is directed to a method of prevention and/or treatment of osteoporosis comprising administering to a mammal in need of such prevention and/or treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.
  • Another aspect of the present invention is directed to a method of increasing bone formation comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.
  • Another aspect of the present invention is directed to a method of increasing bone mineral density comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.
  • Another aspect of the present invention is directed to a method of reducing the incidence of fracture comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.
  • Another aspect of the present invention is directed to a method of enhancing fracture healing comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.
  • Another aspect of the present invention is directed to said methods and wherein said mammal is a human.
  • Another aspect of the present invention is directed to said methods and wherein said mammal is a vertibrate animal, preferably but not limited to bigger animals such as horses, camels, dromedars but not limited thereto.
  • GSK3 inhibitors the compounds of formula (I) hereinbefore defined, in primary and secondary ostopeorosis, where primary osteoporosis includes postmenopausal osteoporosis and senile osteoporosis in both men and women, and secondary osteoporosis includes cortison induced osteoporosis, as well as any other type of induced secondary osteoporosis, are included in the term osteoporosis.
  • these GSK3 inhibitors may also be used in treatments of myeloma. These GSK3 inhibitors may be administered locally or systemically, in different formulation regimes, to treat these conditions.
  • the promotion and increasing of bone formation makes the compounds of the formula (I) hereinbefore defined, suitable to reducing the incidence of fracture, to reduce the rate of fracture and/or increase the rate of fracture healing, to increase cancellous bone formation and/or new bone formation in mammals.
  • the use to promote and increase new bone formation may be in connection with surgery.
  • This present invention can be used during surgery, where the treating surgeon will place the present invention locally in an appropriate formulation, near the deficient bone and/or in the body cavity.
  • the bone may for instance have been broken, and utilizing the present invention as described and claimed herein will then be placed in or near the fracture during open fracture repair. In some instances bone pieces may be missing (e.g. after tumour removal or severe casualties), and utilizing the present invention as described and claimed herein will then be placed near the site of constructive bone surgery.
  • the present invention relates also to the use of the compound of formula (I) as as defined in the present invention in the manufacture of a medicament for the prevention and/or treatment of conditions associated with glycogen synthase kinase-3.
  • the present invention also provides for a method of treatment and/or prevention of conditions associated with glycogen synthase kinase-3 comprising administering to a mammal, including human in need of such treatment and/or prevention a therapeutically effective amount of the compound of formula (I) as as defined in the present invention.
  • the dose required for the therapeutic or preventive treatment of a particular disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • the dosage form and the dose of the medicament may vary and will depend on various factors such as, for example the individual requirement of the animal treated.
  • the term “therapy” also includes “prevention” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • disorder also includes “condition” unless there are specific indications to the contrary.
  • condition also includes “condition” unless there are specific indications to the contrary.
  • the compounds of formula (I) as a free base or a pharmaceutically acceptable salt thereof are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of GSK3 related activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutics agents.
  • the reaction was initiated by the addition of 0.04 ⁇ Ci [ ⁇ - 33 P]ATP (Amersham, UK) and unlabelled ATP at a final concentration of 1 ⁇ M and assay volume of 25 ⁇ l. After incubation for 20 minutes at room temperature, each reaction was terminated by the addition of 25 ⁇ l stop solution containing 5 mM EDTA, 50 ⁇ M ATP, 0.1 % Triton X-100 and 0.25 mg streptavidin coated Scintillation Proximity Assay (SPA) beads (Amersham, UK). After 6 hours the radioactivity was determined in a liquid scintillation counter (1450 MicroBeta Trilux, Wallac). The inhibition curves were analysed by non-linear regression using GraphPad Prism, USA. The K m value of ATP for GSK3 ⁇ , used to calculate the inhibition constants (K;) of the various compounds, was 20 ⁇ M.
  • Typical Ki values for the compounds of the present invention are in the range of about 0.001 to about 10,000 nM.
  • Other values for Kj are in the range of about 0.001 to about 1000 nM.
  • Further values for Ki are in the range of about 0.001 nM to about 700 nM.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Diabetes (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to a compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof. The present invention also relates to pharmaceutical formulations containing said compound and to the use of said compound in therapy. The present invention further relates to a process for the preparation of compound of formula (I) and to new intermediates used therein.

Description

NEW COMPOUNDS :3S4
TECHNICAL FIELD OF PRESENT INVENTION
The present invention relates to new compounds of formula (I), as a free base or a pharmaceutically acceptable salt thereof, to pharmaceutical formulations containing said compounds and to the use of said compounds in therapy. The present invention further relates to a process for the preparation of compounds of formula (I) and to new intermediates used therein.
BACKGROUND OF THE PRESENT INVENTION
Glycogen synthase kinase 3 (GSK3) is a serine / threonine protein kinase composed of two isoforms (α and β), which are encoded by distinct genes but are highly homologous within the catalytic domain. GSK3 is highly expressed in the central and peripheral nervous system. GSK3 phosphorylates several substrates including tau, β-catenin, glycogen synthase, pyruvate dehydrogenase and elongation initiation factor 2b (eIF2b). Insulin and growth factors activate protein kinase B, which phosphorylates GSK.3 on serine 9 residue and inactivates it.
Alzheimer's Disease (AD) dementias, and taupathies AD is characterized by cognitive decline, cholinergic dysfunction and neuronal death, neurofibrillary tangles and senile plaques consisting of amyloid-β deposits. The sequence of these events in AD is unclear, but is believed to be related. Glycogen synthase kinase 3β (GSK3β) or Tau phosphorylating kinase selectively phosphorylates the microtubule associated protein Tau in neurons at sites that are hyperphosphorylated in AD brains. Hyperphosphorylated tau has lower affinity for microtubules and accumulates as paired helical filaments, which are the main components that constitute neurofibrillary tangles and neuropil threads in AD brains. This results in depolymerization of microtubules, which leads to dying back of axons and neuritic dystrophy. Neurofibrillary tangles are consistently found in diseases such as AD, amyotrophic lateral sclerosis, parkinsonism- dementia of Gaum, corticobasal degeneration, dementia pugilistica and head trauma, Down's syndrome, postencephalatic parkinsonism, progressive supranuclear palsy, Niemann-Pick's Disease and Pick's Disease. Addition of amyloid-β to primary hippocampal cultures results in hyperphosphorylation of tau and a paired helical filaments- like state via induction of GSK3β activity, followed by disruption of axonal transport and neuronal death (Imahori and Uchida, J. Biochem. 1997, 121:179-188). GSK3β preferentially labels neurofibrillary tangles and has been shown to be active in pre-tangle neurons in AD brains. GSK3 protein levels are also increased by 50% in brain tissue from AD patients. Furthermore, GSK3β phosphorylates pyruvate dehydrogenase, a key enzyme in the glycolytic pathway and prevents the conversion of pyruvate to acetyl-Co-A (Hoshi et al., PNAS 1996, 93: 2719-2723). Acetyl-Co-A is critical for the synthesis of acetylcholine, a neurotransmitter with cognitive functions. Accumulation of amyloid-β is an early event in AD. GSK Tg mice show increased levels of amyloid-β in brain. Also, PDAPP mice fed with Lithium show decreased amyloid-β levels in hippocampus and decreased amyloid plaque area (Su et al., Biochemistry 2004, 43: 6899-6908). Thus, GSK3β inhibition may have beneficial effects in progression as well as the cognitive deficits associated with Alzheimer's disease and other above-referred to diseases.
Chronic and Acute Neurodegenerative Diseases
Growth factor mediated activation of the PI3K /Akt pathway has been shown to play a key role in neuronal survival. The activation of this pathway results in GSK3β inhibition. Recent studies (Bhat et. al., PNAS 2000, 97: 11074-11079) indicate that GSK3β activity is increased in cellular and animal models of neurodegeneration such as cerebral ischemia or after growth factor deprivation. For example, the active site phosphorylation was increased in neurons vulnerable to apoptosis, a type of cell death commonly thought to occur in chronic and acute degenerative diseases such as cognitive disorders, Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, Huntington's Disease and HIV dementia and traumatic brain injury; and as in ischemic stroke. Lithium was neuroprotective in inhibiting apoptosis in cells and in the brain at doses that resulted in the inhibition of GSK3β. Thus GSK3β inhibitors could be useful in attenuating the course of neurodegenerative diseases. Bipolar Disorders (BD)
Bipolar Disorders are characterised by manic episodes and depressive episodes. Lithium has been used to treat BD based on its mood stabilising effects. The disadvantage of lithium is the narrow therapeutic window and the danger of overdosing that can lead to lithium intoxication. The discovery that lithium inhibits GSK3 at therapeutic concentrations has raised the possibility that this enzyme represents a key target of lithium's action in the brain (Stambolic et al., Curr. Biol. 1996, 68(12):1664-1668, 1996; Klein and Melton; PNAS 1996, 93:8455-8459; Gould et al., Neuropsychopharmacology, 2005, 30:1223-1237). GSK3 inhibitor has been shown to reduce immobilisation time in forced swim test, a model to assess on depressive behavior (O'Brien et al., J Neurosci 2004, 24(30): 6791-6798). GSK3 has been associated with a polymorphism found in bipolar II disorder (Szczepankiewicz et al., Neuropsychobiology. 2006, 53: 51-56). Inhibition of GSK3β may therefore be of therapeutic relevance in the treatment of BD as well as in AD patients that have affective disorders.
Schizophrenia
Accumulating evidence implicates abnormal activity of GSK3 in mood disorders and schizophrenia. GSK3 is involved in signal transduction cascades of multiple cellular processes, particularly during neural development. (Kozlovsky et al., Am. J. Psychiatry, 2000, 157, 5: 831-833) found that GSK3β levels were 41% lower in the schizophrenic patients than in comparison subjects. This study indicates that schizophrenia involves neurodevelopmental pathology and that abnormal GSK3 regulation could play a role in schizophrenia. Furthermore, reduced β-catenin levels have been reported in patients exhibiting schizophrenia (Cotter et al., Neuroreport 1998, 9(7): 1379-1383). Atypical antipsychotic such as olanzapine, clozapine, quetiapine, and ziprasidone, inhibits GSK3 by increasing ser9 phosphorylation suggesting that antipsychotics may exert their beneficial effects via GSK3 inhibition (Li X. et al., Int. J.of Neuropsychopharmacol, 2007, 10: 7-19, Epubl. 2006, May 4).
Diabetes
Insulin stimulates glycogen synthesis in skeletal muscles via the dephosphorylation and thus activation of glycogen synthase. Under resting conditions, GSK3 phosphorylates and inactivates glycogen synthase via dephosphorylation. GSK3 is also over-expressed in muscles from Type II diabetic patients (Nikoulina et al., Diabetes 2000 Feb; 49(2): 263- 71). Inhibition of GSK3 increases the activity of glycogen synthase thereby decreasing glucose levels by its conversion to glycogen. In animal models of diabetes, GSK3 inhibitors lowered plasma glucose levels up to 50 % (Cline et al., Diabetes, 2002, 51:
2903-2910; Ring et al., Diabetes 2003, 52: 588-595). GSK3 inhibition may therefore be of therapeutic relevance in the treatment of Type I and Type II diabetes and diabetic neuropathy.
Alopecia
GSK3 phosphorylates and degrades β-catenin. β-catenin is an effector of the pathway for keratonin synthesis, β-catenin stabilisation may be lead to increase hair development. Mice expressing a stabilised β-catenin by mutation of sites phosphorylated by GSK3 undergo a process resembling de novo hair morphogenesis (Gat et al., Cell, 1998, 95(5): 605-14)). The new follicles formed sebaceous glands and dermal papilla, normally established only in embryogenesis. Thus GSK3 inhibition may offer treatment for baldness.
Inflammatory disease
The discovery that GSK3 inhibitors provide anti-inflammatory effects has raised the possibility of using GSK3 inhibitors for therapeutic intervention in inflammatory diseases. (Martin et al., Nat. Immunol. 2005, 6(8): 777-784; Jope et al., Neurochem. Res. 2006, DOI 10.1007/sl 1064-006-9128-5)). Inflammation is a common feature of a broad range of conditions including Alzheimer's Disease and mood disorders.
Cancer
GSK3 is overexpressed in ovarian, breast and prostate cancer cells and recent data suggests that GSK3b may have a role in contributing to cell proliferation and survival pathways in several solid tumor types. GSK3 plays an important role in several signal transduction systems which influence cell proliferation and survival such as WNT, PI3 Kinase and NFkB. GSK3b deficient MEFs indicate a crucial role in cell survival mediated NFkB pathway (Ougolkov AV and Billadeau DD., Future Oncol. 2006 Feb; 2(1): 91-100.). Thus, GSK3 inhibitors may inhibit growth and survival of solid tumors, including pancreatic, colon and prostate cancer.
Bone-related disorders and conditions It has been shown that GSK3 inhibitors could be used for treatment of bone-related disorders. This has been discussed in e.g. Tobias et al., Expert Opinion on Therapeutic Targets, Feb 2002, pp 41-56.GSK3 inhibitors could be used for treatment of bone-related disorders or other conditions, which involves a need for new and increased bone formation. Remodeling of the skeleton is a continuous process, controlled by systemic hormones such as parathyroid hormone (PTH), local factors (e.g. prostaglandin E2), cytokines and other biologically active substances. Two cell types are of key importance: osteoblasts (responsible for bone formation) and osteoclasts (responsible for bone resorption). Via the RANK, RANK ligand and osteoprotegerin regulatory system these two cell types interact to maintain normal bone turnover (Bell NH, Current Drug Targets - Immune, Endocrine & Metabolic Disorders, 2001, 1:93-102).
Osteoporosis is a skeletal disorder in which low bone mass and deterioration of bone microarchitecture lead to increased bone fragility and fracture risk. To treat osteoporosis, the two main strategies are to either inhibit bone resorption or to stimulate bone formation. The majority of drugs currently on the market for the treatment of osteoporosis act to increase bone mass by inhibiting osteoclastic bone resorption. It is recognized that a drug with the capacity to increase bone formation would be of great value in the treatment of osteoporosis as well as having the potential to enhance fracture healing in patients.
Recent in vitro studies suggest a role of GSK3β in osteoblast differentiation. First, it has been shown that glucocorticoids inhibit cell cycle progression during osteoblast differentiation in culture. The mechanism behind this is activation of GSK3β in osteoblasts, resulting in c-Myc down-regulation and impediment of the Gj/S cell cycle transition. The attenuated cell cycle and reduced c-Myc level are returned to normal when GSK3β is inhibited using lithium chloride (Smith et al., J. Biol. Chem, 2002, 277: 18191- 18197). Secondly, inhibition of GSK3β in the pluripotent mesenchymal cell line C3H10T1/2 leads to a significant increase in endogenous β-catenin signaling activity. This, in turn, induces expression of alkaline phosphatase mRNA and protein, a marker of early osteoblast differentiation (Bain et al., Biochem. Biophys. Res. Commun., 2003, 301: 84- 91).
DISCLOSURE OF THE PRESENT INVENTION
The present invention relates to a compound of formula (I):
Figure imgf000007_0001
wherein:
R1 is selected from sulphamoyl, carbamoyl, a group -R5-R6 and a nitrogen linked 4-7 membered saturated ring which optionally contains an additional nitrogen, oxygen or sulphur atom; wherein said ring is optionally substituted on carbon by one or more R7; and wherein if said ring contains an additional nitrogen atom that nitrogen is optionally substituted by R8;
at least one of X1, X2, X3 and X4 is selected from N, the other three X1, X2, X3 or X4 are independently selected from N or C(R9), provided that not more than two of X1, X2, X3 or X4 are selected from N;
R2 is halo or cyano;
R3 is methyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl, wherein the tetrahydropyranyl group is optionally substituted on carbon by one or more R10;
R4 is selected from hydrogen, halo, cyano and C1-3alkyl, wherein C1-3alkyl is optionally substituted with one or more halo; R5 is selected from -0-, -C(O)-, -C(O)O-, -C(O)N(R11)-, -S(OV and -SO2N(R12)-; wherein R11 and R12 are independently selected from hydrogen or C1-6alkyl and said alkyl is optionally substituted by one or more R13; and r is O, 1 or 2;
R6 is selected from C1-6alkyl, carbocyclyl and heterocyclyl; wherein R6 is optionally substituted on carbon by one or more R14; and wherein if said heterocyclyl contains an - NH- moiety that nitrogen is optionally substituted by a group selected from R15;
R7 is selected from halo, cyano, hydroxy, trifluoromethoxy, C1-3alkoxy and C1-3alkyl, wherein said C1-3alkyl is optionally substituted by one or more halo;
R9 is selected from hydrogen, halo, cyano, hydroxy, amino, C1-3alkyl and C1-3alkoxy;
R1 , R13 and R14 are independently selected from halo, cyano, hydroxy, amino, sulphamoyl,
Figure imgf000008_0001
Ci.6alkanoylamino, N-(C1-(5alkyr)carbanioyl, N,N-(Ci-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is O to 2, iV-(C1-6alkyl)sulphamoyl, N,iy-(C1-6alkyl)2Sulphamoyl, C1- βalkylsulphonylamino, carbocyclyl, heterocyclyl, carbocyclylCi-salkyl-R16-, heterocyclylCi-salkyl-R17-, carbocyclyl-R18- and heterocyclyl-R19-; wherein R10, R13 and R1 are independently of each other substituted on carbon by one or more R20; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from R21;
R16, R17, R18 and R19 are independently selected from -O-, -N(R22)-, -C(O)-, -N(R23)C(O)-5 -C(O)N(R24)-, -S(O)s-, -SO2N(R25)- and -N(R26)SO2-; wherein R22, R23, R24, R25 and R26 are independently selected from hydrogen and Ci-6alkyl; and s is O, 1 or 2;
R8, R15 and R21 are independently selected from C1-4alkyl, carbocyclyl, heterocyclyl, -C1- 4alkylcarbocyclyl,
Figure imgf000008_0002
and C1- 4alkoxycarbonyl; wherein R8, R15 and R21 independently of each other may be optionally substituted on carbon by one or more R27; and R20 and R27 are independently selected from halo, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, mesyl, ethylsulphonyl and phenyl;
as a free base or a pharmaceutically acceptable salt thereof.
One aspect of the present invention relates to a compound of formula (I), wherein
R1 is a group -R5-R6 or a nitrogen linked 4-7 membered saturated ring which optionally contains an additional nitrogen, oxygen or sulphur atom; wherein said ring may be optionally substituted on carbon by one or more R7; and wherein if said ring contains an additional nitrogen atom that nitrogen is optionally substituted by R8; at least one of X1, X2, X3 and X4 is selected from N, the other three X1, X2, X3 or X4 are independently selected from N or C(R9) provided that not more than two of X1, X2, X3 or X4 are selected from N;
R2 is halo or cyano;
R3 is methyl or 4-tetrahydropyranyl, wherein said tetrahydropyranyl group is optionally substituted on carbon by one or more R10;
R4 is selected from hydrogen, halo, cyano and C1-3alkyl, wherein said C1-3alkyl is optionally substituted with one or more halo;
R5 is selected from -O-, -C(O)-, -C(O)O-,-C(O)N(Rn)-, -S(O)1- and -SO2N(R12)-; wherein
R11 and R12 are independently selected from hydrogen or C1-6alkyl and said alkyl is optionally substituted by one or more R13; and r is O or 2;
R6 is selected from
Figure imgf000009_0001
carbocyclyl and heterocyclyl; wherein R6 is optionally substituted on carbon by one or more R14; and wherein if said heterocyclyl contains an -
NH- moiety that nitrogen is optionally substituted by a group selected from R15;
R7 is selected from halo, cyano, hydroxy, trifluoromethoxy, C1-3alkoxy and C1-3alkyl, wherein said C1-3alkyl is optionally substituted by one or more halo;
R9 is selected from hydrogen, halo, cyano, hydroxy, Chalky! and C1-3alkoxy; R10, R13 and R14 are independently selected from halo, cyano, hydroxy, amino, sulphamoyl,
C1-6alkyl, C1-6alkoxy, C1-6alkoxyCi-6alkoxy, ^-(Ci.eallcy^amino, N,N-(Ci.6alkyl)2amino,
Ci-6alkanoylamino, iV-(C1-6alkyl)carbamoyl, JV, jV-(C1-6alkyr)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, iV-(C1-6alkyl)sulphamoyl, AζN-Ci-όalkyrhsulphamoyl, C1- 6alkylsulphonylamino, carbocyclyl, heterocyclyl, carbocyclylC1-3alkyl-R16-, heterocyclylC1-3alkyl-R17-, carbocyclyl-R18- and heterocyclyl-R19-; wherein R10, R13 and R14 independently of each other are optionally substituted on carbon by one or more R20; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from R21;
R16, R17, R18 and R19 are independently selected from -O-, -N(R22)-, -C(O)-,-N(R23)C(O)-, -C(O)N(R24)-, -S(O)s-, -SO2N(R25)- and -N(R26)SO2-; wherein R22, R23, R24, R25 and R26 are independently selected from hydrogen or C^alkyl; and s is 0, 1 or 2; R8, R15 and R21 are independently selected from C1-4alkyl, carbocyclyl, heterocyclyl, -C1- 4alkylcarbocyclyl, -Ci-4alkylheterocyclyl, C1-4alkanoyl, C1-4alkylsulphonyl and C1- 4alkoxycarbonyl; wherein R8, R15 and R21 independently of each other may be optionally substituted on carbon by one or more R27; and R20 and R27 are independently selected from halo, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, mesyl and ethylsulphonyl; as a free base or a pharmaceutically acceptable salt, an in vivo hydrolysable ester, solvate or solvate of a salt thereof.
Any or all of the compounds of the present invention have a potent inhibiting effect at GSK3 in addition to a selective inhibiting effect at GSK3.
Another aspect of the present invention relates to a compound of formula (I), wherein R2 is halo.
Yet another aspect of the present invention relates to a compound of formula (I), wherein R2 is fluoro.
Another aspect of the present invention relates to a compound of formula (I), wherein R3 is 4-tetrahydropyranyl or methyl. Yet another aspect of the present invention relates to a compound of formula (I), wherein R4 is hydrogen or C1-3alkyl, wherein said C1-3alkyl is optionally substituted with one or more halo. According to one embodiment of the present invention, R4 is C1-3alkyl. According to another embodiment of the present invention, R4 is methyl. According to one embodiment of the present invention, R4 is trifluoromethyl.
One aspect of the present invention relates to a compound of formula (I), wherein R5 is -C(O)-or -S(O)1-; and r is 0 or 2. According to one embodiment of the present invention is -C(O)-. According to one embodiment of the present invention, -S(O)1-; and r is 2.
One aspect of the present invention relates to a compound of formula (I), wherein R5 is -O- or C(O)O-.
Another aspect of the present invention relates to a compound of formula (I), wherein R5 is -C(O)N(R1 J)- or -SO2N(R12)-; wherein R1 λ and R12 are independently selected from hydrogen or C1-6alkyl.
Yet another aspect of the present invention relates to a compound of formula (I), wherein R6 is C1-6alkyl or heterocyclyl; wherein R6 is optionally substituted on carbon by one or more R14; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from R15. According to one embodiment of the present invention, said C1-6alkyl is methyl, ethyl, butan-2-yl, butan-3-yl, propan-2-yl or tert-butyl. According to another embodiment of the present invention, said heterocyclyl is selected from morpholinyl, homomorpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl, , homopiperidinyl and homopiperazinyl. According to yet another embodiment of the present invention, said heterocyclyl is selected from piperidinyl, pyrrolidinyl, azetidinyl and piperazinyl
According to one embodiment of the present invention, R14 is Ci-6alkoxy, halo, C1-6alkyl, carbocyclyl, heterocyclyl and N,N-(C1-6alkyl)2amino; wherein R14 is optionally substituted on carbon by one or more R20. According to one embodiment of the present invention, R is C1-4alkyl or carbocycle; wherein R15 is optionally substituted on carbon by one or more R27.
One aspect of the present invention relates to a compound of formula (I), wherein R8 is C1- 4alkyl, and wherein R8 may be optionally substituted on carbon by one or more R27. According to one embodiment of the present invention , R 7 is hydroxy, halo, ethoxy, methoxy or phenyl.
Another aspect of the present invention relates to a compound of formula (I), wherein at least one of X2, X3 and X4 is selected from N, the other two X2, X3 or X4 are independently selected from N or C(R9). According to one embodiment of the present invention, X3 or X4 is N.
Yet another aspect of the present invention relates to a compound of formula (I), wherein R9 is hydrogen, methyl, trifluoromethyl, trifluoromethoxy or halo. According to one embodiment of the present invention, R9 is hydrogen. According to one embodiment of the present invention, one of R9 is halo. According to another embodiment of the present invention, said halo is chloro.
Other suitable values of R10 are for example fluoro, cyano, methyl and ethyl and other sutiable values of R11 and R12 are for example hydrogen and C^alkyl.
One aspect of the present invention relates to a compound of formula (I), wherein
R1 is a group -R5-R6; at least one of X1, X2, X3 and X4 is selected from N, the other three X1, X2, X3 or X4 are independently selected from N or C(R9), provided that not more than two of X1, X2, X3 or
X4 are selected from N;
R2 is halo;
R3 is methyl or 4-tetrahydropyranyl; R4 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted with one or more halo; R5 is selected from -O-, -C(O)-, -C(O)O-, -C(O)N(R11)-, -S(O)1- and -SO2N(R12)-; wherein
R11 and R12 are independently selected from hydrogen or C1-6alkyl and said alkyl is optionally substituted by one or more R13 and r is 2;
R6 is C1-6alkyl or heterocyclyl; wherein R6 is optionally substituted on carbon by one or more R14; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from R15;
R9 is hydrogen or halo;
R14 is selected from halo, C1-6alkyl, carbocycle, N,N-(C1-6alkyl)2amino, heterocyclyl and
C1-6alkoxy; wherein R14 is optionally on carbon by one or more R20; R15 is C1-4alkyl or carbocycle; wherein R15 is optionally substituted on carbon by one or more R ; and R and R are independently selected from halo, methoxy, ethoxy, and phenyl.
Another aspect of the present invention relates to a compound of formula (I) wherein R1 is a group -R5-R6; at least one of X1, X2, X3 and X4 is selected from N, the other three X1, X2, X3 or X4 are independently selected from N or C(R9), provided that not more than two of X1, X2, X3 or X4 are selected from N; R2 is halo; R3 is 4-tetrahydropyranyl; R4 is C1-3alkyl; R5 is -C(O) or -S(0)r- and -SO2N(R12)-; and r is 2; R6 is C1-6alkyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from R15; R9 is hydrogen; and R15 is
Figure imgf000013_0001
The present invention also provides a compound selected from:
5-Fluoro-iV-[5-(methylsulfonyl)pyridin-2-yl]-4-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine hydrochloride; Azetidin-l-yl-[3-chloro-5-[[5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone hydrochloride; iV-[5-Chloro-6-(piperidin-l-ylcarbonyl)pyridin-3-yl]-5-fluoro-4-[2-methyl-l-(tetrahydro-
2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine hydrochloride; iV-[5-Chloro-6-(piperidin- 1 -ylcarbonyl)pyridin-3-yl]-4-(l ,2-dimethyl- lH-imidazol-5-yl)-5- fluoropyrimidin-2-amine hydrochloride; iV-[5-Chloro-6-(piperidin-l-ylcarbonyl)pyridin-3-yl]-5-fluoro-4-[l-methyl-2-
(trifluoromethyl)- lH-imidazol-5-yl]pyrimidin-2-amine hydrochloride; and N-[5-Chloro-6-(piperidin- 1 -ylcarbonyl)pyridin-3-yl]-5-fluoro-4-[ 1 -(tetrahydro-2i7-pyran- 4-yl)-2-(trifluoromethyl)-lH-imidazol-5-yl]pyrimidin-2-amine hydrochloride; or other pharmaceutically acceptable salts or free bases thereof.
The present invention also provides a compound selected from:
5-Fluoro-iV-[6-(methylsulfonyl)pyridin-3-yl]-4-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-N- {5-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-2-yl} -4-[2-methyl- 1 -(tetrahydro-
2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine; 5-Fluoro-N- {6-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-3 -yl} -4-[2-methyl- 1 -(tetrahydro-
2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine; iV-[6-(Azetidin-l-ylcarbonyl)pyridin-3-yl]-5-fluoro-4-[2-methyl-l-(tetrahydro-2H-pyran-4- yl)-lH-imidazol-5-yl]pyrimidin-2-amine;
(6-Bthoxy-pyridin-3-yl)-{5-fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4- yl]-pyrimidin-2-yl}-amine;
{5-Fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-(2- methoxy-pyrimidin-5-yl)-amine;
N-Butan-2-yl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-
N-propyl-pyridine-2-carboxamide; (3,3-Difluoropyrrolidin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]-
(3 -methyl- 1 -piperidy l)methanone;
5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-iV-methyl-N- propan-2-yl-pyridine-2-carboxamide;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]-
[4-(4-fluorophenyl)- 1 -piperidyl]methanone;
(4-Ethylpiperazin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]methanone; (4-Butylpiperazin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]methanone; N-Ethyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N"- propan-2-yl-pyridine-2-carboxamide;
[5-[[5-Fluoro-4-[2-methyl-3-(oxaQ-4-yl)imidazol-4-yl]pyrimidin-2-yl]aniino]pyridin-2-yl]-
( 1 -piperidyl)methanone; [5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]-
(4-propan-2-ylpiperazin- 1 -yl)methanone;
5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-iV,N- dipropan-2-yl-ρyridine-2-carboxamide;
(2,6-Dimethyl-l-piperidyl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone;
5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N,N- dipropyl-pyridine-2-carboxamide;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]-
(4-methoxy- 1 -piperidyl)methanone; N-Ethyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N- methyl-pyridine-2-carboxamide;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidm-2-yl]amino]pyridin-2-yl]-
(4-methyl- 1 -piperidyl)methanone;
(4-Benzylpiperazin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin- 2-yl]amino]pyridin-2-yl]methanone;
(4,4-Difluoro-l-piperidyl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone;
N-Benzyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N- propan-2-yl-pyridine-2-carboxamide; 5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N-methyl-iV'-
(2-methylpropyl)pyridine-2-carboxamide;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]-
(4-fluoro- 1 -piperidyl)methanone; iV-Benzyl-iV'-ethyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidm-2- yl]amino]pyridine-2-carboxamide;
(4-Butan-2-ylpiperazin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone; iV-(Cyclopropylmethyl)-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]-N-propyl-pyridine-2-carboxamide;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]-
[4-(4-fluorophenyl)piperazin- 1 -yl]methanone; [5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]-
(4-propylpiperazin- 1 -yl)methanone; i\yV-Diethyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-carboxamide;
N-(3-Dimethylamino-2,2-dimethyl-propyl)-5-[[5-fluoro-4-[2-methyl-3-(oxan-4- yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridine-2-carboxamide;
(3,5-Dimethyl-l-piperidyl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone;
Methyl 5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-carboxylate; Azetidin-l-yl-[3-chloro-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]methanone;
[3-Chloro-5-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]-(4-methylpiperazin-l-yl)methanone;
[3-Chloro-5-[[5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]-(4-methylpiperazin- 1 -yl)methanone;
-V-[6-(Azetidin- 1 -ylcarbonyl)pyridin-3-yl]-4-( 1 ,2-dimethyl- lH-imidazol-5-yl)-5- fluoropyrimidin-2-amine;
4-(l,2-Dimethyl-li7-imidazol-5-yl)-5-fluoro-N-{6-[(4-methylpiperazin-l- yl)carbonyl]pyridin-3-yl}pyrimidin-2-amine; N-[6-(Azetidin-l-ylcarbonyl)-5-chloropyridin-3-yl]-4-(l,2-dimethyl-lH-imidazol-5-yl)-5- fluoropyrimidin-2-amine;
N- {5-Chloro-6-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-3-yl} -4-(l ,2-dimethyl- IH- imidazol-5-yl)-5-fluoropyrimidin-2-amine;
{ 5 -Fluoro-4- [2-methyl-3 -(tetrahydro-pyran-4-yl)-3H-imidazol-4-y 1] -pyrimidin-2-y 1} -[6- (propan-2-ylsulfonyl)-pyridin-3-yl]-amine;
(6-Ethanesulfonyl-pyridin-3-yl)-{5-fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H- imidazol-4-yl]-ρyrimidin-2-yl}-amine; 5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)-2,4-dihydroimidazol-4-yl]pyrimidin-2-yl]amino]- N-(2,2,2-trifluoroethyl)pyridine-2-sulfonamide;
N^-Dimethyl-5-[[4-[2-methyl-3-(oxan-4-yl)-2,4-dihydroimidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-sulfonamide; and {5-Fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-[6-(4- methyl-piperazine- 1 -sulfonyl)-pyridin-3 -yl]-amine; as a free base or a pharmaceutically acceptable salt thereof.
The present invention also provides a compound selected from: Lithium 5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-carboxylate;
Azetidin- 1 -yl-(3,5-dichloropyridin-2-yl)methanone;
(3,5-Dichloropyridin-2-yl)-(4-methylpiperazin-l-yl)methanone;
5-Bromo-pyridine-2-sulfonic acid (2,2,2-trifluoro-ethyl)-amide; 1 -(5-Bromo-pyridine-2-sulfonyl)-4-methyl-piperazine;
5-Bromo-pyridine-2-sulfonic acid dimethylamide; and
3,5-Dichloro-2-(piperidin-l-ylcarbonyl)pyridine.
Said compound(s) can be used as intermediates in processes for obtaining a compound of formula (I).
In this specification the term "alkyl" includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific for the straight chain version only. For example, "C1-6alkyl" and "C1-4alkyl" include methyl, ethyl, propyl, isopropyl and t-butyl. However, references to individual alkyl groups such as 'propyl' are specific for the straight-chained version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only. A similar convention applies to other radicals, for example "carbocyclylC1-3alkyl- R16" includes carbocyclylmethyl-R16, 1-carbocyclylethyl-R16 and 2-carbocyclylethyl-R16.
The term "halo" refers to fluoro, chloro, bromo and iodo. Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
A "4-7 membered saturated heterocyclic group" is a saturated monocyclic ring containing 4-7 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH2- group can optionally be replaced by a -C(O)- and a sulphur atom may be optionally oxidised to form the S-oxides. Examples and suitable values of the term "4-7 membered saturated heterocyclic group" are morpholino, piperidyl, 1,4-dioxanyl, 1,3-dioxolanyl, 1,2- oxathiolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, homopiperazinyl and tetrahydropyranyl.
A "nitrogen linked 4-7 membered saturated ring which optionally contains an additional nitrogen, oxygen or sulphur atom" is a saturated monocyclic ring containing 4-7 atoms linked to the X*-X4 containing ring of formula (I) via a nitrogen atom contained in the ring.
The ring optionally contains an additional heteroatom selected from nitrogen, sulphur or oxygen, wherein a -CH2- group can optionally be replaced by a -C(O)-, and the optional sulphur atom may be optionally oxidised to form the S-oxides. Particular examples of a "nitrogen linked 4-7 membered saturated ring which optionally contains an additional nitrogen, oxygen or sulphur atom" are piperazin-1-yl and morpholino, particularly morpholino.
A "heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH2- group can optionally be replaced by a -C(O)-, a ring nitrogen atom may optionally bear a C1-6alkyl group and form a quaternary compound or a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides. Examples and suitable values of the term "heterocyclyl" are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5- dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, iV-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-JV-oxide and quinoline-JV-oxide. In one aspect of the present invention a "heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH2- group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides.
A "carbocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH2- group can optionally be replaced by a -C(O)-. Particularly "carbocyclyl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for "carbocyclyl" include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.
Examples of "C1-6alkoxy" include methoxy, ethoxy and propoxy. Examples of "Ci-6alkanoylamino" include formamido, acetamido and propionylamino. Examples of "C1-6alkylS(O)a wherein a is 0,1 or 2" include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of "C1-6alkanoyl" include propionyl and acetyl. Examples of "iV-(C1-6alkyl)amino" include methylamino and ethylamino. Examples of "JV,JV-(C1-6alkyl)2amino" include di-iV-methylamino, di-(JV-ethyl)amino and N-ethyl-JV-methylamino. Examples of "JV-(C1-6alkyl)sulphamoyl" are JV- (methyl)sulphamoyl and JV-(ethyl)sulphamoyl.
Figure imgf000019_0001
are N,JV-(dimethyl)sulphamoyl and N-(methyl)-JV-(ethyl)sulphamoyl. Examples of "JV-(C1. 6alkyl)carbamoyl" are methylaminocarbonyl and ethylaminocarbonyl. Examples of "N,JV- (C1-6alkyl)2carbamoyl" are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of "C1-6alkylsulphonylamino" include methylsulphonylamino, isopropylsulphonylamino and t-butylsulphonylamino. Examples of "C^ealkylsulphonyl" include methylsulphonyl, isopropylsulphonyl and t-butylsulphonyl. The terms "-CMalkylcarbocyclyl" and "-C1-4alkylheterocyclyl" includes both straight and branched chain alkyl groups of between one and four carbon atoms that then link to a carbocycle or heterocycle respectively. The terms carbocycle and heterocycle are as defined above. Non-limiting examples of Ci^ahkylcarbocyclyl therefore include benzyl, 2- phenylethyl, 1-phenylethyl, cyclopropylmethyl and cyclohexylethyl. Non-limiting examples of C1-4alkylheterocyclyl include pyridin-3-ylmethyl, oxolan-2yl-methyl, 2-(4- piperidyl)ethyl and l-thiophen-2-ylethyl.
A suitable pharmaceutically acceptable salt of a compound of the present invention is, for example, an acid-addition salt of a compound of the present invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morphorine or tris-(2-hydroxyethyl)amine.
Some compounds of the formula (I) may have stereogenic centres and/or geometric isomeric centres (E- and Z-isomers), and it is to be understood that the present invention encompasses all such optical, diastereoisomers and geometric isomers that possess GSK3 inhibitory activity.
The present invention relates to any and all tautomeric forms of the compounds of the formula (I) that possess GSK3 inhibitory activity.
The definition of compounds of formula (I) also includes in vivo hydrolysable esters, solvates or solvates of salts thereof. It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the present invention encompasses all such solvated forms that possess GSK3 inhibitory activity.
Methods of Preparation
The present invention also provides a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof or in vivo hydrolysable ester thereof, which process comprises: a) reacting a pyrimidine of formula (II):
Figure imgf000021_0001
with a compound of formula (III):
Figure imgf000021_0002
wherein Y is a displaceable group; and R1, R2, R3, R4, X1, X2, X3 and X4 are, unless otherwise specified, as defined in formula (I); and thereafter optionally: b) converting a compound of the formula (I) into another compound of formula (I); c) removing any protecting groups; and d) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.
Y is, as mentioned above, a displaceable group. Suitable values for Y are, for example, a halo (such as a chloro, bromo or iodo) or sulphonyloxy group (such as trifluoromethanesulphonyloxy group). According to one embodiment of the present invention, Y is chloro, bromo or iodo. Specific reaction conditions for the above reactions are as follows: Step a): Amines of formula (II) and compounds of formula (III) may be reacted together under standard Buchwald-Hartwig conditions, (for example see J. Am. Chem. Soc, 118, 7215; J. Am. Chem. Soc, 119, 8451; J. Am. Chem. Soc, 125, 6653; J. Org. Chem., 62, 1568 and 6066) for example in the presence of palladium acetate, in a suitable solvent for example an aromatic solvent such as toluene, benzene or xylene, with a suitable base for example an inorganic base such as caesium carbonate or an organic base such as potassium-/-butoxide, in the presence of a suitable ligand such as 2,2'- bis(diphenylphosphino)- 1 , 1 '-binaphthyl or 2-dicyclohexylphosphino-2',4',6'-triiso-propyl- l,l'-biphenyl and at a temperature in the range of 25 to 80°C.
Pyrimidines of the formula (II), wherein R3 is methyl; and R2 and R4 are as defined in formula (I), may be prepared according to Scheme 1 :
Figure imgf000022_0001
28% NH4OH / PrOH 1 :3 MW 140 C, 10 bar, 3 h 78%
Figure imgf000022_0002
(H) Scheme 1
A synthesis of pyrimidines of formula (II) is described in Scheme 2, wherein Rx is selected from the same or different Ci-6alkyl and R2, R and R4 are as defined in formula (I).
Figure imgf000023_0001
Scheme 2
Compounds of formula (III) are commercially available compounds, or they are known in the literature, or they can be prepared by standard processes known in the art.
Compounds of formula (IV) in which R3 has the general structure Ra-CH-Rb, wherein Ra and Rb are hydrogen or form together a tetrahydropyran ring, wherein R4 is hydrogen or C^aHcyl, wherein said C^alkyl may optionally be substituted with one or more halo and wherein R2 is fluoro and Rx is as defined above, may be prepared according to Scheme 3, wherein,
Figure imgf000023_0002
DMFDMA DMF1 Δ
Figure imgf000023_0003
Scheme 3 Compounds of formula (Va), (Vb) and (Vc) are commercially available compounds, or they are known in the literature, or they can be prepared by standard processes known in the art. Compound (Vf) can exist in either E or Z conformation around the alkene.
A compound of formula (Ia) can be prepared by reacting an acid intermediate (VI) with primary or secondary amines as shown in Scheme 4. This reaction can be achieved by mixing the acid or carboxylate salt with a coupling agent in a polar, aprotic solvent followed by addition of the primary or secondary amine. The amidation conditions involve, for example, taking a mixture of the carboxylate or acid, a coupling agent (such as HBTU or CDI), a base, such as DIPEA, together in a solvent such as DCM, N-methyl pyrrolidinone or dimethylformamide and then adding the amine at room temperature. In this example C(O)NR28R29 is defined as -R5-R6 above.
Figure imgf000024_0001
(Vl) (Ia)
X=OH I Acid
X=OLi Lithium carboxylate salt
Scheme 4
It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the present invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halo group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1999). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group that may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on- carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a /-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well-known in the chemical art.
General Methods All solvents used were analytical grade and commercially available anhydrous solvents were routinely used for reactions. Reactions were typically run under an inert atmosphere of nitrogen or argon.
1H, 19F and 13C NMR spectra were recorded on a Varian Unity+ 400 NMR Spectrometer equipped with a 5mm BBO probehead with Z-gradients, or a Varian Gemini 300 NMR spectrometer equipped with a 5mm BBI probehead, or a Bruker Avance 400 NMR spectrometer equipped with a 60 μl dual inverse flow probehead with Z-gradients, or a Bruker DPX400 NMR spectrometer equipped with a 4-nucleus probehead equipped with Z-gradients, or a Bruker Avance 600 NMR spectrometer equipped with a 5mm BBI probehead with Z-gradients. Unless specifically noted in the examples, spectra were recorded at 400 MHz for proton, 376 MHz for fluorine-19 and 100 MHz for carbon-13. The following reference signals were used: the middle line of DMSO-Je δ 2.50 (IH), δ 39.51 (13C); the middle line of CD3OD δ 3.31 (IH) or δ 49.15 (13C); CDCl3 δ 7.26 (IH) and the middle line OfCDCl3 δ 77.16 (13C) (unless otherwise indicated). NMR spectra are reported either from high to low field or from low to high field.
Mass spectra were recorded on a Waters LCMS consisting of an Alliance 2795 (LC), Waters PDA 2996 and a ZQ single quadrupole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode. The capillary voltage was 3 kV and cone voltage was 30 V. The mass spectrometer was scanned between m/z 100-700 with a scan time of 0.3s. Separations were performed on either Waters X-Terra MS C8 (3.5 μm, 50 or 100 mm x 2.1 mm i.d.) or an ACE 3 AQ (100 mm x 2.1 mm i.d.) obtained from ScantecLab. Flow rates were regulated to 1.0 or 0.3 mL/min, respectively. The column temperature was set to 40 °C. A linear gradient was applied using a neutral or acidic mobile phase system, starting at 100% A (A: 95:5 10 mM NH4OAc:MeCN, or 95:5 8 mM HCOOH:MeCN) ending at 100% B (MeCN).
Alternatively, mass spectra were recorded on a Waters LCMS consisting of an Alliance 2690 Separations Module, Waters 2487 Dual 1 Absorbance Detector (220 and 254 nm) and a Waters ZQ single quadrupole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode. The capillary voltage was 3 kV and cone voltage was 30 V. The mass spectrometer was scanned between m/z 97-800 with a scan time of 0.3 or 0.8 s. Separations were performed on a Chromolith Performance RP-18e (100 x 4.6 mm). A linear gradient was applied starting at 95% A (A: 0.1% HCOOH (aq.)) ending at 100% B (MeCN) in 5 minutes. Flow rate: 2.0 mL/min.
Microwave heating was performed in a single-mode microwave cavity producing continuous irradiation at 2450 MHz.
HPLC analyses were performed on an Agilent HPlOOO system consisting of G1379A Micro Vacuum Degasser, G1312A Binary Pump, G1367A Well plate auto-sampler, G1316A Thermostatted Column Compartment and G1315B Diode Array Detector. Column: X-Terra MS, Waters, 3.0 x 100 mm, 3.5 μm. The column temperature was set to 40 0C and the flow rate to 1.0 ml/min. The Diode Array Detector was scanned from 210- 300 nm, step and peak width were set to 2 nm and 0.05 min, respectively. A linear gradient was applied, starting at 100 % A (A: 95:5 10 mM NH4OAc:MeCN) and ending at 100% B (B: MeCN), in 4 min.
Alternatively, HPLC analyses were performed on a Gynkotek P580 HPG consisting of gradient pump with a Gynkotek UVD 170S UV-vis.-detector equipped with a Chromolith Performance RP column (Cl 8, 100 mm x 4.6 mm). The column temperature was set to +25 0C. A linear gradient was applied using MeCN/0.1 trifluoroacetic acid in MiUiQ water, run from 10% to 100% MeCN in 5 minutes. Flow rate: 3 ml/min.
A typical workup procedure after a reaction consisted of extraction of the product with a solvent such as ethyl acetate, washing with water followed by drying of the organic phase over MgSO4 or Na2SO4, filtration and concentration of the solution in vacuo.
Thin layer chromatography (TLC) was performed on Merck TLC-plates (Silica gel 60 F254) and UV visualized the spots. Flash chromatography was performed on a Combi Flash® Companion™ using RediSep™ normal-phase flash columns. Typical solvents used for flash chromatography were mixtures of chloroform/methanol, DCM/methanol, heptane/ethyl acetate, chloroform/methanol/ NH3 (aq.) and DCM/methanol/NH3 (aq.). SCX ion exchange columns were performed on Isolute® columns. Chromatography through ion exchange columns were typically performed in solvents such a methanol.
Preparative chromatography was run on a Waters autopurifϊcation HPLC with a diode array detector. Column: XTerra MS C8, 19 x 300 mm, 10 μm. Narrow gradients with MeCN/(95:5 0.1M NH4OAcMeCN) were used at a flow rate of 20 ml/min. Alternatively, purification was achieved on a semi preparative Shimadzu LC-8A HPLC with a Shimadzu SPD-IOA UV-vis.-detector equipped with a Waters Symmetry® column (C18, 5 μm, 100 mm x 19 mm). Narrow gradients with MeCN/0.1% trifluoroacetic acid in MiIIiQ Water were used at a flow rate of 10 ml/min. The formation of hydrochloride salts of the final products were typically performed in solvents or solvents mixtures such as diethyl ether, tetrahydrofuran, DCM/toluene, DCM/methanol, followed by addition of IM hydrogen chloride in diethyl ether.
The following abbreviations have been used: aq. aqueous;
CDI carbonyl diimidazole;
CHCl3 chloroform;
CDCl3 deuterated chloroform;
CH2Cl2 dichloromethane;
Cs2CO3 caesium carbonate;
DCM dichloromethane;
DIPEA N,N-diisopropylethylamine;
DMF ΛζTV-dimethylformamide;
DMFDMA dimethylformamide dimethylacetal;
DMSO dimethyl sulphoxide;
EtOAc ethyl acetate;
EtOH ethanol;
HBTU O-Benzotriazole-N^iV.iV'.N'-tetramethyl-uronium-hexafluoro- phosphate
HOAc acetic acid;
HCOOH formic acid;
MeCN acetonitrile;
MeOH methanol;
Me3SnCl trimethyltin chloride;
MgSO4 magnesium sulphate;
Min minutes;
NaBH3CN sodium cyanoborohydride;
NaHCO3 sodium bicarbonate;
NaOMe sodium methoxide;
Na2SO4 sodium sulphate; n-BuOH n-butanol; NH3 ammonia;
NH4OAc ammonium acetate;
NH4OH ammonium hydroxide; o.n. overnight
Pd/C palladium on carbon;
Pd(PPh3)2Cl2 bis(triphenylphosphine)palladium dichloride;
Pd2(dba)3 tris(diben2ylideneacetone)dipalladium;
PrOH propan-1-ol; r.t. or RT room temperature;
Ret. T retention time;
Selectfluor iV-fluoro-iV"-chloromethyl-triethylenediamine-bis(tetrafluoroborate);
THF tetrahydrofuran; t-BuLi tert-butyllithium;
Xantphos 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene; and
X-Phos 2-dicyclohexylphosphino-2',4',6'-triiso-propyl-l,r-biphenyl.
Starting materials used were either available from commercial sources or prepared according to literature procedures and had experimental data in accordance with those reported.
Compounds have been named either using ACD/Name, versions 8.08 or 9, software from Advanced Chemistry Development, Inc. (ACD/Labs), Toronto ON, Canada, www.acdlabs.com, 2004 or named according to the IUPAC convention.
General methods A to C
In the following general methods A to C, the groups R1, R2, R3, R4, X1, X2, X3, X4 and Y are used independently to indicate the diversity of substitution within each structure. The identity of R1, R2, R3, R4, X1, X2, X3, X4 and Y will be clear to a person skilled in the art based on the starting materials and intermediates for each specific example. For instance in Example 1, which refers to General method A, Al is 5-fluoro-4-[2-methyl-l-(tetrahydro- 2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine such that R3 is 4-tetrahydropyranyl and R4 is methyl and A2 is 2-bromo-5-(methylsulfonyl)pyridine such that X1 is N, X2, X3 and X4 are CH and R1 is sulphonylmethane.
General Method A
Figure imgf000031_0001
Al (1.01-1.27 equiv.), A2 (1.0 equiv.) and Cs2CO3 (1.6-2.25 equiv.) were mixed in anhydrous 1,4-dioxane and the mixture was flushed with argon for 5 minutes before Pd2(dba)3 (0.05-0.2 equiv.) and X-Phos or Xantphos (0.10-0.20 equiv.) were added. The mixture was flushed with argon, then heated in a sealed tube at +90 - +100 0C until the reaction was complete. Workup was done according to one of the following procedures: 1) The reaction mixture was diluted with a mixture of H2CVCH2Cl2, the product was extracted with CH2Cl2, the combined organic phase was dried (Mg2SO4), filtered and concentrated. 2) The reaction mixture was diluted with CH2Cl2, filtered and concentrated. 3) The solvent was removed in vacuo and the residue was taken up in CH2Cl2 and washed with diluted NaHCO3 (aq.) or water. The organic layer was dried (Na2SO4), filtered and concentrated. Purification was performed using preparative HPLC or chromatography on silica. Either the freebase or HCl salt was prepared.
General Method B
Figure imgf000031_0002
B1 B2 B3
To a solution of Bl (0.12 mmol, 1.0 equiv.) in anhydrous DMF (0.65 mL) were added HBTU (59 mg, 0.15 mmol, 1.2 equiv.), amine B2 or a salt thereof (0.16 mmol, 1.3 equiv.) and DIPEA (48 mg, 0.37 mmol, 3 equiv. for free amines and 1 additional equiv. for each equiv. of salt). The reaction mixture was shaken o.n. at r.t. The crude product was purified by preparative HPLC. General Method C
Figure imgf000032_0001
Thionyl chloride (5 mL) was added to Cl (1.0 equiv.). After addition of 2 drops of anhydrous DMF, the reaction mixture was refluxed for 30 minutes under an atmosphere of nitrogen. The solvent was evaporated in vacuo and the residue was dissolved in CH2Cl2 (until a clear solution was obtained). C2 (1.0 equiv.) was added dropwise followed by addition of triethylamine (1.0 equiv.). The reaction mixture was stirred at r.t. for 30 minutes before it was diluted with CH2Cl2, washed with saturated NaHCO3 (aq.), dried (Na2SO4) and filtered. The solvent was evaporated in vacuo and the crude product was purified using flash column chromatography.
EXAMPLES
The present invention will further be described in more detail by the following Examples, which are not to be construed as limiting the present invention.
Example 1
5-Fluoro-N-[5-(methylsulfonyl)pyridin-2-yl]-4-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine hydrochloride
Figure imgf000032_0002
The title compound was prepared in accordance with general method A using 5-fluoro-4- [2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine (as described in Example 6) (50 mg, 0.18 mmol) and 2-bromo-5-(methylsulfonyl)pyridine (42 mg, 0.18 mmol) to give the title compound (34 mg, 44%). 1B. NMR (CDCl3) δ ppm 9.19 (s, 1 H) 8.91 (d, J=2.02 Hz, 1 H) 8.48 - 8.53 (m, 2 H) 8.12 (dd, J=8.84, 2.53 Hz, 1 H) 7.65 (d, J=3.79 Hz, 1 H) 5.10 (tt, J=12.28, 4.26 Hz, 1 H) 4.10 (dd, J=I 1.62, 4.29 Hz, 2 H) 3.34 - 3.44 (m, 2 H) 3.09 (s, 3 H) 2.66 (s, 3 H) 2.46 (qd, J=12.46, 4.55 Hz, 2 H) 1.91 (dd, J=12.25, 2.65 Hz, 2 H); MS (ES) m/z 433 (M+l).
Example 2
5-Fluoro-N-[6-(methylsulfonyl)pyridin-3-yl]-4-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine
Figure imgf000033_0001
The title compound was prepared in accordance with general method A using 5-fluoro-4- [2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine (as described in Example 6) (50 mg, 0.18 mmol) and 5-bromo-2-(methylsulfonyl)pyridine (42 mg, 0.18 mmol) to give the title compound (36 mg, 46%). 1H NMR (chloroform -d) δ ppm 8.85 (d, J=2.53 Hz, 1 H) 8.34 - 8.39 (m, 2 H) 8.11 (s, 1 H) 8.00 (d, J=8.84 Hz, 1 H) 7.69 (d, J=3.79 Hz, 1 H) 4.99 - 5.09 (m, 1 H) 4.10 (dd, J=11.62, 4.80 Hz, 2 H) 3.36 (td, J=I 1.87, 1.77 Hz, 2 H) 3.20 (s, 3 H) 2.65 (s, 3 H) 2.48 - 2.60 (m, 2 H) 1.87 (dd, J=12.38, 3.28 Hz, 2 H); MS (ES) m/z 433 (M+l).
Example 3 5-Fluoro-N-{5-[(4-methylpiperazin-l-yl)carbonyl]pyridin-2-yl}-4-[2-methyl-l- (tetrahydro-2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine
Figure imgf000034_0001
The title compound was prepared in accordance with general method A using 5-fluoro-4- [2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine (as described in Example 6) (35 mg, 0.13 mmol) and l-[(6-chloropyridin-3-yl)carbonyl]-4- methylpiperazine (reported in WO 2003082853) (27 mg, 0.11 mmol) to give the title compound (60 mg, 100%). MS (ES, retention time: 2.53min) m/z 385 (M+l).
Example 4
5-Fluoro-N-{6-[(4-methylpiperazin-l-yl)carbonylJpyridm-3-yl}-4-f2-methyl-l- (tetrahydro-2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine
Figure imgf000034_0002
The title compound was prepared in accordance with general method A using 5-fluoro-4- [2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrirnidin-2-amine (as described in Example 6) (26 mg, 0.095 mmol) and l-[(5-bromopyridin-2-yl)carbonyl]-4- methylpiperazine (obtained from Example 4b) (27 mg, 0.095 mmol) to give the title compound in 61% (28 mg) yield.
1H NMR (400 MHz, DMSCW6) δ ppm 9.95 (s, 1 H) 8.79 (d, J=2.26 Hz, 1 H) 8.64 (d, J=2.76 Hz, 1 H) 8.11 (dd, J=8.66, 2.64 Hz, 1 H) 7.55 (d, J=8.78 Hz, 1 H) 7.35 (d, J=3.76 Hz, 1 H) 5.03-4.91 (m, 1 H) 3.81 (dd, J=I 1.42, 4.14 Hz, 2 H) 3.67-3.56 (m, 2 H) 3.56-3.47 (m, 2 H) 3.11 (t, J=11.29 Hz, 2 H) 2.54 (s, 3 H) 2.40-2.31 (m, 2 H) 2.31-2.24 (m, 2 H) 2.18 (s, 3 H) 2.24-2.10 (m, 2 H) 1.78 (dd, J=12.17, 2.38 Hz, 2 H). MS (ES) m/z 481 (M+l). l-[(5-Bromopyridin-2-yl)carbonyl]-4-methylpiperazine was prepared as follows:
Example 4(a) 5-Bromopyridine-2-carbonyl chloride
Figure imgf000035_0001
Thionylchloride (8.15 g, 68.5 mmol) and anhydrous DMF (catalytic amount) were added to 5-bromopyridine-2-carboxylic acid (0.50 g, 2.48 mmol) and the reaction mixture was refluxed until a clear solution was obtained. Excess thionylchloride was removed in vacuo to yield a crude product that was used directly without further purification or analysis.
Example 4(b) l-[(5-Bromopyridin-2-yl)carbonyl]-4-methylpiperazine
Figure imgf000035_0002
1-methylpiperazine (0.13 g, 1.3 mmol) and triethylamine (0.13 g, 1.3 mmol) were sequentially added to a stirred solution of 5-bromopyridine-2-carbonyl chloride (0.27 g, 1.24 mmol), obtained in example 4(a), in CH2Cl2 (5 mL) and the reaction was stirred at ambient temperature until reaction was complete. The organic phase was diluted (CH2Cl2), washed with i) saturated aqueous NaHCO3, ii) water. Absolute EtOH was then added followed by evaporation to dryness. The crude product was obtained in 89% (0.31 g) yield. This material was used in the next step (Example 4) without further purification. 1H NMR (400 MHz, DMSO-J6) δ ppm 8.72 (d, J=2.26 Hz, 1 H) 8.18 (dd, J=8.41, 2.38 Hz, 1 H) 7.55 (d, J=8.28 Hz, 1 H) 3.68-3.58 (m, 2 H) 3.40-3.33 (m, 2 H) 2.40-2.33 (m, 2 H) 2.29-2.22 (m, 2 H) 2.19 (s, 3 H). MS (ES) m/z 286 (81Br) (M+l).
Example 5
N-[6-(Azendin-l-ylcarbonyl)pyridin-3-yl]-5-fluoro-4-[2-methyl-l-(tetrahydro-2H-pyran-
4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine
Figure imgf000035_0003
The title compound was prepared in accordance with general method A, with the exception that a second purification on a silica gel column was necessary to obtain a pure material, using 5-fluoro-4-[2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2- amine (as described in Example 6) (36 mg, 0.13 mmol) and 2-(azetidin-l-ylcarbonyl)-5- bromopyridine (reported in WO 2005014571) (32 mg, 0.13 mmol) to give the title compound in 18% (10 mg) yield.
1H NMR (400 MHz, DMSCW6) δ ppm 10.03 (s, 1 H) 8.88 (d, J=2.26 Hz, 1 H) 8.66 (d, J=2.51 Hz, 1 H) 8.12 (dd, J=8.66, 2.64 Hz, 1 H) 7.89 (d, J=8.53 Hz, 1 H) 7.37 (d, J=3.51 Hz3 1 H) 5.06-4.95 (m, 1 H) 4.57 (t, J=7.65 Hz, 2 H) 4.05 (t, J=7.70 Hz, 2 H) 3.82 (dd, J=I 1.42, 4.14 Hz, 2 H) 3.12 (t, J=11.04 Hz, 2 H) 2.55 (s, 3 H) 2.31-2.13 (m, 4 H) 1.81 (dd, J=12.05, 2.26 Hz, 2 H). MS (ES) m/z 438 (M+l).
The main intermediates were prepared as followed in Examples 6-9: Example 6 5-Fluoro-4-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine Example 6Ca) 4-[N-Acetyl-N-(tetrahydro-2H-pyran-4-yl)]amino-5-methylisoxazole
Figure imgf000036_0001
5-Methyl-4-amino-isoxazole (Reiter, L.A., J. Org. Chem. 1987, 52, 2714-2726) (0.68 g, 5.1 mmol) and acetic acid (0.61 g, 10.2 mmol) were dissolved in MeOH (20 mL). Tetrahydro-2H-pyran-4-one (0.76 g, 7.6 mmol) was added and the mixture was cooled to 0 - (-5) °C and stirred for 1 h. Sodium cyanoborohydride (0.32 g, 5.1 mmol) was added to the reaction mixture at -5 °C, causing weak exothermic and gas evolution. The cooling bath was removed and the mixture was stirred at r.t. for 1 h, followed by the addition of a second portion of sodium cyanoborohydride (0.1 g, 1.6 mmol). After stirring for 2 h at r.t., the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in toluene and re-concentrated. The residue was dissolved in TΗF (10 mL) and acetic anhydride (1.56 g, 15.3 mmol) was added. The resulting mixture was stirred overnight at r.t. then for 1 h at +50 0C. The volatiles were removed in vacuo and the residue was dissolved in toluene and concentrated in vacuo to give the title compound (1.36 g, 78%).
1H NMR (CDCl3) ppm δ 8.04 (s, 1 H), 4.86-4.73 (m, 1 H), 4.00-3.89 (m, 2 H), 3.52-3.42 (m, 2 H), 2.35 (s, 3 H), 1.81 (s, 3 H), 1.70-1.57 (m, 2 H), 1.49-1.23 (m, 2 H); MS (ESI) m/z 225 (M+l).
Example 6(b) 5-Acetyl-2-methyl~l-(tetrahydro-2H-pyran-4-yl)-lH-imidazole
Figure imgf000037_0001
4-[iV-Acetyl-iV-(tetrahydro-2H-pyran-4-yl)]amino-5-methylisoxazole (4.8 g, 21.4 mmol) was dissolved in EtOH (30 ml), and the mixture was hydrogenated over PaVC (10%, wet paste, 0.10 g) at 3 bar. The reaction mixture was stirred at 50 0C for 3 h. An additional amount of Pd/C (10%, wet paste, 0.15 g) was added and the mixture was continued stirring at +50 0C for 3 h. Sodium methoxide (1.70 g, 31.46 mmol) was added and the resulting mixture was heated to reflux for 3O h. Ammonium chloride was added to quench the reaction. The mixture was filtrated through diatomaceous earth and the filtrate was evaporated in vacuo. The residue was diluted with saturated sodium bicarbonate (aq.) and extracted with EtOAc, then with CHCl3. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc) to give the title compound (3.7 g, 83%). 1H NMR (CDCl3) δ 7.70 (s, 1 H), 5.40-5.30 (m, 1 H), 4.13-4.01 (m, 2 H), 3.57-3.44 (m, 2 H), 2.57 (s, 3 H), 2.44 (s, 3 H), 2.43-2.30 (m, 2 H), 1.80-1.72 (m, 2 H).
Example 6(c) (2E)-3-Dimethylammo~l-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)-lH- imidazol-5-yl]prop-2-en-l-one
Figure imgf000037_0002
5-Acetyl-2-methyl-l-(tetrahydro-2H-pyran-4-yl)-lH-imidazole (3.7 g, 17.79 mmol) was dissolved in DMFDMA/DMF (1:1, 100 mL) and the mixture was stirred under reflux overnight. After cooling to r.t. the mixture was extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (CH2Cl2MeOH 15:1) to give the title compound (3.85 g, 82%). 1H NMR (CDCl3) δ 7.65 (d, J= 12.6 Hz, 1 H), 7.46 (s, 1 H), 5.55-5.42 (m, 2 H), 4.08 (dd, J= 11 Hz, 4.4 Hz, 2 H), 3.52 (t, J= 11 Hz, 2 H), 2.99 (br s, 6 H), 2.56 (s, 3 H), 2.45-2.32 (m, 2 H), 1.80-1.72 (m, 2 H); MS (ESI) m/z 264 (M+l).
Example 6(d) (2Z)-3-Dimethylamino-2-fluoro-l-[2-methyl-l-(tetr-ahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]prop-2-en-l-one
Figure imgf000038_0001
Selectfluor (7.75 g, 21.87 mmol) was added in portions to a stirred solution of (2£)-3- dimethylamino-l-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-5-yl]prop-2-en-l- one (3.85 g, 14.58 mmol) in MeOH (100 mL) at r.t. After stirring at r.t. for 3 h the reaction mixture was cooled in ice/acetone and filtered. The filtrate was evaporated under reduced pressure and the residue was taken into CH2Cl2. It was washed with aq. ammonia, brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (CH2Cl2ZMeOH 15:1). The reaction was not run to completion, and the reaction was repeated again with Selectfluor (1.5 equiv.) followed by the same workup. The title compound (1.47 g, 36%).
1HNMR (CDCl3, 300 MHz) δ 7.34 (s, 1 H), 6.84 (d, J= 27.9 Hz, 1 H), 5.00-4.88 (m, 1 H), 4.04 (dd, J= 11.2 Hz, 4.2 Hz, 2 H), 3.46 (t, J= 11 Hz, 2 H), 3.08 (s, 6 H), 2.53 (s, 3 H), 2.42-2.28 (m, 2 H), 1.84-1.75 (m, 2 H); MS (ESI) m/z 282 (M++l). Example 6(e) 5-Fluoro-4-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-5- ylJpyrimidin-2-amine
Figure imgf000039_0001
A reaction mixture of (2Z)-3-dimethylamino-2-fluoro-l-[2-methyl-l-(tetrahydro-2H- pyran-4-yl)-lH-imidazol-5-yl]prop-2-en-one (1.47 g, 5.22 mmol), guanidine carbonate (2.35 g, 13.06 mmol) and sodium methoxide (4.0 equiv.) in 1-butanol was heated in a microwave reactor for 10 minutes at 140 °C under argon or nitrogen atmosphere. The mixture was filtered and the filter was rinsed with CH2Cl2. The solvent was evaporated in vacuo and the crude product was purified using flash column chromatography (CH2Cl2ZMeOH 20: 1) to give the title compound (1.21 g, 84%).
1H NMR (CDCl3, 300 MHz) δ 8.17 (d, J= 3.3 Hz, 1 H), 7.59 (d, J= 3.9 Hz, 1 H), 5.27-5.13 (m, 1 H), 4.93 (br s, 2 H), 4.13 (dd, J= 11.5 Hz, 4.3 Hz, 2 H), 3.48 (t, J= 11 Hz, 2 H), 2.62 (s, 3 H), 2.58-2.40 (m, 2 H), 1.95-1.84 (m, 2 H); MS (ESI) m/z 278 (M+ 1).
Example 7
4-(l,2-Dimethyl-lH-imidazol-5-yl)-S-fluoropyrimidin-2-amine
Example 7 fa) l,2-Dimethyl-5-(trimethylstannyl)-lN-imidazole
Figure imgf000039_0002
1,2-Dimethylimidazole (0.960 g, 10.0 mmol) was diluted in dry THF (50 mL) under an argon atmosphere and the solution was cooled to -78°C. tert-Butyllithium (1.7M in pentane, 6.47 mL, 11.0 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred for 1 h at -78 °C and then treated with a solution of trimethyltin chloride (2.2 g, 11.0 mmol) in anhydrous THF (10 mL). The mixture was stirred for 60 h from -78°C to r.t.. The solvent was then evaporated in vacuo to give the title compound (1.29 g, 50%). The crude product was used in the next step without further purification.
1H NMR (CDCl3) δ ppm 6.87 (s, 1 H), 3.56 (s, 3 H), 2.41 (s, 3 H), 0.45-0.18 (m, 9 H); MS (CI) m/z 261 (120Sn) (M+l). Example Kb) 2-Chloro-4-(l,2-dimethyl-lH-imidazol-5-yl)-5-fluoropyrimidine
Figure imgf000040_0001
l,2-Dimethyl-5-(trimethylstannyl)-lH-imidazole (0.950 g, 3.68 mmol) and 2,4-dichloro~5- fluoropyrimidine (0.601 g, 3.60 mmol) were diluted in anhydrous DMF (20 mL) and the solution was degassed with argon. Pd(PPh3)2Cl2 (0.126 g, 0.17 mmol) was added and the reaction mixture was stirred at +80 °C for 15 h. The reaction mixture was cooled down to r.t. and concentrated under reduced pressure. Saturated potassium fluoride (aq., 50 mL) was added and the mixture was stirred for 30 minutes before extraction with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (heptane/EtOAc, 7:3) to give the title compound (0.41 g, 50%).
1H NMR (CDCl3, 600 MHz) δ ppm 8.40 (d, J=2.9 Hz, 1 H), 7.86 (d, J=4.4 Hz, 1 H), 3.97 (s, 3 H), 2.53 (s, 3 H); MS (ESI) m/z 227 (M+l).
Example 7(c) 4-(l,2-Dimethyl-lH-imidazol-5-yl)-5-fluoropyrimidin-2-amine
Figure imgf000040_0002
2-Chloro-4-(l,2-dimethyl-lH-imidazol-5-yl)-5-fluoropyrimidine (0.295 g, 1.30 mmol) was dissolved in 1-propanol (3.0 mL) in a microwave vial. Ammonium hydroxide (28%, 1.0 mL) was added, the vial was sealed and the mixture heated in a microwave oven (+140 °C, 4h). The reaction mixture was cooled to r.t. and the solvent was evaporated. The residue was partitioned between CH2Cl2 and IM aqueous HCl. The aqueous phase, containing the product, was neutralized with saturated aqueous NaHCO3 and the product extracted with CH2Cl2. The organic phase was co-evaporated with ethanol and the residue was purified by flash chromatography using (CH2Cl2ZMeOH gradient; 100:1 to 94:6) to give the title compound (0.210 g, 78%).
1H NMR (CDCl3) δ ppm 8.15 (d, J=3.5 Hz, 1 H), 7.71 (d, J=4.3 Hz, 1 H), 4.87 (br s, 2 H), 3.97 (s, 3 H)5 2.49 (s, 3 H); MS (ESI) m/z 208 (M+l). Example 8
5-Fluoro-4-[l-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-lH-imidazol-5- ylJpyrimidin-2-amine
Example 8(a) 5-Acetyl-l-(tetrahydro-2H-pyran-4-yl)- 2-trifluoromethyl-lH-imidazole
Figure imgf000041_0001
5-Methyl-4-amino-isoxazole (1.7 g, 17.25 mmol) and acetic acid (1.1 g, 19 mmol) were dissolved in methanol (50 mL). Tetrahydro-2H-pyran-4-one (1.9 g, 19 mmol) was added and the mixture was cooled to 0 - (-5) 0C and stirred for 1 h. Sodium cyanoborohydride (0.812 g, 12.9 mmol) was added in portions to the reaction mixture at -5 °C, causing weak exothermic and gas evolution. The cooling bath was removed and the mixture was stirred at r.t. for 2 h followed by addition of water (20 mL). The methanol was removed from the reaction mixture, and the intermediate amine was extracted with ethyl acetate (3x80 mL). The combined organic layers were dried (Na2SO4), concentrated to dryness, dissolved in toluene and re-concentrated. The crude intermediate amine, was dissolved in CH2Cl2 (20 mL) and pyridine (2 mL, 26 mmol) was added. The mixture was cooled to 0°C and trifluoroacetic anhydride (4.35 g, 20.7 mmol) was added dropwise. The mixture was continued stirring for 2 h at r.t. and was then washed with water and saturated NaHCO3. The aqueous layer was extracted with CH2Cl2 (2x30 mL), the organic extracts were dried (Na2SO4) and concentrated to dryness to give a second crude intermediate, 4-[N- (tetrahydro-2H-pyran-4-yl)]-N-trifluoroacetyl-amino-5-methylisoxazole. MS (ES) m/z 279 (M++!). The title compound was prepared in accordance with the general method of Example 6 (b) using the intermediate 4-[N-(tetrahydro-2H-pyran-4-yl)]-N-trifluoroacetyl- amino-5-methylisoxazole (max 17.25 mmol), with the exception that the product was purified by flash chromatography (heptane/EtOAc 3:2), giving the title compound (3.03 g, 67%).
1H ΝMR (CDCl3, 300 MHz) δ 7.85 (s, 1 H), 4.89-4.75 (m, 1 H), 4.17-4.07 (m, 2 H), 3.54- 3.44 (m, 2 H), 2.75-2.60 (m, 2 H), 2.56 (s, 3 H), 1.72-1.63 (m, 2 H); MS (ES) m/z 263 (M+l). Example 8(b) (2E)-3-Dimethylamino-l-[l-(tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl- lH-imidazol-5-yl]prop-2~en-l-one
Figure imgf000042_0001
The title compound was prepared in accordance with the general method of Example 6(c) with the exception that the product was purified by flash chromatography (EtOAc). Using
5-acetyl-l-(tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl-lH-imidazole (3.03 g, 11.55 mmol) the title compound was obtained (3.2 g, 87 %).
1H NMR (CDCl3, 300 MHz) δ 7.72 (d, J= 12.3 Hz, 1 H), 7.49 (s, 1 H), 5.50 (d, J= 12.3
Hz, 1 H), 4.89-4.75 (m, 1 H), 4.14-4.05 (m, 2 H), 3.54-3.44 (m, 2 H), 3.16 (br. s, 3 H), 2.93 (br. s, 3 H), 2.86-2.72 (m, 2 H), 1.80-1.72 (m, 2 H); MS (ES) m/z 318 (M+l).
Example 8(c) (2Z)-3-Dimethylamino-2-fluoro-l-[l-(tetrahydro-2H-pyran-4-yl)-2- trtfluoromethyl-lH~imidazol-5-yl]prop-2-en-l-one
Figure imgf000042_0002
Selectfluor (0.370 g, 1.04 mmol) was added in portions to a stirred solution of (2E)-3- dimethylamino- 1 -[ 1 -(tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl- lH-imidazol-5-yl]prop- 2-en-l-one (0.300 g, 0.946 mmol) in MeCN (20 rnL) at 0 0C. After stirring for 0.5 h at r.t. more Selectfluor (0.050 g, 0.14 mmol) was added, and the mixture was stirred for 0.5 h. The solvent was evaporated in vacuo, diluted with 3% aqueous NH3 (20 mL) and extracted with CHCl3 (3x20mL). The organic extracts were dried (Na2SO4), evaporated in vacuo and the crude product was purified by flash chromatography (heptane/EtOAc 1:2), followed by neat EtOAc) to obtain the title compound (0.170 g, 53 %).
1H NMR (CDCl3, 300 MHz) δ 7.34 (s, 1 H), 6.85 (d, J= 26.7 Hz, 1 H), 4.67-4.54 (m, 1 H), 4.11-4.03 (m, 2 H)5 3.50-3.38 (m, 2 H), 3.14 (s, 6 H), 2.72-2.56 (m, 2 H), 1.83-1.74 (m, 2 H); MS (ES) m/z 336 (M+l). Example 8(d) 5-Fluoro-4-[l-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-lH-imidazol- 5-yl]pyrimidin-2-amine
Figure imgf000043_0001
The title compound was prepared in accordance with the method in 6(e) by using (2Z)-3- dimethylamino-2-fluoro- 1 -[ 1 -(tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl- lH-imidazol-
5-yl]prop-2-en-l-one (0.330 g, 1.0 mmol) and guanidine carbonate (0.45 g, 2.50 mmol).
After purification by flash chromatography (heptane/EtOAc 1 :2), the title compound was obtained (0.17O g, 51 %).
1H NMR (CDCl3, 300 MHz) δ 8.29 (s, 1 H), 7.63 (d, J= 2.7 Hz, 1 H), 5.10 (br.s., 2 H), 4.88-4.76 (m, 1 H), 4.16-4.07 (m, 2 H), 3.53-3.42 (m, 2 H), 2.80-2.65 (m, 2 H), 1.89-1.81
(m, 2 H); MS (ES) m/z 332 (M+l).
Example 9 5-Fluoro-4-[l-methyl-2-(trifluoromethyl)-lH-imidazol-5-yl]pyrimidin-2-amine Example 9(a) 2,2,2-Trifluoro-N-methyl-N-(5-methylisoxazol-4-yl)acetamide
Figure imgf000043_0002
Trifluoroacetic anhydride (10 mL, 71 mmol) in CH2Cl2 (100 mL) was added to N,5- dimethylisoxazol-4-amine (Reiter, L.A., J. Org. Chem. 1987, 52, 2714-2726) (6.68g, 59.6 mmol) in DCM (200 mL) and pyridine (6 mL, 74 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min and at r.t. for 2 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with H2O and saturated NaHCO3 (aq). The organic layer was dried (Na2SO4), concentrated in vacuo to give the title compound (12.4 g, 100%). MS (ESI) m/z 208 (M+). Example 9(b) l-[l-Methyl-2-(trifluoromethyl)-lH-imidazol-5-yl]ethanone
Figure imgf000044_0001
2,2,2-Trifluoro-N-methyl-N-(5-methylisoxazol-4-yl)acetamide (12.4 g , 59.6 mmol, obtained from Example 9(a)) in EtOH (30 ml) was hydrogenated over Pd/C (10%, 1.0 g) at 50 psi. The reaction mixture was stirred at +50 °C overnight. Sodium methoxide (5.0 g, 87.7 mmol) was added and the resulting mixture was heated to reflux overnight. The mixture was filtered through diatomaceous earth and the residue was diluted with saturated NaHCO3 (aq.) and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (Heptane:EtOAc 2: 1) to give the title compound (6.1 g, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (s, 1 H), 4.07 (s, 3 H), 2.54 (s, 3 H); MS (ESI) m/z 192 (M+).
Example 9(c) (2E)-3-(Dimethylamino)-l-[l-methyl-2-(trifluoromethyl)-lH-imidazol-5- ylJprop-2-en-l-one
Figure imgf000044_0002
l-[l-Methyl-2-(trifluoromethyl)-lH-imidazol-5-yl]ethanone (6.0 g, 31 mmol, obtained from Example 9(b)) was dissolved in DMFDMA/DMF (1:1, 46 mL) and the mixture was stirred at +100 °C overnight. After cooling to r.t. the mixture was diluted with H2O and extracted with CH2Cl2 (three times). The organic phases were combined, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (7.11 g, 93%). MS (ESI) m/z 247 (M+); MS (ESI) m/z 248 (M + 1).
Example 9(d) (2Z)-3-(Dimethylamino)-2-fluoro-l-[l-methyl-2-(trtfluoromethyl)-lH- imidazol-5-yl]prop-2-en-l-one
Figure imgf000045_0001
Selectfluor (10.9 g, 30.8 mmol) was added in portions to a stirred solution of (2E)-3- (dimethylamino)- 1 - [ 1 -methyl-2-(trifluoromethyl)~ lH-imidazol-5 -y l]prop-2-en- 1 -one (7.0 g, 28.3 mmol, obtained from Example 9(c)) in CH3CN (250 mL) at 0 0C. After stirring at 0 °C for 1.5 h the reaction mixture was diluted with H2O and extracted with CH2Cl2 (three times). The organic phases were combined, dried (Na2SO4), filtered and concentrated in vacuo to give the crude title compound that was used in the next step without any further purification. MS (ESI) m/z 265 (M+); MS (ESI) m/z 266 (M + 1).
Example 9(e) 5-Fluoro-4-[l-methyl-2-(trifluoromethyl)-lH-imidazol-5-yl]pyrimidin-2- amine
Figure imgf000045_0002
A reaction mixture of (2Z)-3-(dimethylamino)-2-fluoro-l-[l-methyl-2-(trifluoromethyl)- lH-imidazol-5-yl]prop-2-en-l-one (28.3 mmol, crude from Example 9(d)), guanidine carbonate (13.5 g, 75 mmol) and NaOMe (6.5 g, 120 mmol) in 1-butanol (250 mL) was heated to reflux under argon atmosphere for 2.5 h. The mixture was diluted with H2O and extracted with CH2Cl2. The organic phases were combined, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Heptane:EtOAc 1: 1 to Heptane:EtOAc 1: 2) to give the title compound (1.76 g, 21%). 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (d, J=3.03 Hz, 1 H) 7.74 (d, J=4.04 Hz, 1 H) 5.02 (br. s., 2 H) 4.14 (s, 3 H); MS (ESI) m/z 261 (M+).
Example 10
(6-Ethoxy-pyridin-3-yl)-{5-fluoro-4 -[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4- yl]-pyrinιidin-2-yl}-amine
Figure imgf000046_0001
The title compound was prepared in accordance with the general method A using 5-fluoro- 4-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine (as described in Example 6) (50 mg, 0.18 mmol) and 5-bromo-2-ethoxy-pyridine (36 mg, 0.18 5 mmol) to give the title compound (27 mg, 38%).
1H NMR (CDCl3) δ ppm 8.24 (m, 2 H) 7.68 (m, 1 H) 7.56 (m, 1 H) 7.36 (br s, 1 H) 6.70 (d, J=8.84 Hz, 1 H) 5.11 (m, 1 H) 4.32 (q, J=7.07, 2 H) 3.95 - 3.91 (m, 2 H) 3.05 (m, 2 H) 2.61 (s, 3 H) 2.35-2.24 (m, 2 H) 1.75 (m, 2 H), 1.39 (t, J=7.07 Hz, 3 H); MS (ES) m/z 399 (M+l). 0
Example 11
{5-Fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-(2- methoxy-pyrimidin-5-yl)-amine
Figure imgf000046_0002
s The title compound was prepared in accordance with the general method A using 5-fluoro- 4-[2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine (as described in Example 6) (50 mg, 0.18 mmol) and 5-bromo-2-methoxy-pyrimidine (34 mg, 0.18 mmol) to give the title compound (8 mg, 12%). 1Η NMR (CDC13) δ ppm 8.70 (s, 2 Η) 8.29 (m, 1 Η) 7.62 (d, J=4.04 Hz, 1 H) 7.11 (s, 1 H)o 5.06 (m, 1 H) 4.03 (m, 1 H) 4.01 (s, 3 H) 3.17 (m, 2 H) 2.63 (s, 3 H) 2.41 (m, 2 H) 1.81 (m, 2 H); MS (ES) m/z 386 (M+l). Examples 12-40
The following Examples 12-40 were prepared by the general procedure B using the appropriate starting materials which include: lithium 5-[[5-fluoro-4-[2-methyl-3-(oxan-4- yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridine-2-carboxylate (as described below) and the amine necessary to deliver the amide shown in the table below.
Lithium 5-FF5-fluoro-4-F2-methyl-3-(oxan-4-yl)imidazol-4-ylJpyrimidin-2- yllamino]vyridine-2-carboxvlate
Figure imgf000047_0001
Methyl 5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-carboxylate (prepared as described in Example 41) (1.49 g, 3.61 mmol) in MeOH (70 mL) was heated at 600C for 30 min. The flask was removed from the oil bath and a solution of LiOH monohydrate (167 mg, 3.97 mmol) in water (13 mL) was added dropwise during one minute. The mixture was heated at 60°C during 4h, allowed to cool and concentrated to a yellow powder which was dried under vacuum to yield 1.44 g (99%) of the title compound. The isolated material was used in amidation reactions without further purification.
1H NMR (400 MHz3 DMSO-d6) δ ppm 8.52 (d, 1 H), 8.02 (d, 1 H), 7.83 (d, 1 H), 7.32 (d, 1 H), 5.08-4.99 (m, 1 H), 3.82-3.78 (m, 2 H), 3.06 (t, 2 H), 2.56 (s, 3 H), 2.22-2.14 (m, 2 H), 1.79-1.77 (m, 2 H); MS (ESI) m/z 399 (M+l).
Example 12
N-Butan-2-yl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl] amino] -N-propyl-pyridine-2-carboxamide
Figure imgf000047_0002
Amine: N-propylbutan-2-amine Yield: 56% m/z* (M+l): 496
NMR: 9.90 (s, 1 H), 8.75 - 8.80 (m, 1 H), 8.64 (d, 1 H), 8.08 - 8.18 (m, 1 H), 7.40 - 7.48 (m, 1 H), 7.36 (d, 1 H), 4.93 - 5.05 (m, 1 H), 4.15 - 4.25 (m, 0.5 H), 3.80 - 3.87 (m, 2 H), 3.70 - 3.79 (m, 0.5 H), 3.09 - 3.19 (m, 2 H), 2.98 - 3.08 (m, 1 H), 2.54 (s, 3 H), 2.11 - 2.25 (m, 2 H), 1.80 (d, 2 H), 1.30 - 1.74 (m, 4 H), 1.17 - 1.26 (m, 1 H), 1.14 (d, 2 H), 0.84 - 0.95 (m, 3 H), 0.68 (t, 2 H), 0.61 (t, 1 H).
Example 13
(3,3-Difluoropyrrolidin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone
Figure imgf000048_0001
Amine: 3,3-Difluoropyrrolidine Yield: 62% m/z* (M+l): 488
NMR: 10.08 (s, 0.6 H), 10.06 (s, 0.4 H), 8.85 - 8.91 (m, 1 H), 8.67 (d, 1 H), 8.18 (dd, 1 H), 7.86 (d, 0.6 H), 7.81 (d, 0.4 H), 7.37 (d, 1 H), 4.93 - 5.07 (m, 1 H), 4.28 (t, 1 H), 4.05 (t, 1 H), 3.92 (t, 1 H), 3.83 (dd, 2 H), 3.75 (t, 1 H), 3.14 (t, 2 H), 2.55 (s, 3 H), 2.35 - 2.48 (m, 2 H), 2.12 - 2.27 (m, 2 H), 1.81 (d, 2 H).
Example 14
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2- yl]-(3-methyl-l-piperidyl)methanone
Figure imgf000048_0002
Amine: 3-Methylpiperidine Yield: 68% m/z* (M+l): 480
NMR: 9.93 (s, 1 H), 8.79 (s, 1 H), 8.64 (d, 1 H), 8.08 - 8.15 (m, 1 H), 7.51 (d, 1 H), 7.36 s (d, 1 H), 4.93 - 5.05 (m, 1 H), 4.23 - 4.36 (m, 1 H), 3.78 - 3.87 (m, 2.5 H), 3.69 - 3.79 (m, 1 H), 3.06 - 3.17 (m, 2 H), 2.94 - 3.05 (m, 0.5 H), 2.64 - 2.84 (m, 1 H)5 2.54 (s, 3 H), 2.11 - 2.24 (m, 2 H), 1.75 - 1.83 (m, 3 H), 1.53 - 1.73 (m, 2 H), 1.36 - 1.49 (m, 1 H), 1.11 - 1.22 (m, 1 H), 0.92 (d, 1.5 H), 0.74 (d, 1.5 H) o Example 15
5-[[5-Fluoro-4-[2-methyl-3~(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N-methyl-N- propan-2-yl-pyridine-2-carboxamide
Figure imgf000049_0001
Amine: N-Methylpropan-2-amino s Yield: 39% m/z* (M+l): 454
ΝMR: 9.92 (s, 1 H), 8.79 (s, 1 H), 8.64 (d, 1 H), 8.06 - 8.16 (m, 1 H), 7.44 - 7.54 (m, 1 H), 7.36 (d, 1 H), 4.92 - 5.03 (m, 1 H), 4.66 - 4.77 (m, 0.4 H), 3.99 - 4.09 (m, 0.6 H), 3.83 (dd, 2 H), 3.12 (t, 2 H), 2.82 (s, 2 H), 2.80 (s, 1 H), 2.54 (s, 3 H), 2.11 - 2.25 (m, 2 H), 1.79 (d,0 2 H), 1.08 - 1.18 (m, 6 H).
Example 16
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2- yl]-[4-(4-fluorophenyl)-l-piperidyl]methanone
5
Figure imgf000049_0002
Amine : 4-(4-Fluorophenyl)piperidine Yield: 62% m/z* (M+l): 560
NMR: 9.95 (s, 1 H), 8.80 (d, 1 H), 8.64 (d, 1 H), 8.13 (dd, 1 H), 7.57 (d, 1 H), 7.36 (d, 1 s H), 7.30 (dd, 2 H), 7.11 (t, 2 H), 4.93 - 5.03 (m, 1 H), 4.59 - 4.69 (m, 1 H), 3.98 - 4.07 (m, 1 H), 3.82 (dd, 2 H), 3.06 - 3.21 (m, 3 H), 2.79 - 2.91 (m, 2 H)5 2.54 (overlap, s, 3 H), 2.12 - 2.24 (m, 2 H), 1.69 - 1.92 (m, 4 H), 1.52 - 1.66 (m, 2 H).
Example 17 o (4-Ethylpiperazin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin- 2-yl]amino]pyridin-2-yl]methanone
Figure imgf000050_0001
Amine: 1-Ethylpiperazine Yield: 77% s m/z* (M+l): 495
NMR: 9.96 (s, 1 H), 8.80 (d, 1 H), 8.65 (d, 1 H), 8.13 (dd, 1 H), 7.55 (d, 1 H), 7.36 (d, 1 H), 4.93 - 5.03 (m, 1 H), 3.82 (dd, 2 H), 3.62 (br. s., 2 H), 3.53 (br. s., 2 H), 3.12 (t, 2 H), 2.55 (s, 3 H), 2.41 (br. s., 2 H), 2.30 - 2.38 (m, 4 H), 2.11 - 2.24 (m, 2 H), 1.79 (dd, 2 H), 1.00 (t, 3 H). 0
Example 18
(4-Butylpiperazin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-
2-yl]amino]pyridin-2-yl]methanone
Figure imgf000050_0002
5 Amine: 1-Butylpiperazine Yield: 64% m/z* (M+l): 523
NMR: 9.96 (s, 1 H), 8.80 (d, 1 H), 8.65 (d, 1 H), 8.12 (dd, 1 H), 7.55 (d, 1 H), 7.36 (d, 1 H), 4.93 - 5.03 (m, 1 H), 3.82 (dd, 2 H), 3.62 (br. s., 2 H), 3.52 (br. s., 2 H), 3.12 (t, 2 H), s 2.55 (s, 3 H), 2.41 (br. s., 2 H), 2.33 (br. s., 2 H), 2.25 - 2.31 (m, 2 H), 2.11 - 2.24 (m, 2 H), 1.79 (dd, 2 H), 1.22 - 1.46 (m, 4 H), 0.88 (t, 3 H).
Example 19
N-Ethyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N- I0 propan-2-yl-pyridine-2-carboxamide
Figure imgf000051_0001
Amine: N-Ethylpropan-2-amine Yield: 59% m/z* (M+l): 468 is ΝMR: 9.91 (s, 1 H), 8.78 (d, 1 H), 8.64 (d, 1 H), 8.11 (d, 1 H), 7.45 (d, 1 H), 7.37 (d, 1 H), 4.92 - 5.04 (m, 1 H), 3.98 - 4.09 (m, 1 H), 3.83 (dd, 2 H), 3.13 (t, 2 H), 2.55 (s, 3 H), 2.11 - 2.26 (m, 2 H), 1.79 (d, 2 H), 1.08 - 1.27 (m, 9 H), 0.99 (t, 1 H).
Example 20
20 [5-[[S-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2- yl]-(l-piperidyl)methanone
Figure imgf000051_0002
Amine: Piperidine Yield: 50% 5 m/z* (M+l): 466 NMR: 9.93 (s, 1 H), 8.79 (s., 1 H)5 8.62 - 8.67 (m, 1 H), 8.08 - 8.15 (m, 1 H), 7.50 (d, 1 H), 7.36 (d, 1 H), 4.92 - 5.04 (m, 1 H), 3.78 - 3.87 (m, 2 H), 3.58 (br. s., 2 H), 3.42 (br. s., 2 H), 3.12 (t, 2 H), 2.54 (s, 3 H), 2.10 - 2.25 (m, 2 H), 1.79 (d, 2 H), 1.58 - 1.66 (m, 2 H), 1.55 (br. s., 2 H), 1.48 (br. s., 2 H).
Example 21
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2- yl]-(4-propan-2-ylpiperazin-l-yl)methanone
Figure imgf000052_0001
Amine: l-Propan-2-ylpiperazine
Yield: 100% m/z* (M+l): 509
NMR: 9.95 (s, 1 H), 8.80 (d, 1 H), 8.64 (d, 1 H), 8.12 (dd, 1 H), 7.55 (d, 1 H), 7.36 (d, 1
H), 4.92 - 5.04 (m, 1 H), 3.82 (dd, 2 H), 3.61 (br. s., 2 H), 3.50 (br. s., 2 H), 3.12 (t, 2 H), 2.63 - 2.72 (m, 1 H), 2.55 (s, 3 H), 2.41 (br. s., 2 H), 2.11 - 2.25 (m, 2 H), 1.75 - 1.84 (m, 2
H), 0.97 (d, 6 H).
Example 22
5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N,N- dipropan-2-yl-pyridine-2-carboxamide
Figure imgf000052_0002
Amine : N-Propan-2-ylpropan-2-amine Yield: 44% m/z* (M+l): 482 NMR: 9.87 (s, 1 H), 8.74 (d, 1 H), 8.63 (d, 1 H), 8.09 (dd, 1 H), 7.39 (d, 1 H), 7.35 (d, 1 H), 4.92 - 5.04 (m, 1 H), 3.81 - 3.84 (m, 3 H), 3.57 (br. s., 1 H), 3.12 (t, 2 H), 2.54 (s, 3 H), 2.11 - 2.25 (m, 2 H), 1.79 (dd, 2 H), 1.43 (br. s., 6 H), 1.12 (br. s., 6 H).
5 Example 23
(2,6-Dimethyl-l-piperidyl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin~2-yl]methanone
Figure imgf000053_0001
Amine: 2,6-Dimethylpiperidine I0 Yield: 39% m/z* (M+l): 494
NMR: 9.89 (s, 1 H), 8.77 (d, 1 H), 8.64 (d, 1 H), 8.11 (dd, 1 H), 7.43 (d, 1 H), 7.36 (d, 1
H), 4.91 - 5.06 (m, 1 H), 4.38 (br. s., 2 H), 3.76 - 3.90 (m, 2 H), 3.13 (t, 2 H), 2.54 (s, 3 H),
2.10 - 2.26 (m, 2 H), 1.73 - 1.88 (m, 3 H), 1.39 - 1.68 (m, 5 H), 1.22 (d, 6 H). is
Example 24
5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N,N- dipropyl-pyridine-2-carboxamide
Figure imgf000053_0002
2Q Amine: iV-Propylpropan-1 -amine
Yield: 69% m/z* (M+l): 482
NMR: 9.92 (s, 1 H), 8.77 (d, 1 H), 8.64 (d, 1 H), 8.14 (dd, 1 H), 7.49 (d, 1 H), 7.36 (d, 1
H), 4.94 - 5.04 (m, 1 H), 3.83 (dd, 2 H), 3.34 - 3.40 (m, 4 H), 3.13 (t, 2 H), 2.54 (s, 3 H), 25 2.11 - 2.25 (m, 2 H), 1.80 (d, 2 H), 1.46 - 1.66 (m, 4 H), 0.90 (t, 3 H), 0.68 (t, 3 H). Example 25
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2- yl]-(4-methoxy-l-piperidyl)methanone
Figure imgf000054_0001
5 Amine: 4-Methoxypiperidine
Yield: 68% nVz* (MH-I): 496
NMR: 9.95 (s, 1 H), 8.80 (d, 1 H)3 8.64 (d, 1 H), 8.12 (dd, 1 H), 7.54 (d, 1 H), 7.36 (d, 1
H)3 4.93 - 5.04 (m, 1 H), 3.95 (br. s., 1 H), 3.82 (dd, 2 H), 3.67 (br. s., 1 H), 3.39 - 3.49 (m, io 2 H), 3.26 (s, 3 H), 3.12 (t, 2 H), 2.55 (s, 3 H), 2.11 - 2.25 (m, 2 H), 1.74 - 1.96 (m, 4 H),
1.44 (br. s., 2 H).
Example 26 N-Ethyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N-
I5 methyl-pyridine-2-carboxamide
Figure imgf000054_0002
Amine: JV-Methylethanamine Yield: 67% m/z* (M+l): 440 0 NMR: 9.93 (s, 1 H), 8.79 (s., 1 H), 8.64 (d, 1 H), 8.09 - 8.15 (m, 1 H), 7.52 (dd, 1 H), 7.36 (d, 1 H), 4.94 - 5.04 (m, 1 H), 3.83 (dd, 2 H), 3.46 (q, 1 H), 3.35 - 3.40 (overlap, m, 1 H), 3.13 (t, 2 H)32.99 (s, 1.5 H)32.95 (s3 1.5 H), 2.54 (s, 3 H), 2.12 - 2.25 (m, 2 H), 1.75 - 1.84 (m, 2 H)3 1.12 (q, 3 H). Example 27
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2- yl]-(4-methyl-l-piperidyl)methanone
Figure imgf000055_0001
Amine: 4-Methylpiperidine
Yield: 75% m/z* (M+l): 480
NMR: 9.93 (s, 1 H), 8.78 (d, 1 H), 8.64 (d, 1 H), 8.11 (dd, 1 H), 7.50 (d, 1 H), 7.36 (d, 1
H), 4.93 - 5.03 (m, 1 H), 4.44 (d, 1 H), 3.77 - 3.88 (m, 3 H), 3.07 - 3.17 (m, 2 H), 3.01 (t, 1 H), 2.69 - 2.80 (m, 1 H), 2.54 (s, 3 H), 2.11 - 2.24 (m, 2 H), 1.79 (d, 2 H), 1.51 - 1.74 (m, 3
H), 1.02 - 1.15 (m, 2 H), 0.92 (d, 3 H).
Example 28
(4-Benzylpiperazin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin- 2-yl]amino]pyridin-2-yl]methanone
Figure imgf000055_0002
Amine: 1-Benzylpiperazine Yield: 66% m/z* (M+l): 557 NMR: 9.95 (s, 1 H), 8.79 (d, 1 H), 8.64 (d, 1 H), 8.12 (dd, 1 H), 7.55 (d, 1 H), 7.36 (d, 1 H), 7.22 - 7.34 (m, 5 H), 4.93 - 5.03 (m, 1 H), 3.82 (dd, 2 H), 3.63 (br. s., 2 H), 3.54 (br. s., 2 H), 3.51 (s, 2 H), 3.11 (t, 2 H), 2.54 (s, 3 H), 2.42 (br. s., 2 H), 2.36 (br. s., 2 H), 2.11 - 2.24 (m, 2 H), 1.75 - 1.83 (m, 2 H). Example 29
(4,4-Difluoro-l-piperidyl)-[5-[[5-fluoro-4-[2~methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone
Figure imgf000056_0001
5 Amine: 4,4-Difluoropiperidine
Yield: 56% m/z* (M+l): 502
NMR: 9.99 (s, 1 H), 8.82 (d, 1 H), 8.65 (d, 1 H), 8.15 (dd, 1 H), 7.63 (d, 1 H), 7.36 (d, 1
H), 4.92 - 5.05 (m, 1 H), 3.83 (dd, 2 H), 3.74 (br. s., 2 H), 3.67 (br. s., 2 H), 3.13 (t, 2 H),o 2.55 (s, 3 H), 2.12 - 2.25 (m, 2 H), 2.04 (br. s., 4 H), 1.79 (d, 2 H).
Example 30
N-Benzyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N- propan-2-yl-pyridine-2-carboxamide
Figure imgf000056_0002
Amine: N-Benzylpropan-2-amine Yield: 61% m/z* (M+l): 530
NMR: 9.95 (s, 0.7 H), 9.88 (br. s., 0.3 H), 8.85 (br. s, 0.7 H), 8.72 (br. s., 0.3 H), 8.65 (br.o s., 0.7 H), 8.62 (br. s, 0.3 H), 8.14 (d, 0.7 H), 8.05 (d, 0.3 H), 7.49 - 7.59 (m, 1 H), 7.13 - 7.39 (m, 6 H), 4.88 - 5.06 (m, 1 H), 4.69 (br. s., 0.6 H), 4.63 (s, 1.4 H), 4.39 - 4.50 (m, 0.3 H), 4.15 - 4.27 (m, 0.7 H), 3.72 - 3.88 (m, 2 H)5 3.04 - 3.20 (m, 2 H), 2.54 (s, 3 H), 2.08 - 2.26 (m, 2 H), 1.68 - 1.85 (m, 2 H), 1.14 (d, 2 H), 1.08 (d, 4 H). Example 31
5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N-methyl-N-
(2-methylpropyl)pyridine-2-carboxamide
Figure imgf000057_0001
Amine: N,2-Dimethylpropan-1 -amine
Yield: 74% m/z* (M+l): 468
ΝMR: 9.93 (s, 1 H), 8.80 (d, 1 H), 8.64 (s, 1 H), 8.09 - 8.17 (m, 1 H), 7.50 (dd, 1 H), 7.36
(d, 1 H), 4.94 - 5.05 (m, 1 H), 3.78 - 3.87 (m, 2 H), 3.26 - 3.30 (overlap, m, 2 H), 3.08 - 3.19 (m, 2 H), 2.97 (s, 3 H), 2.55 (br. s., 3 H), 2.11 - 2.24 (m, 2 H), 1.98 - 2.08 (m, 0.5 H),
1.84 - 1.92 (m, 0.5 H), 1.80 (d, 2 H), 0.91 (d, 3 H), 0.69 (d, 3 H).
Example 32
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2- yl]-(4-fluoro-l-piperidyl)methanone
Figure imgf000057_0002
Amine: 4-Fluoropiperidine Yield: 44% m/z* (M+l): 484 ΝMR: 9.96 (s, 1 H), 8.81 (d, 1 H), 8.65 (d, 1 H), 8.13 (dd, 1 H), 7.57 (d, 1 H), 7.36 (d, 1 H), 4.93 - 5.04 (m, 1.5 H), 4.83 - 4.90 (m, 0.5 H), 3.83 (dd, 2 H), 3.43 - 3.75 (m, 4 H), 3.13 (t, 2 H), 2.55 (s, 3 H), 2.12 - 2.25 (m, 2 H), 1.65 - 2.02 (m, 6 H). Example 33
N-Benzyl-N-ethyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-carboxamide
Figure imgf000058_0001
Amine: N-Benzylethanamine Yield: 71% m/z* (M+l): 516
ΝMR: 9.96 (br. s., 0.6 H), 9.95 (br. s., 0.4 H), 8.82 - 8.85 (m, 0.6 H), 8.78 - 8.80 (m, 0.4 H), 8.62 - 8.66 (m, 1 H), 8.09 - 8.17 (m, 1 H), 7.58 - 7.64 (m, 1 H), 7.25 - 7.38 (m, 6 H), 4.91 - 5.03 (m, 1 H), 4.71 (br. s., 1 H), 4.69 (s, 1 H), 3.73 - 3.87 (m, 2 H), 3.33 - 3.37 (m, 2 H), 3.03 - 3.19 (overlap, m, 2 H), 2.55 (br. s., 3 H), 2.07 - 2.24 (m, 2 H), 1.71 - 1.84 (m, 2 H), 1.07 (t, 3 H).
Example 34 (4-Butan-2-ylpiperazin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2~yl]amino]pyridin~2-yl]methanone
Figure imgf000058_0002
Amine: l-Butan-2-ylpiperazine Yield: 68% m/z* (M+l): 523
NMR: 9.95 (s, 1 H), 8.80 (d, 1 H), 8.64 (d, 1 H), 8.12 (dd, 1 H), 7.55 (d, 1 H), 7.36 (d, 1 H), 4.93 - 5.04 (m, 1 H), 3.82 (dd, 2 H), 3.60 (br. s., 2 H), 3.49 (br. s., 2 H), 3.12 (t, 2 H), 2.55 (s, 3 H), 2.31 - 2.48 (m, 4 H), 2.11 - 2.25 (m, 2 H), 1.79 (d, 2 H), 1.41 - 1.55 (m, 1 H), 1.20 - 1.32 (m, 2 H), 0.90 (d, 3 H), 0.86 (t, 3 H). Example 35
(N-fCyclopropylmethyty-S-HS-fluoro^-β-methylS-ζoxan^-ytyimidazol^-ylJpyrimidin-
2-yl]amino]-N-propyl-pyridine-2-carboxamide
Figure imgf000059_0001
Amine: N-(Cy clopropylmethyl)propan-l -amine Yield: 73% m/z* (M+l): 494 Ret T.: 0.99.
Example 36
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2- yl]-[4-(4-fluorophenyl)piperazin-l-yl]methanone
Figure imgf000059_0002
Amine: l-(4-Fluorophenyl)piperazine Yield: 75% m/z* (M+l): 561
NMR: 9.98 (s, 1 H), 8.83 (d, 1 H)5 8.65 (d, 1 H), 8.15 (dd, 1 H), 7.62 (d, 1 H), 7.36 (d, 1 H), 7.06 (t, 2 H), 6.94 - 7.02 (m, 2 H), 4.92 - 5.04 (m, 1 H), 3.80 - 3.87 (m, 2 H), 3.78 (br. s, 2 H), 3.73 (br. s, 2 H), 3.04 - 3.20 (m, 6 H), 2.55 (s, 3 H), 2.11 - 2.26 (m, 2 H), 1.80 (d, 2 H).
Example 37
[5-[[5-Fluoro-4-[2~methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2~yl]amino]pyridin-2- yl]-(4-propylpiperazin-l-yl)methanone
Figure imgf000060_0001
Amine: 1-Propylpiperazine Yield: 93% m/z* (M+l): 509 NMR: 9.96 (s, 1 H), 8.80 (d, 1 H), 8.65 (d, 1 H), 8.12 (dd, 1 H), 7.55 (d, 1 H), 7.36 (d, 1 H), 4.93 - 5.04 (m, 1 H), 3.78 - 3.86 (m, 2 H), 3.62 (br. s., 2 H), 3.52 (br. s., 2 H), 3.12 (t, 2 H), 2.55 (s, 3 H), 2.41 (br. s., 2 H), 2.33 (br. s., 2 H), 2.22 - 2.28 (m, 2 H), 2.11 - 2.22 (m, 2 H), 1.75 - 1.83 (m, 2 H), 1.38 - 1.50 (m, 2 H), 0.86 (t, 3 H).
Example 38
N,N-Diethyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-carboxamide
Figure imgf000060_0002
Amine: N-Ethylethanamine Yield: 60% m/z* (M+l): 454
NMR: 9.92 (s, 1 H), 8.79 (d, 1 H), 8.65 (d, 1 H), 8.13 (dd, 1 H), 7.52 (d, 1 H), 7.36 (d, 1 H), 4.92 - 5.04 (m, 1 H), 3.83 (dd, 2 H), 3.43 (q, 2 H), 3.34 - 3.38 (overlap, m, 2 H), 3.13 (t, 2 H), 2.55 (s, 3 H), 2.12 - 2.26 (m, 2 H), 1.80 (d, 2 H), 1.06 - 1.18 (m, 6 H).
Example 39
N-(3-Dimethylamino-2,2-dimethyl-propyl)-5-[[5-fluoro-4-[2-methyl-3-(oxan-4- yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridine-2-carboxamide
Figure imgf000061_0001
Amine: N,N,2,2-Tetramethylpropane-l,3-diamine Yield: 51% m/z* (MH-I): 511 ΝMR: 10.04 (s, 1 H), 8.88 (d, 1 H), 8.76 (t, 1 H), 8.66 (d, 1 H), 8.16 (dd, 1 H), 7.96 (d, 1 H), 7.38 (d, 1 H), 4.96 - 5.07 (m, 1 H), 3.80 (dd, 2 H), 3.22 (d, 2 H), 3.08 (t, 2 H), 2.55 (s, 3 H), 2.26 (s, 6 H), 2.15 - 2.21 (m, 4 H), 1.81 (d, 2 H), 0.88 (s, 6 H).
Example 40 (3,5-Dimethyl-l-piperidyl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyriιnidin-2-yl]amino]pyridin-2-yl]methanone
Figure imgf000061_0002
Amine: 3,5-Dimethylpiperidine Yield: 30% m/z* (M+l): 494
ΝMR: 9.93 (s, 1 H), 8.78 (d, 1 H), 8.64 (d, 1 H), 8.12 (dd, 1 H), 7.50 (d, 1 H), 7.36 (d, 1 H), 4.94 - 5.05 (m, 1 H), 4.46 (d, 1 H), 3.83 - 3.77 (m, 3 H), 3.11 (q, 2 H), 2.54 (s, 3 H), 2.26 - 2.13 (m, 3 H), 1.79 (d, 3 H), 1.58 (br. s., 2 H)5 0.91 (d, 3 H), 0.81 (q, 1 H), 0.73 (d, 3 H).
* Purity analysis was run on a Water Acquity system with PDA (Waters 2996) and Waters ZQ mass spectrometer. Column; Acquity UPLC™ BEH C8 1.7 μm 2.1 x 50mm. The column temperature was set to 65°C. A linear 2 min gradient from 100% A (A: 95% 0.01 M NH4OAc in MiIIiQ water and 5% MeCN) to 100% B (5% 0.01 M NH4OAc in MiIIiQ water and 95% MeCN) was applied for LC-separation at flow rate 1.2 mL/min. The PDA was scanned from 210-350 nm and 254 nm was extracted for purity determination. The ZQ mass spectrometer was run with ESI in pos/neg switching mode. The Capillary Voltage was 3 kV and the Cone Voltage was 30V.
Example 41
Methyl 5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-carboxylate
Figure imgf000062_0001
General Method A was followed using 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-amine (as described in Example 6) (1.30 g, 4.69 mmol), methyl 5- bromopyridine-2-carboxylate (1.42 g, 6.56 mmol), Cs2CO3 (2.44 g, 7.50 mmol), Pd2(dba)3 (215 mg, 0.23 mmol) and X-Phos (224 mg, 0.47 mmol). The mixture was heated at 90°C for 7h and kept at r.t over night followed by the addition of methyl 5-bromopyridine-2- carboxylate (0.48 g, 2.22 mmol), Cs2CO3 (0.41 g, 1.26 mmol), Pd2(dba)3 (60 mg, 0.066 mmol), X-Phos (62 mg, 0.13 mmol) and 1,4-dioxane (5 mL). The mixture was heated at 90°C for 4.5h. Work-up by Method 1 and silica chromatography (0→7% MeOH in DCM) gave a yellow sticky solid. Trituration with CH3CN and recrystallization from EtOH gave the title compound (1.3 g, 67%).
1H NMR (400 MHz, CDCl3) δ ppm 8.75 (d, 1 H), 8.38 (d, 1 H), 8.34 (dd, 1 H), 8.12 (d, 1 H), 7.70 (d, 1 H), 7.47 (br. s, 1 H), 5.10-5.03 (m, 1 H), 4.10 (dd, 2 H), 4.01 (s, 3 H) 3.75- 3.71 (m, 1 H), 3.36-3.29 (m, 2 H), 2.67 (s, 3 H), 2.59-2.51 (m, 2 H), 1.91-1.87 (m, 2 H); MS (ESI) m/z 413 (M+l).
Example 42 Azeήdiiι-l-yl~[3-chloro-5-[[5-fluoro-4~[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]methanone
Figure imgf000063_0001
General Method A was followed using 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-amine (as described in Example 6) (0.070 g, 0.252 mmol), azetidin-1-yl- (3,5-dichloropyridin-2-yl)methanone (as described in Example 48(a)) (0.0583 g, 0.252 mmol), Cs2CO3 (0.131 g, 0.403 mmol), Pd2(dba)3 (22.9 mg, 0.025 mmol) and X-Phos (23.8 mg, 0.050 mmol). The mixture was heated at 900C for 24 h and kept at r.t over night followed by the addition of Pd2(dba)3 (14 mg, 0.0153 mmol) and X-Phos (16 mg, 0.0336 mmol). The mixture was heated at 90°C for 6 h. Work-up by Method 2 and preparative HPLC followed by silica chromatography (0→5% MeOH in DCM) gave the title compound (0.0145 g) in 6.6% yield.
1H NMR (400 MHz, CDCl3) δ ppm 8.49 (d, 1 H), 8.36-8.33 (m, 2 H), 7.93 (br. s, 1 H), 7.66 (d, 1 H), 5.13-5.05 (m, 1 H), 4.27-4.23 (m, 2 H), 4.19-4.16 (m, 2 H), 4.14-4.07 (m, 2 H), 3.38-3.32 (m, 2 H), 2.64 (s, 3 H), 2.55-2.45 (m, 2 H), 2.37-2.29 (m, 2 H), 1.91-1.87 (m, 2 H); MS (ESI) m/z All (M-I).
Example 43
[3-Chloro-5-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]-(4-methylpiperazin-l-yl)methanone
Figure imgf000063_0002
General Method A using 5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4- yl]pyrimidin-2-amine (as described in Example 8) (0.060 g, 0.181 mmol), (3,5- dichloropyridin-2-yl)-(4-methylpiperazin-l-yl)methanone (as described in Example 49(a)) (0.0496 g, 0.181 mmol), Cs2CO3 (0.094 g, 0.29 mmol), Pd2(dba)3 (16.5 mg, 0.018 mmol) and X-Phos (17.2 mg, 0.036 mmol). The mixture was heated at 900C for 17 h, followed by the addition of Pd2(dba)3 (12 mg, 0.013 mmol) and X-Phos (13 mg, 0.027 mmol) and then was heated at 9O0C for an additional 3 h. Work-up by Method 2 and purification by preparative HPLC gave the title compound (0.033 g) in 15% yield. 1HNMR (400 MHz, CDCl3) δ ppm 8.52 (d, 1 H)5 8.47 (d, 1 H), 8.36 (d, 1 H), 8.10 (br. s, 1 H), 7.73 (d, 1 H), 4.89-4.81 (m, 1 H), 4.12 (dd, 2 H)5 3.86-3.83 (m, 2 H), 3.51-3.44 (m, 2 5 H), 3.29-3.27 (m, 2 H), 2.76-2.66 (m, 2 H), 2.52-2.50 (m, 2 H), 2.40-2.37 (m, 2 H), 2.32 (s, 3 H), 1.90-1.86 (m, 2 H); MS (ESI) m/z 570 (M+l).
Example 44
[3-Chloro-5-[[5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- i o yl]amino]pyridin-2-yl]-(4-methylpiperazin-l-yl)methanone
Figure imgf000064_0001
General Method A was followed using 5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol- 4-yl]pyrimidin-2-amine (as described in Example 9) (0.16 g, 0.62 mmol), (3,5- dichloropyridin-2-yl)-(4-methylpiperazin-l-yl)methanone (as described in Example 49(a)) is (0.17 g, 0.62 mmol), Cs2CO3 (0.32 g, 0.99 mmol), Pd2(dba)3 (43.0 mg, 0.047 mmol) and X-Phos (44.3 mg, 0.093 mmol). The mixture was heated at 9O0C for 17 h. Work-up by Method 1 and purification by preparative HPLC gave the title compound (0.054 g) in 17% yield. 1H NMR (400 MHz, DMSO-J6) δ ppm 10.35 (s, 1 H), 8.82 (d, 1 H), 8.75 (d, 1 H), 8.45 (d,
20 1 H), 7.77 (d, 1 H), 4.11 (s, 3 H), 3.61 - 3.67 (m, 2 H), 3.10 - 3.16 (m, 2 H), 2.32 - 2.41 (m, 2 H), 2.21 - 2.30 (m, 2 H), 2.19 (s, 3 H); MS (ESI) m/z 498 (M-I).
Example 45
Azetidin-l-yl-[3-chloro-5-[[5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4- 25 yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone hydrochloride
Figure imgf000064_0002
General Method A was followed using 5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol- 4-yl]pyrimidin-2-amine (as described in Example 9) (0.20 g, 0.75 mmol), azetidin-1-yl- (3,5-dichloropyridin-2-yl)methanone (as described in Example 48(a)) (0.17 g, 0.75 mmol), Cs2CO3 (0.39 g, 1.2 mmol), Pd2(dba)3 (51.7 mg, 0.056 mmol) and X-Phos (53.8 mg, 0.11 mmol). The mixture was heated at 90°C for 17 h. Work-up by Method 1 and purification by preparative HPLC followed by hydrochloride formation gave the title compound (0.054 g) in 15% yield.
1H NMR (400 MHz, DMSO-J6) δ ppm 10.41 (s, 1 H), 8.83 (d, 1 H), 8.75 (d, 1 H), 8.45 (d, 1 H), 7.77 (d, 1 H), 4.11 (s, 3 H), 4.01 - 4.08 (m, 4 H), 2.20 - 2.31 (m, 2 H); MS (ESI) m/z 457 (M+l).
Example 46
N-[6-(Azetidin-l-ylcarbonyl)pyridin-3-yl]-4-(l,2-dimethyl-lH-imidazol-5-yl)-S- fluoropyrimidin-2-amine
Figure imgf000065_0001
The title compound was prepared in accordance with the general method A using 4-(l,2- dimethyl-lH-imidazol-5-yl)-5-fluoropyrimidin-2-amine (as described in Example 7) (30 mg, 0.145 mmol) and 2-(azetidin-l-ylcarbonyl)-5-bromopyridine (41 mg, 0.17 mmol) (reported in WO 2005014571) to give the title compound (22 mg, 41%). 1H NMR (400 MHz, CDCl3) δ ppm 8.69 (d, J=2.53 Hz, 1 H) 8.31 (d, J=3.03 Hz, 1 H) 8.14 - 8.20 (m, 1 H) 8.07 - 8.12 (m, 1 H) 7.77 (d, J=4.29 Hz, 1 H) 7.36 - 7.50 (m, 1 H) 4.72 (t, J=7.71 Hz, 2 H) 4.25 (t, 2 H) 3.93 (s, 3 H) 2.50 (s, 3 H) 2.31 - 2.44 (m, 3 H); MS (ESI) m/z 368 (M + l).
Example 47
4-(l,2-Dimethyl-lH-imidazol-5-yl)-5-fluoro~N-{6-[(4-methylpiperazin-l- yl)carbonyl]pyridin-3-yl}pyrimidin-2-amine
Figure imgf000066_0001
The title compound was prepared in accordance with the general method A using 4-(l,2- dimethyl-lH-imidazol-5-yl)-5-fluoropyrimidin-2-amine (as described in Example 7) (40 mg, 0.193 mmol) and l-[(5-bromopyridin-2-yl)carbonyl]-4-methylpiperazine (as described in Example 4(b)) (55 mg, 0.23 mmol) to give the title compound (45 mg, 57%). 1H NMR (400 MHz, CDCl3) δ ppm 8.70 (d, J=2.53 Hz, 1 H) 8.30 (d, J=3.28 Hz, 1 H) 8.18 (dd, J=8.59, 2.53 Hz, 1 H) 7.76 (d, J=4.29 Hz, 1 H) 7.70 (d, J=8.59 Hz, 1 H) 3.93 (s, 3 H) 3.81 - 3.87 (m, J=5.81 Hz, 2 H) 3.71 - 3.78 (m, 2 H) 2.50 - 2.57 (m, 2 H) 2.49 (s, 3 H) 2.40 - 2.46 (m, 2 H) 2.33 (s, 3 H); MS (ESI) m/z 411 (M + 1).
Example 48
N-fo-fAzetidin-l-ylcarbonylJ-S-chloropyridinS-ylJ^-fl^-dimethyl-lH-imidazol-S-ylJS- fluoropyrimidin-2-amine
Figure imgf000066_0002
Example 48 fa) 2-(Azetidin-l-ylcarbonyl)-3,5-dichloropyridine
Figure imgf000066_0003
The title compound was prepared in accordance with the general method C using 3,5- dichloropyridine-2-carboxylic acid (500 mg, 2.6 mmol) and azetidine (150 mg, 2.6 mmol) to give the title compound (430 mg, 72%).
1H NMR (400 MHz, CDCl3) δ ppm 8.45 (d, J=2.02 Hz, 1 H) 7.80 (d, J=2.02 Hz, 1 H) 4.27
(t, J=7.83 Hz, 2 H) 4.15 (t, J=7.71 Hz, 2 H) 2.28 - 2.42 (m, 2 H); MS (ESI) m/z 231 (M+
1). Example 48(b) N-fό-fAzetidin-l-vlcarbonyD-S-chloropvridin-S-ylJ^-OJ-dimethyl-lH- xmidazol-5-yl)-5-fluoropyrimidin-2-amine
Figure imgf000067_0001
The title compound was prepared in accordance with the general method A using 4-(l,2- dimethyl-lH-imidazol-5-yl)-5-fluoropyrimidin-2-amine (as described in Example 7) (50 mg, 0.24 mmol) and 2-(azetidin-l-ylcarbonyl)-3,5-dichloropyridine (as described above)
(57 mg, 0.25 mmol) to give the title compound (26 mg, 27%). .
1R NMR (400 MHz, CDCl3) δ ppm 8.50 (d, J=2.27 Hz, 1 H) 8.39 (d, J=2.27 Hz, 1 H) 8.30
(d, J=3.28 Hz, 1 H) 8.07 (s, 1 H) 7.77 (d, J=4.29 Hz, 1 H) 4.26 (t, J=7.83 Hz, 2 H) 4.19 (t, 2 H) 3.94 (s, 3 H) 2.49 (s, 3 H) 2.29 - 2.39 (m, 2 H); MS (ESI) m/z 402 (M + 1).
Example 49
N-fS-Chloro-ό-lø-methylpiperazin-l-ytycarbonylJpyridin-S-ylj^-ζl^-dimethyl-lH- imidazol-5-yl)-5-fluoropyrimidin-2-amine
Figure imgf000067_0002
Example 49 fa) (3,5-Dichloropyridin-2-yl)-(4-methylpiperazin-l-yl)methanone
Figure imgf000067_0003
The title compound was prepared in accordance with the general method C using 3,5- dichloropyridine-2-carboxylic acid (555 mg, 2.89 mmol) and 1-methylpiperazine (320 μL, 2.89 mmol) to give the title compound (417 mg, 53 %).
1H NMR (400 MHz, CDCl3) δ ppm 8.49 (d, J=2.02 Hz, 1 H) 7.79 (d, J=2.02 Hz, 1 H) 3.82 - 3.88 (m, 2 H) 3.22 - 3.27 (m, 2 H) 2.50 - 2.55 (m, 2 H) 2.37 - 2.42 (m, 2 H) 2.33 (s, 3 H); MS (ESI) /w/z 274 (M+ l). Example 49{b) N-f5-Chloro-6-[(4-methvlpiperazin-l-vl)carbonvnvvndin-3-vU-4-d, 2- dimethyl-lH-imidazol-5-yl)~5-fluoropyrimidin-2-amine
Figure imgf000068_0001
The title compound was prepared in accordance with the general method A using 4-(l,2- dimethyl-lH"-imidazol-5-yl)-5-fluoropyrimidin-2-amine (as described in Example 7) (50 mg, 0.24 mmol) and (3,5-dichloropyridin-2-yl)-(4-methylpiperazin-l-yl)methanone (as described above) (66 mg, 0.24 mmol) to give the title compound (29 mg, 27%). 1HNMR (400 MHz, CDCl3) δ ppm 8.47 (d, J=2.27 Hz, 1 H) 8.36 (d, J=2.27 Hz, 1 H) 8.28 (d, J=3.03 Hz, 1 H) 8.18 (s, 1 H) 7.76 (d, J=4.29 Hz, 1 H) 3.94 (s, 3 H) 3.85 (t, 2 H) 3.29 (t, 2 H) 2.51 (t, 2 H) 2.48 (s, 3 H) 2.39 (t, 2 H) 2.32 (s, 3 H); MS (ESI) m/z 445 (M + 1).
Example 50
{5-Fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-[6-
(propan-2-ylsulfonyl)-pyridin-3-yl]-amine
Figure imgf000068_0002
Example 50 fa) 5-Bromo-2-isopropylsulfanyl-pyridine
Figure imgf000068_0003
5-Bromo-2-chloro-pyridine (516.0 mg, 2.681 mmol) was dissolved in DMF (10 mL) and sodium 2-propanethiolate (1.5 g, 15.28 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour where after analysis by GC- MS showed only little starting material left. Water (10 mL) was added followed by extraction with CH2Cl2 (3 x 20 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to afford the title compound (600 mg, 96%). 1H NMR (400 MHz, CDCl3) δ ppm 1.38 (d, J=6.82 Hz, 6 H) 3.87 - 4.02 (m, 1 H) 7.04 (d, J=8.59 Hz, 1 H) 7.56 (dd, J=8.59, 2.53 Hz5 1 H) 8.47 (d, J=I .77 Hz, 1 H); MS (ESI) m/z 233 (M + 1).
Example 50(b) 5-Bromo-2-(propan-2-ylsulfonyl)-pyridine
Figure imgf000069_0001
5-Bromo-2-isopropylsulfanyl-pyridine (271.8 mg, 1.171 mmol) was dissolved in CH2Cl2 (2.5 mL) and mCPBA (1010 mg, 2.927 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 30 min where after analysis by LC-MS showed that all starting material was transformed into desired product. The reaction was quenched by addition of NaOH (5 mL, IM) and another 5 mL OfCH2Cl2 was added followed by extraction with CH2Cl2 (3 x 10 mL), and washing with water (10 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to afford the title compound (266 mg, 86%). 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (d, J=6.82 Hz, 6 H) 3.68 - 3.80 (m, 1 H) 7.99 (d, J=7.58 Hz, 1 H) 8.11 (dd, J=8.21, 2.15 Hz, 1 H) 8.80 - 8.84 (m, 1 H); MS (ESI) m/z 265 (M + 1).
Example 50(c) {5-Fluoro-4-f2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-ylJ- pyrimidin-2-yl}-[6-(propan-2-ylsulfonyl)-pyridin-3-yl]-amine
Figure imgf000069_0002
5-Fluoro-4-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine (as described in Example 6) (157.3 mg, 0.567 mmol), 5-bromo-2-(propan-2-ylsulfonyl)- pyridine (149.8 mg, 0.567 mmol), Cs2CO3 (370 mg, 1.134 mmol), Pd2(dba)3 (26 mg, 0.028 mmol) and XantPhos (33 mg, 0.057 mmol) were weighed out in a 50 mL round-bottom flask and dioxane (13 mL) was added. The system was flushed with argon and then heated to 90°C and stirred for 17 hours. Water (60 mL) was added and the mixture was extracted with CH2Cl2 (3 x 60 mL). Drying (Na2SO4), filtration and concentration afforded a crude material, which was purified by preparative HPLC to afford the title compound (102 mg, 39%).
5 1H NMR (400 MHz, CDCl3) δ ppm 1.31 (d, J=6.82 Hz, 6 H) 1.87 (dd, J=13.14, 3.79 Hz, 2 H) 2.45 - 2.59 (m, 2 H) 2.64 (s, 3 H) 3.31 - 3.41 (m, 2 H) 3.59 - 3.71 (m, 1 H) 4.09 (dd, J=I 1.62, 4.55 Hz, 2 H) 4.99 - 5.10 (m, 1 H) 7.67 (d, J=4.04 Hz, 1 H) 7.98 (d, J=8.84 Hz, 1 H) 8.26 (s, 1 H) 8.36 - 8.41 (m, 2 H) 8.86 (d, J=2.02 Hz, 1 H);MS (ESI) m/z 462 (M + 1).
io Example 51
(6-Ethanesulfonyl-pyridin-3-yl)-{S-fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H- imidazol-4-yl]-pyrimidin-2-yl}-amine
Figure imgf000070_0001
Example 51 fa) 5-Bromo-2-ethyl$ulfanyl-pyridine
Figure imgf000070_0002
5-Bromo-2-chloro-pyridine (5.0 g, 25.98 mmol) was dissolved in DMF (94 mL) and sodiumethanethiolate (10.9 g, 129.9 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour where after analysis by GC-MS showed only small amounts of starting material left. Water (100 mL) was added followed by 20 extraction with CH2Cl2 (3 x 200 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to afford the title compound (5.0 g, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 1.32 - 1.42 (m, 3 H) 3.09 - 3.20 (m, 2 H) 7.05 (dd, J=8.46, 2.65 Hz, 1 H) 7.53 - 7.61 (m, 1 H) 8.47 (s, 1 H); MS (ESI) m/z 219 (M + 1). S Example 5 Kb) 5-Bromo-2-ethanesulfonyl-pyridine
Figure imgf000070_0003
5~Bromo-2-ethylsulfanyl-pyridine (5.0 g, 22.92 mmol) was dissolved in CH2Cl2 (62 mL) and mCPBA (12.9 g, 57.3 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 30 min where after analysis by LC-MS showed that all starting material was transformed into desired product. The reaction was quenched by addition of NaOH (100 mL, IM) and another 100 mL of CH2Cl2 was added followed by extraction with CH2Cl2 (3 x 200 mL), and washing with water (200 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to afford the title compound (5.7 g, 99%). 1HNMR (400 MHz, CDCl3) δ ppm 1.30 (t, 3 H) 3.41 (q, J=7.58 Hz, 2 H) 7.99 (d, J=7.58 Hz, 1 H) 8.11 (dd, J=8.34, 2.27 Hz, 1 H) 8.80 (d, J=2.27 Hz, 1 H); MS (ESI) m/z 251 (M + I)-
Example 51(c)(6-Ethanesulfonyl-pyridin-3-yl)-{5-fluoro-4-[2-methyl-3-(tetrahydro-pyran- 4-yl)-3H-imidazol-4-yl]-pyrimidin-2-yl}~amine
Figure imgf000071_0001
5-Fluoro-4-[2-methyl- 1 -(tetrahydro-2H"-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine (as described in Example 6) (836.6 mg, 3.017 mmol), 5-bromo-2-ethanesulfonyl-pyridine (754.6 mg, 3.017 mmol), Cs2CO3 (2.0 g, 6.033 mmol), Pd2(dba)3 (138 mg, 0.151 mmol) and XantPhos (175 mg, 0.302 mmol) were weighed out in a 250 mL round-bottom flask and dioxane (68 mL) was added. The system was flushed with argon and then heated to 90°C and stirred for 17 hours. Water (150 mL) was added and the mixture was extracted with CH2Cl2 (3 x 150 mL). The combined organic phases were washed with HCl (4 x 100 mL, 2M). The combined acidic H2O-phases were neutralized with 50% NaOH (aq) until neutral or slightly basic and then extracted with CH2Cl2 (3 x 150 mL). Drying (Na2SO4), filtration and concentration afforded a crude material, which was purified by preparative HPLC to afford the title compound (790 mg, 59%).
1H NMR (400 MHz5 CDCl3) δ ppm 1.30 (t, J=7.45 Hz, 3 H) 1.89 (dd, J=12.88, 4.04 Hz, 2 H) 2.52 - 2.65 (m, 2 H) 2.67 (s, 3 H) 3.34 - 3.44 (m, 4 H) 4.13 (dd, J=I 1.62, 4.80 Hz, 2 H) 4.97 - 5.10 (m, 1 H) 7.71 (d, J=3.79 Hz, 1 H) 7.87 (s, 1 H) 8.02 (d, J=8.59 Hz5 1 H) 8.37 - 8.42 (m, 2 H) 8.85 (d, J=2.53 Hz, 1 H); MS (ESI) m/z 448 (M + 1).
Example 52 5-[[5-Fluoro-4-[2-inethyl-3-(oxan-4-yl)-2,4-dihydroimidazol-4-yl]pyrimidin-2-yl]amino]- N-(2,2,2-trifluoroethyl)pyridine-2-sulfonamide
Figure imgf000072_0001
Example 52(a) 2-Ben∑ylsulfanyl-5-bromo-pyridine
Figure imgf000072_0002
Potassium fert-butoxide (2.79 g, 24.84 mmol) was dissolved in DMF (10 mL) and benizylmercaptane (2.57 g, 20.70 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 15 min and then cooled to 0 °C. 5-Bromo-2-chloro-pyridine (3.98 g, 20.70 mmol) dissolved in DMF ( 4 mL) was added dropwise at 0 0C and the mixture was heated at 80 0C for 1.5 hours. The mixture was poured into water (100 mL) and extracted with ether (3 x 100 mL). The combined organic phases were washed with brine (100 mL), water (100 mL) and dried (Na2SO4). Concentration afforded the title compound (5.52 g, 95%). MS (ESI) m/z 281 (M + 1).
Example 52(b) 5-Bromopyridine-2-sulfonyl chloride
Figure imgf000072_0003
2-Benzylsulfanyl-5-bromo-pyridine (3.0 g, 10.71 mmol) was dissolved in CH2Cl2 (500 mL) in a 1 L Schlenk flask and water (250 mL) and HCOOH (250 mL) was added. The heterogeneous mixture was cooled to 0 °C and Cl2 gas was bubbled through the vigorously stirred mixture from a Pasteur pipette. The chlorine gas addition was continued for three minutes or until the mixture turned deep yellow. The organic phase was separated and diluted with CH2Cl2 (100 mL). The aqueous phase was extracted with CH2Cl2 (3 x 250 mL) and the combined organic phases were washed with IM NaOH (500 mL) followed by brine (500 mL). Drying (Na2SO4) and concentration afforded the title compound (2.73 g, 99%). MS (ESI) m/z 258 (M + 1).
Example 52 (c) 5-Bromo-pyridine-2~$ulfonic acid (2,2,2-trifluoro-ethyl)-amide
Figure imgf000073_0001
5-Bromopyridine-2-sulfonyl chloride (100.7 mg, 0.393 mmol) was dissolved in CH2Cl2 (1 mL) and 2,2,2-trifluoro-ethylamine (34 μL, 0.432 mmol) was added. Stirring was continued at room temperature for 3 hours and saturated aqueous NaHCO3 (1 mL) was added. The mixture was diluted with CH2Cl2 (5 mL) and the aqueous phase was extracted with CH2Cl2 (3 x 5 mL). The combined organic phases were dried (Na2SO4) and concentrated to afford the title compound (49 mg, 39%). MS (ESI) m/z 320 (M + 1).
Example 52 (d) 5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)-2,4-dihydroimidazol-4- yl]pyrimidin-2-yl]amino]-N-(2,2,2-trifluoroethyl)pyridine-2-sulfonamide
Figure imgf000073_0002
5-Fluoro-4-[2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine (as described in Example 6) (42.1 mg, 0.152 mmol), 5-bromo-pyridine-2-sulfonic acid (2,2,2-trifiuoro-ethyl)-amide (48.5 mg, 0.152 mmol), Cs2CO3 (79.2 mg, 0.243 mmol), Pd2(dba)3 (7 mg, 0.008 mmol) and XantPhos (9 mg, 0.016) mmol) were weighed out in a 25 mL round-bottom flask and dioxane (3 mL) was added. The system was flushed with argon and then heated to 9O0C and stirred for 17 hours. Water (30 mL) was added and the mixture was extracted with CH2Cl2 (3 x 30 mL). Drying (Na2SO4), filtration and concentration afforded a crude material, which was purified by preparative HPLC to afford the title compound (3 mg, 3%). 1H NMR (400 MHz, CDCl3) δ ppm 1.83 - 1.92 (m, 2 H) 2.53 - 2.65 (m, 2 H) 2.68 (s, 3 H) 3.39 (t, J=I 1.87 Hz, 2 H) 3.73 - 3.85 (m, 2 H) 4.11 - 4.20 (m, 2 H) 5.00 (br. s., 1 H) 5.74 (br. s., 1 H) 7.73 (br. s., 1 H) 7.81 (s, 1 H) 7.93 (d, J=8.84 Hz, 1 H) 8.33 - 8.42 (m, 2 H) 8.81 (s, 1 H); MS (ESI) m/z 516 (M + 1).
Example 53
N,N-Dimethyl-5-[[4-[2-methyl-3-(oxan-4-yl)-2,4-dihydroimidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-sulfonamide
Figure imgf000074_0001
Example 53 fa) 5 -Bromo-pyridine-2 'sulfonic acid dimethylamide
Figure imgf000074_0002
5-Bromopyridine-2-sulfonyl chloride (as described in Example 52) (129.4 mg, 0.505 mmol) was dissolved in CH2Cl2 (1 mL) and dimethylamine (29 μL, 0.555 mmol) was added. Stirring was continued at room temperature for 3 hours and saturated aqueous NaHCO3 (1 mL) was added. The mixture was diluted with CH2Cl2 (5 mL) and the aqueous phase was extracted with CH2Cl2 (3 x 5 mL). The combined organic phases were dried (Na2SO4) and concentrated to afford the title compound (97 mg, 67%). MS (EST) m/z 266 (M + 1).
Example 53(b) N,N-Dimethyl-5-[[4-[2-methyl-3-(oxan-4-yl)-2, 4-dihydroimidazol-4- yl]pyrimidin-2-yl]amino]pyridine-2-sulfonamide
Figure imgf000074_0003
5-Fluoro-4-[2-methyl-l-(tetxahydro-2H-pyran-4-yl)-lH'-imidazol-5-yl]pyrimidin-2-amine (as described in Example 6) (98.1 mg, 0.354 mmol), 5-bromo-pyridine-2-sulfonic acid diethylamide (93.8 mg, 0.354 mmol), Cs2CO3 (230.5 mg, 0.708 mmol), Pd2(dba)3 (16 mg, 0.018 mmol) and XantPhos (21 mg, 0.035) mmol) were weighed out in a 25 mL round-bottom flask and dioxane (5 mL) was added. The system was flushed with argon and then heated to 90°C and stirred for 17 hours. Water (30 mL) was added and the mixture was extracted with CH2Cl2 (3 x 30 mL). Drying (Na2SO4), filtration and concentration afforded a crude material which was purified by preparative HPLC to afford the title compound (9 mg, 6%). 1H NMR (400 MHz, CDCl3) δ ppm 1.88 (dd, J=12.63, 3.79 Hz, 2 H) 2.50 - 2.63 (m, 2 H) 2.66 (s, 3 H) 2.91 (s, 6 H) 3.31 - 3.42 (m, 2 H) 4.12 (dd, J=I 1.62, 4.80 Hz, 2 H) 4.98 - 5.09 (m, 1 H) 7.70 (d, J=3.54 Hz, 1 H) 7.86 - 7.91 (m, 2 H) 8.32 (dd, J=8.72, 2.65 Hz, 1 H) 8.38 (d, J=2.78 Hz, 1 H) 8.83 (d, J=2.53 Hz, 1 H); MS (ESI) m/z 462 (M + 1).
Example 54
N-fS-Chloro-ό-φiperidin-l-ylcarbonytypyridin-S-ylJ-S-fluoro^-β-methyl-l-ζtetrahydro- 2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine hydrochloride
Figure imgf000075_0001
Example 54(a) 3,5-Dichloro-2-(piperidin-l-ylcarbonyl)pyridine
Figure imgf000075_0002
3,5-Dichloro-2-pyridine carboxylic acid (1.25 g, 6.5 mmol) was suspended in thionyl chloride (10 ml). DMF (2 drops) was added and the mixture was refluxed for 15 minutes under an atmosphere of nitrogen. The solvent was evaporated. Toluene was added and the solvent was evaporated to give a solid. The solid was dissolved in DCM (8 ml) and the mixture was cooled to 0° C. Piperidine (0.64 ml, 6.5 mmol) was added dropwise followed by triethylamine (0.91 ml, 6.5 mmol). The cooling bath was removed. The mixture was stirred under nitrogen atmosphere until RT was reached and then for an additional 15 minutes. The mixture was washed with aqueous sodium bicarbonate and the organic phase was dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography eluting with gradients of heptane and ethyl acetate to give the title compound (1.28 g, 76%).
1H NMR (400 MHz, CDCl3) δ ppm 8.46 (d, 1 H) 7.77 (d, 1 H) 3.74 (m., 2 H) 3.11 - 3.16 (m, 2 H) 1.64 - 1.71 (m, 4 H) 1.55 (m, 2 H) MS (ESI) m/z 259; 261 (M+l).
Example 54(b) N-[5-Chloro-6-(piperidin-l-ylcarbonyl)pyridin-3-yl]-5-fluoro-4-[2- methyl-l-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine hydrochloride
Figure imgf000076_0001
5-Fluoro-4-[2-methyl- 1 -(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine (as described in Example 6) (150 mg, 0.54 mmol), 3,5-dichloro-2-(piperidin-l- ylcarbonyl)pyridine (as described in Example 54(a)) (124 mg, 0.48 mmol) and caesium carbonate (351 mg, 1.08 mmol) were suspended in dioxane (4 ml). Pd2(dba)3 (26 mg, 0.029 mmol) and Xantphos (27 mg, 0.047 mmol) were added and the mixture was stirred at 90° C under argon atmosphere for 16 h. Pd2(dba)3 (5 mg) was added and the mixture was heated at 90° C for 4 h. The mixture was diluted with DCM and filtered through diatomeous earth. The organic phase was washed with aqueous sodium bicarbonate and evaporated. The residue was dissolved in DMSO and purified by preparative ΗPLC. The fractions containing the product were pooled and concentrated. Aqueous sodium bicarbonate was added and the mixture was extracted with DCM (x4). The organic phase was dried (MgSO4), filtered and concentrated. The residue was dissolved in DCM (1 ml) and 1 M hydrochloric acid in ether (0.2 ml) was added. The solvent was evaporated to give the title compound (40 mg, 14%).
1H NMR (400 MHz, DMSO-J6) δ ppm 7.39 - 7.43 (m, 2 H) 7.14 (d, 1 H) 6.67 (d, 1 H) 3.88 - 3.99 (m, 1 H) 2.74 (dd, 2 H) 1.95 - 2.07 (m, 4 H) 1.64 (s, 3 H) 1.06 - 1.20 (m, 2 H) 0.80 (dd, 2 H) 0.44 - 0.52 (m, 4 H) 0.31 - 0.40 (m, 2 H). MS (ESI) m/z 500; 502 (M+l). Example 55
N-fS-Chloro-ό-φiperidin-l-ylcarbonytypyridin-S-ylJ-^β^-dimethyl-lH-imidazolS-yl)- 5~flιιoropyrimidin-2-amine hydrochloride
Figure imgf000077_0001
(1 ,2-Dimethyl-lH-imidazol-5-yl)-5-fluoropyrimidin-2-amine (as described in Example 7) (50 mg, 0.24 mmol), 3,5-dichloro-2-(piperidin-l-ylcarbonyl)pyridine (as described in Example 54(a)) (62 mg, 0.24 mmol) and caesium carbonate (156 mg, 0.48 mmol) were suspended in dioxane (2 ml). Pd2(dba)3 (22 mg, 0.024 mmol) and Xantphos (23 mg, 0.040 mmol) were added and the mixture was stirred at 90° C under argon atmosphere for 16 h. The mixture was diluted with DCM and filtered through diatomeous earth. The organic phase was washed with aqueous sodium bicarbonate and concentrated. The residue was dissolved in DMSO and purified by preparative HPLC. The fractions containing the product were pooled and concentrated. Aqueous sodium bicarbonate was added and the mixture was extracted with DCM (x4). The organic phase was dried (MgSO4), filtered and concentrated. The residue was dissolved in DCM (1 ml) and 1 M hydrochloric acid in ether (0.1 ml) was added. The solvent was evaporated to give the title compound (28 mg, 25%). 1H NMR (400 MHz, DMSO-J6) δ ppm 10.40 (s, 1 H) 8.85 (d, 1 H) 8.78 (d, 1 H) 8.41 (d, 1 H) 8.21 (d, 1 H) 4.03 (s, 3 H) 3.59 - 3.65 (m, 2 H) 3.07 - 3.12 (m, 2 H) 2.68 (s, 3 H) 1.42 - 1.66 (m, 6 H). MS (ESI) m/z 430; 432 (M+ 1).
Example 56
N-fS-Chloro-ό-φiperidin-l-ylcarbonyljpyridinS-ylJ-S-βuoro^-fl-methyl^- (trifluoromethyl)-lH-imidazol-5-yl]pyrimidin-2-amitte hydrochloride
Figure imgf000077_0002
5-Fluoro-4-[ 1 -methyl-2-(trifluoromethyl)- lH-imidazol-5-yl]pyrimidin-2-amine (as described in Example 9) (130 mg, 0.50 mmol), 3,5-dichloro-2-(piperidin-l- ylcarbonyl)pyridine (as described in Example 54(a)) (130 mg, 0.50 mmol) and caesium carbonate (326 mg, 1.0 mmol) were suspended in dioxane (4 ml). Pd2(dba)3 (27 mg, 0.030 mmol) and Xantphos (29 mg, 0.050 mmol) were added and the mixture was stirred at 90° C under argon atmosphere for 16 h. Pd2(dba)3 (10 mg, 0.011 mmol) was added and the mixture was heated at 90°C under argon atmosphere for 6 h. The mixture was diluted with
5 DCM and filtered through diatomeous earth. The organic phase was washed with aqueous sodium bicarbonate and concentrated. The residue was dissolved in DMSO and purified by preparative HPLC. The fractions containing the product were pooled and concentrated. Aqueous sodium bicarbonate was added and the mixture was extracted with DCM (x4). The organic phase was dried (MgSO4), filtered and concentrated. The residue was io dissolved in DCM (1 ml) and 1 M hydrochloric acid in ether (0.1 ml) was added. The solvent was evaporated to give the title compound (13 mg, 5%).
1H NMR (400 MHz, DMSO-J6) δ ppm 10.34 (s, 1 H) 8.81 (d, 1 H) 8.75 (d, 1 H) 8.43 (d, 1 H) 7.76 (d, 1 H) 4.10 (s, 3 H) 3.58 - 3.65 (m, 2 H) 3.05 - 3.13 (m, 2 H) 1.42 - 1.66 (m, 6 H). MS (ESI) m/z 482; 484 (M+l).
I5
Example 57
N-fS-Chloro-ό-φiperidin-l-ylcarbonyfypyridin-S-ylJ-S-fluoro-^fl-ftetrahydro^H- pyran-4-yl)-2-(trifluoromethyl)-lH-imidazol-5-yl]pyriτnidin-2-amine hydrochloride
Figure imgf000078_0001
20 5-Fluoro-4-[l-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-lJH-imidazol-5-yl]pyrimidin- 2-amine (as described in Example 8) (70 mg, 0.21 mmol), 3,5-dichloro-2-(piperidin-l- ylcarbonyl)pyridine (as described in Example 54(a)) (55 mg, 0.21 mmol) and caesium carbonate (137 mg, 0.42 mmol) were suspended in dioxane (2 ml). Pd2(dba)3 (19 mg, 0.021 mmol) and Xantphos (20 mg, 0.035 mmol) were added and the mixture was stirred 5 at 90° C under argon atmosphere for 16 h. The mixture was diluted with DCM and filtered through diatomeous earth. The organic phase was washed with brine and concentrated. The residue was dissolved in DMSO and purified by preparative ΗPLC. The fractions containing the product were pooled and concentrated. Aqueous sodium bicarbonate was added and the mixture was extracted with DCM (χ4). The organic phase was dried (MgSO4), filtered and concentrated. The residue was dissolved in DCM (1 ml) and 1 M hydrochloric acid in ether (0.2 ml) was added. The solvent was evaporated. The residue was dissolved in DCM and methanol and the solvent was evaporated to give the title compound (66 mg, 53%).
1H NMR (400 MHz, DMSO-J6) δ ppm 10.36 (s, 1 H) 8.89 (d, 1 H) 8.74 (d, 1 H) 8.35 (d, 1 H) 7.59 (d, 1 H) 4.76 - 4.86 (m, 1 H) 3.83 (dd, 2 H) 3.25 (t, 2 H) 3.05 - 3.11 (m, 2 H) 2.08 ■ 2.20 (m, 2 H) 1.85 - 1.93 (m, 2 H) 1.40 - 1.66 (m, 6 H). MS (ESI) m/z 554; 556 (M+l).
Example 58
{5-Fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-[6- (4-methyl-piperazine-l-sulfonyl)-pyridin-3-yl]-amine
Figure imgf000079_0001
Example 58(a) l-(5-Bromo-pyridine-2-sulfonyl)-4-methyl-piperazine
Figure imgf000079_0002
5-Bromopyridine-2-sulfonyl chloride (as described in Example 52(b) (55.0 mg, 0.214 mmol) was dissolved in CH2Cl2 (1 mL) and 1-methyl-piperazine (26 μL, 0.236 mmol) was added. Stirring was continued at room temperature for 3 hours and saturated aqueous NaHCO3 (1 mL) was added. The mixture was diluted with CH2Cl2 (5 mL) and the aqueous phase was extracted with CH2Cl2 (3 x 5 mL). The combined organic phases were dried (Na2SO4) and concentrated to afford the title compound (61 mg, 89%). 1H NMR (400 MHz, CDCl3) δ ppm 2.29 (s, 3 H) 2.33 - 2.38 (m, 2 H) 2.45 - 2.50 (m, 2 H) 3.10 - 3.18 (m, 2 H) 3.30 - 3.37 (m, 2 H) 7.31 (d, J=4.29 Hz, 1 H) 7.81 (d, J=7.58 Hz, 1 H) 8.04 (dd, J=8.34, 2.27 Hz, 1 H); MS (ESI) m/z 321 (M + 1). Example 58(b) {5-Fluoro-4-[2-methyl-3-(tetrahydro-pyran~4-yl)-3H-imidazol-4-yl]- pyrimidin-2-yl}-[6-(4-methyl-piperazme-l-sulfonyl)-pyridin-3-yl]-amιne
Figure imgf000080_0001
5-Fluoro-4-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine 5 (as described in Example 6) (56.0 mg, 0.202 mmol), l-(5-bromo-pyridine-2-sulfonyl)-4- methyl-piperazine (as described in Example58(a)) (64.7 mg, 0.202 mmol), Cs2CO3 (131.7 mg, 0.404 mmol), Pd2(dba)3 (9 mg, 0.010 mmol) and XantPhos (12 mg, 0.020) mmol) were weighed out in a 25 mL round-bottom flask and dioxane (5 mL) was added. The system was flushed with argon and then heated to 90°C and stirred for 17 hours. Water (30o mL) was added and the mixture was extracted with CH2Cl2 (3 x 30 mL). Drying (Na2SO4), filtration and concentration afforded a crude material, which was purified by preparative HPLC to afford the title compound (18 mg, 17%).
1H NMR (400 MHz, CDCl3) δ ppm 1.83 - 1.92 (m, 2 H) 2.31 (s, 3 H) 2.46 - 2.62 (m, 6 H) 2.65 (s, 3 H) 3.28 - 3.44 (m, 6 H) 4.12 (dd, J=I 1.62, 4.80 Hz, 2 H) 4.97 - 5.09 (m, 1 H)s 7.70 (br. s., 1 H) 7.83 - 7.90 (m, 2 H) 8.32 - 8.39 (m, 2 H) 8.77 (d, J=2.02 Hz, 1 H); MS (ESI) m/z 518 (M + 1).
Pharmaceutical forinulaitons
According to one aspect of the present invention there is provided a pharmaceutical0 formulation comprising the compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof, in an essentially pure and isolated form, for use in the prevention and/or treatment of conditions associated with glycogen synthase kinase-3.
The formulation used in accordance with the present invention may be in a form suitables for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment, patch or cream, for rectal administration as a suppository and for local administration in a body cavity or in a bone cavity.
The formulation may be in a form suitable for oral administration, for example as a tablet, for parenteral injection as a sterile solution or suspension. In general the above formulation may be prepared in a conventional manner using pharmaceutically carriers or diluents.
Suitable daily doses of the compound of formula (I) as a free base and pharmaceutically acceptable salts thereof in the treatment of a mammal, including human, are approximately 0.01 to 250 mg/kg bodyweight at per oral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration. The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.
The compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof, in an essentially pure and isolated form, may be used on its own but will usually be administered in the form of a pharmaceutical formulation in which the active ingredient is in association with pharmaceutically acceptable diluents, excipients or inert carrier. Dependent on the mode of administration, the pharmaceutical formulation may comprise from 0.05 to 99 %w (per cent by weight), for example from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
A diluent or carrier includes water, aqueous poly(ethylene glycol), magnesium carbonate, magnesium stearate, talc, a sugar (such as lactose), pectin, dextrin, starch, tragacanth, microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose or cocoa butter.
A formulation of the present invention can be in a unit dosage form such as a tablet or an injectable solution. The tablet may additionally comprise a disintegrant and/or may be coated (for example with an enteric coating or coated with a coating agent such as hydroxypropyl methylcellulose). The present invention further provides a process for the preparation of a pharmaceutical formulation of the present invention which comprises mixing of the compound of formula (I) or a pharmaceutically acceptable salt thereof, a hereinbefore defined, with pharmaceutically acceptable diluents, excipients or inert carriers.
An example of a pharmaceutical formulations of the present invention is an injectable solution comprising the compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof, as hereinbefore defined, and sterile water, and, if necessary, either a base sodium hydroxide or an acid hydrochloric acid to bring the pH of the final formulation to about pH in the range of about 4 to 6 , particularly about 5, and optionally a surfactant to aid dissolution. A suitable base is sodium hydroxide. A suitable acid is hydrochloric acid.
A suitable pharmaceutically acceptable salt of the compound of formula (I) useful in accordance to the present invention is, for example, an acid-addition salt, which is sufficiently basic, for example an inorganic or organic acid. In addition a suitable pharmaceutically acceptable salt of the compounds of the present invention, which is sufficiently acidic, is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base, which affords a physiologically-acceptable cation.
Medical uses
It has been found that the compounds of formula (I) defined in the present invention, are well suited for inhibiting glycogen synthase kinase-3 (GSK3). Accordingly, said compound of the present invention is expected to be useful in the prevention and/or treatment of conditions associated with glycogen synthase kinase-3 activity, i.e. the compounds may be used to produce an inhibitory effect of GSK3 in mammals, including human, in need of such prevention and/or treatment.
GSK3 is highly expressed in the central and peripheral nervous system and in other tissues. Thus, it is expected that compound of the present invention is well suited for the prevention and/or treatment of conditions associated with glycogen synthase kinase-3 in the central and peripheral nervous system. In particular, the compound of the present invention is expected to be suitable for prevention and/or treatment of conditions associated with cognitive disorders and predemented states, especially dementia, Alzheimer's Disease (AD), Cognitive Deficit in Schizophrenia (CDS), Mild Cognitive Impairment (MCI), Age- Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD) and Cognitive Impairement No Dementia (CIND), diseases associated with neurofibrillar tangle pathologies, Frontotemporal dementia (FTD), Frontotemporal dementia Parkinson's Type (FTDP), progressive supranuclear palsy (PSP), Pick's Disease, Niemann-Pick's Disease, corticobasal degeneration (CBD), traumatic brain injury (TBI) and dementia pugilistica.
One embodiment of the present invention relates to the prevention and/or treatment of Alzheimer's Disease, especially the use in the delay of the disease progression of Alzheimer's Disease.
Other conditions are selected from the group consisting of Down's syndrome, vascular dementia, Parkinson's Disease (PD), postencephelatic parkinsonism, dementia with Lewy bodies, HIV dementia, Huntington's Disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases (MND, Creuztfeld- Jacob's disease and prion diseases.
Other conditions are selected from the group consisting of attention deficit disorder
(ADD), attention deficit hyperactivity disorder (ADHD) and affective disorders, wherein the affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, and dysthymia.
Other conditions are selected from the group consisting of Type I diabetes, Type II diabetes, diabetic neuropathy, alopecia, inflammatory diseases and cancer.
One embodiment of the present invention relates to the use of a compound of the formula (I), as defined in the present invention, in the prevention and/or treatment of bone-related disorders or conditions in mammals. One aspect of the present invention is directed to the use of a compound of the formula (I) , as defined in the present invention to treat osteoporosis.
One aspect of the present invention is directed to the use of a compound of the formula (I), as defined in the present invention to increase and promote bone formation in mammals.
One aspect of the present invention is directed to the use of a compound of the formula (I), as defined in the present invention to increase bone mineral density in mammals.
Another aspect of the present invention is directed to the use of a compound of the formula (I), as defined in the present invention to reduce the rate of fracture and/or increase the rate of fracture healing in mammals.
Another aspect of the present invention is directed to the use of a compound of the formula (I), as defined in the present invention to increase cancellous bone formation and/or new bone formation in mammals.
Another aspect of the present invention is directed to a method of prevention and/or treatment of bone-related disorders comprising administering to a mammal in need of such prevention and/or treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.
Another aspect of the present invention is directed to a method of prevention and/or treatment of osteoporosis comprising administering to a mammal in need of such prevention and/or treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.
Another aspect of the present invention is directed to a method of increasing bone formation comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention. Another aspect of the present invention is directed to a method of increasing bone mineral density comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.
Another aspect of the present invention is directed to a method of reducing the incidence of fracture comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.
Another aspect of the present invention is directed to a method of enhancing fracture healing comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.
Another aspect of the present invention is directed to said methods and wherein said mammal is a human.
Another aspect of the present invention is directed to said methods and wherein said mammal is a vertibrate animal, preferably but not limited to bigger animals such as horses, camels, dromedars but not limited thereto.
The use of the GSK3 inhibitors, the compounds of formula (I) hereinbefore defined, in primary and secondary ostopeorosis, where primary osteoporosis includes postmenopausal osteoporosis and senile osteoporosis in both men and women, and secondary osteoporosis includes cortison induced osteoporosis, as well as any other type of induced secondary osteoporosis, are included in the term osteoporosis. In addition to this, these GSK3 inhibitors may also be used in treatments of myeloma. These GSK3 inhibitors may be administered locally or systemically, in different formulation regimes, to treat these conditions.
The promotion and increasing of bone formation makes the compounds of the formula (I) hereinbefore defined, suitable to reducing the incidence of fracture, to reduce the rate of fracture and/or increase the rate of fracture healing, to increase cancellous bone formation and/or new bone formation in mammals. The use to promote and increase new bone formation may be in connection with surgery. This present invention can be used during surgery, where the treating surgeon will place the present invention locally in an appropriate formulation, near the deficient bone and/or in the body cavity. The bone may for instance have been broken, and utilizing the present invention as described and claimed herein will then be placed in or near the fracture during open fracture repair. In some instances bone pieces may be missing (e.g. after tumour removal or severe casualties), and utilizing the present invention as described and claimed herein will then be placed near the site of constructive bone surgery.
The present invention relates also to the use of the compound of formula (I) as as defined in the present invention in the manufacture of a medicament for the prevention and/or treatment of conditions associated with glycogen synthase kinase-3.
The present invention also provides for a method of treatment and/or prevention of conditions associated with glycogen synthase kinase-3 comprising administering to a mammal, including human in need of such treatment and/or prevention a therapeutically effective amount of the compound of formula (I) as as defined in the present invention.
The dose required for the therapeutic or preventive treatment of a particular disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. For veterinary use the amounts of different components, the dosage form and the dose of the medicament may vary and will depend on various factors such as, for example the individual requirement of the animal treated.
In the context of the present specification, the term "therapy" also includes "prevention" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
In the context of the present specification, the term "disorder" also includes "condition" unless there are specific indications to the contrary. Non-medical use
In addition to their use in therapeutic medicine, the compounds of formula (I) as a free base or a pharmaceutically acceptable salt thereof, are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of GSK3 related activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutics agents.
Pharmacology Determination of ATP competition in Scintillation Proximity GSK3β Assay.
GSK3 β scintillation proximity assay.
The competition experiments were carried out in duplicate with 10 different concentrations of the inhibitors in clear-bottom microtiter plates (Wallac, Finland). A biotinylated peptide substrate, Biotin-Ala-Ala-Glu-Glu-Leu-Asp-Ser-Arg-Ala-Gly-Ser(PO3H2)-Pro-Gln-Leu (AstraZeneca, Lund), was added at a final concentration of 1 μM in an assay buffer containing 1 mU recombinant human GSK3β (Dundee University, UK), 12 mM morpholinepropanesulfonic acid (MOPS), pH 7.0, 0.3 mM EDTA, 0.01% β- mercaptoethanol, 0.004 % Brij 35 (a natural detergent), 0.5 % glycerol and 0.5 μg BSA/25 μl. The reaction was initiated by the addition of 0.04 μCi [γ-33P]ATP (Amersham, UK) and unlabelled ATP at a final concentration of 1 μM and assay volume of 25 μl. After incubation for 20 minutes at room temperature, each reaction was terminated by the addition of 25 μl stop solution containing 5 mM EDTA, 50 μM ATP, 0.1 % Triton X-100 and 0.25 mg streptavidin coated Scintillation Proximity Assay (SPA) beads (Amersham, UK). After 6 hours the radioactivity was determined in a liquid scintillation counter (1450 MicroBeta Trilux, Wallac). The inhibition curves were analysed by non-linear regression using GraphPad Prism, USA. The Km value of ATP for GSK3β, used to calculate the inhibition constants (K;) of the various compounds, was 20 μM.
The following abbreviations have been used: MOPS Morpholinepropanesulfonic acid EDTA Ethylenediaminetetraacetic acid BSA Bovin Serum Albumin ATP Adenosine Triphosphate
SPA Scintillation Proximity Assay
GSK3 Glycogen synthase kinase 3
s Results
Typical Ki values for the compounds of the present invention are in the range of about 0.001 to about 10,000 nM. Other values for Kj are in the range of about 0.001 to about 1000 nM. Further values for Ki are in the range of about 0.001 nM to about 700 nM.
I0 Table 1. Specimen results fi'om assay.
Figure imgf000088_0001

Claims

1. A compound of formula (I) :
Figure imgf000089_0001
wherein: R1 is selected from sulphamoyl, carbamoyl, a group -R5-R6 and a nitrogen linked 4-7 membered saturated ring which optionally contains an additional nitrogen, oxygen or sulphur atom; wherein said ring is optionally substituted on carbon by one or more R7; and wherein if said ring contains an additional nitrogen atom that nitrogen is optionally substituted by R8;
at least one of X1, X2, X3 and X4 is selected from N, the other three X1, X2, X3 or X4 are independently selected from N or C(R9), provided that not more than two of X1, X2, X3 or X4 are selected from N;
R2 is halo or cyano;
R3 is methyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl, wherein the tetrahydropyranyl group is optionally substituted on carbon by one or more R10;
R4 is selected from hydrogen, halo, cyano and C1-3alkyl, wherein Ci-3alkyl is optionally substituted with one or more halo;
R5 is selected from -O-, -C(O)-, -C(O)O-, -C(O)N(R11)-, -S(O)r- and -SO2N(R12)-; wherein R11 and R12 are independently selected from hydrogen or C1-6alkyl and said alkyl is optionally substituted by one or more R13; and r is 0, 1 or 2; R6 is selected from Q-βalkyl, carbocyclyl and heterocyclyl; wherein R6 is optionally substituted on carbon by one or more R14; and wherein if said heterocyclyl contains an - NH- moiety that nitrogen is optionally substituted by a group selected from R15;
R7 is selected from halo, cyano, hydroxy, trifluoromethoxy, C1-3alkoxy and C1-3alkyl, wherein said C1-3alkyl is optionally substituted by one or more halo;
R9 is selected from hydrogen, halo, cyano, hydroxy, amino, C1-3alkyl and C1-3alkoxy;
R10, R13 and R14 are independently selected from halo, cyano, hydroxy, amino, sulphamoyl, C^alkyl, C1-6alkoxy, C^alkoxyQ-ealkoxy, N-(C1-6alkyl)amino, N,JV-(C1-6alkyl)2amino,
Figure imgf000090_0001
C1-OaIlCyIS(O)3 wherein a is 0 to 2,
Figure imgf000090_0002
N,N-(C1-6alkyl)2sulphamoyl, C1- 6alkylsulphonylamino, carbocyclyl, heterocyclyl, carbocyclylCi^alkyl-R16-, heterocyclylC1-3alkyl-R17-, carbocyclyl-R18- and heterocyclyl-R19-; wherein R10, R13 and R1 are independently of each other substituted on carbon by one or more R20; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from R21;
R16, R17, R18 and R19 are independently selected from -O-, -N(R22)-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -S(O)s-, -SO2N(R25)- and -N(R26)SO2-; wherein R22, R23, R24, R25 and R26 are independently selected from hydrogen and d^alkyl; and s is 0, 1 or 2;
R8, R15 and R21 are independently selected from C1-4alkyl, carbocyclyl, heterocyclyl, -C1-4aUcylcarbocyclyl, -C1-4alkylheterocyclyl, C1-4alkanoyl, C1-4alkylsulphonyl and C1- 4alkoxycarbonyl; wherein R8, R15 and R21 independently of each other may be optionally substituted on carbon by one or more R27; and
R20 and R27 are independently selected from halo, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, mesyl, ethylsulphonyl and phenyl; as a free base or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein R1 is a group -R5 -R6 or a nitrogen linked 4-7 membered saturated ring which optionally contains an additional nitrogen, oxygen or sulphur atom; wherein said ring may be optionally substituted on carbon by one or more R7; and wherein if said ring contains an additional nitrogen atom that nitrogen is optionally substituted by R8;
at least one of X1, X2, X3 and X4 is selected from N, the other three X1, X2, X3 or X4 are independently selected from N or C(R9) provided that not more than two of X1, X2, X3 or X4 are selected from N;
R2 is halo or cyano;
R3 is methyl or 4-tetrahydropyranyl, wherein said tetrahydropyranyl group is optionally substituted on carbon by one or more R10;
R4 is selected from hydrogen, halo, cyano and Ci-3alkyl, wherein said Ci-3alkyl is optionally substituted with one or more halo;
R5 is selected from -O-, -C(O)-, -C(O)OTC(O)N(R1 ')-, -S(O)r- and -SO2N(R12)-; wherein R11 and R12 are independently selected from hydrogen or Ci-6alkyl and said alkyl is optionally substituted by one or more R ; and r is 0 or 2;
R is selected from C1-6alkyl, carbocyclyl and heterocyclyl; wherein R is optionally substituted on carbon by one or more R1 ; and wherein if said heterocyclyl contains a -NH- moiety that nitrogen is optionally substituted by a group selected from R15;
R7 is selected from halo, cyano, hydroxy, trifluoromethoxy, C^alkoXy and Ci-3alkyl, wherein said C1-3alkyl is optionally substituted by one or more halo; R9 is selected from hydrogen, halo, cyano, hydroxy, C1-3alkyl and C1-3alkoxy;
R10, R13 and R14 are independently selected from halo, cyano, hydroxy, amino, sulphamoyl, C1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkoxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, Cϊ-galkanoylamino, iV-CCi-galkytycarbamoyl, iV,iV-(Ci-6alkyl)2carbamoyl, C1-OaIlCyIS(O)3 wherein a is 0 to 2, JV-(C1-6alkyl)sulphamoyl, N,JV-C1-6alkyl)2sulphamoyl, Ci-ealkylsulphonylamino, carbocyclyl, heterocyclyl, carbocyclylCi-3alkyl-R16-, heterocyclyld-salkyl-R17-, carbocyclyl-R18- and heterocyclyl-R19-; wherein R10, R13 and R14 independently of each other are optionally substituted on carbon by one or more R20; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from R21;
R16, R17, R18 and R19 are independently selected from -O-, -N(R22)-, -C(O)-,-N(R23)C(O)-, -C(O)N(R24)-, -S(O)s-, -SO2N(R25)- and -N(R26)SO2-; wherein R22, R23, R24, R25 and R26 are independently selected from hydrogen or C1-6alkyl; and s is 0, 1 or 2;
R8, R15 and R21 are independently selected from C1-4alkyl, carbocyclyl, heterocyclyl, -C1-4alkylcarbocyclyl, -C1-4alkylheterocyclyl, C1-4alkanoyl, C1-4alkylsulphonyl and C1-4alkoxycarbonyl; wherein R8, R15 and R21 independently of each other may be optionally substituted on carbon by one or more R ; and
R20 and R27 are independently selected from halo, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, mesyl and ethylsulphonyl; as a free base or a pharmaceutically acceptable salt, an in vivo hydrolysable ester, solvate or solvate of a salt thereof.
3. A compound according to claim 1 or 2, wherein R2 is halo.
4. A compound according to any one of claims 1 to 3, wherein R2 is fluoro.
5. A compound according to any one of claims 1 to 4, wherein R3 is 4-tetrahydropyranyl or methyl.
6. A compound according to any one of claims 1 to 5, wherein R4 is hydrogen or C1-3alkyl, wherein said C1-3alkyl is optionally substituted with one or more halo.
7. A compound according to claim 6, wherein R4 is C1-3alkyl.
8. A compound according to claim 7, wherein R4 is methyl.
9. A compound according to claim 6, wherein R4 is trifluoromethyl.
10. A compound according to any one of claims 1 to 9, wherein R5 is -C(O)-or -S(O)1--; and r is 0 or 2.
11. A compound according to claim 10, wherein R5 is -C(O)-.
12. A compound according to claim 10, wherein R5 is -S(O)r-; and r is 2.
13. A compound according to any one of claims 1 to 9, wherein R5 is -O- or C(O)O-.
14. A compound according to any one of claims 1 to 9, wherein R5 is -C(O)N(R11)- or - SO2N(R12)-; wherein R11 and R12 are independently selected from hydrogen or Ci-βalkyl.
15. A compound according to any one of claims 1 to 14, wherein R6 is C1-6alkyl or heterocyclyl; wherein R6 is optionally substituted on carbon by one or more R14; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from R15.
16. A compound according to claim 15, wherein said C1-6alkyl is methyl, ethyl, butan-2-yl, butan-3-yl, propan-2-yl or tert-butyl.
17. A compound according to claim 15 or claim 16, wherein said heterocyclyl is selected from morpholinyl, homomorpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl, , homopiperidinyl and homopiperazinyl.
18. A compound according to claim 17, wherein said heterocyclyl is selected from piperidinyl, pyrrolidinyl, azetidinyl and piperazinyl.
19. A compound according to claim 15, wherein R14 is Ci-βalkoxy, halo, Ci-βalkyl, carbocyclyl, heterocyclyl and N,N-(C1-6alkyl)2amino; wherein R14 is optionally substituted on carbon by one or more R20.
20. A compound according to claim 15, wherein R15 is C1-4alkyl or carbocycle; wherein R15 is optionally substituted on carbon by one or more R27.
21. A compound according to any one of claims 1 to 20, wherein R8 is C1-4alkyl, and wherein R8 may be optionally substituted on carbon by one or more R27.
22. A compound according to claim 20 or claim 21, wherein R27 is hydroxy, halo, ethoxy, methoxy or phenyl.
23. A compound according to any one of claims 1 to 22, wherein at least one of X2, X3 and X4 is selected from N, the other two X2, X3 or X4 are independently selected from N or C(R9).
24. A compound according to claim 23, wherein X3 or X4 is N.
25. A compound according to any one of claims 1 to 24, wherein R9 is hydrogen, methyl, trifluoromethyl, trifluoromethoxy or halo.
26. A compound according to claim 25, wherein R9 is hydrogen.
27. A compound according to claim 25, wherein one of R9 is halo.
28. A compound according to claim 27, wherein said halo is chloro.
29. A compound according to claim 1 or claim 2, wherein R1 is a group -R5-R6; at least one of X1, X2, X3 and X4 is selected from N, the other three X1, X2, X3 or X4 are independently selected from N or C(R9), provided that not more than two of X1, X2, X3 or
X4 are selected from N;
R2 is halo; R3 is methyl or 4-tetrahydropyranyl;
R4 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted with one or more halo;
R5 is selected from -O-, -C(O)-, -C(O)O-, -C(O)N(R11)-, -S(O)1- and -SO2N(R12)-; wherein
R11 and R12 are independently selected from hydrogen or
Figure imgf000095_0001
and said alkyl is optionally substituted by one or more R13 and r is 2; R6 is C1-6alkyl or heterocyclyl; wherein R6 is optionally substituted on carbon by one or more R14; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from R15;
R9 is hydrogen or halo;
R14 is selected from halo, Ci-6alkyl, carbocycle, N,N-(C1-6alkyl)2amino, heterocyclyl and Ci-βalkoxy; wherein R14 is optionally on carbon by one or more R20;
R15 is C1-4alkyl or carbocycle; wherein R15 is optionally substituted on carbon by one or more R27; and
R20 and R27 are independently selected from halo, methoxy, ethoxy, and phenyl.
30. A compound according to claim 1 or 2, wherein,
R1 is a group -R5-R6; at least one of X1, X2, X3 and X4 is selected from N, the other three X1, X2, X3 or X4 are independently selected from N or C(R9), provided that not more than two of X1, X2, X3 or
X4 are selected from N; R2 is halo;
R3 is 4-tetrahydropyranyl;
R4 is C1-3alkyl; R5 is -C(O) or -S(OV and -SO2N(R12)-; and r is 2;
R6 is C1-6alkyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from R15; R9 is hydrogen; and R15 is C1-4alkyl.
31. A compound selected from:
5-Fluoro-N-[5-(methylsulfonyl)pyridin-2-yl]-4-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine hydrochloride; Azetidin-l-yl-[3-chloro-5-[[5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone hydrochloride;
N-[5-Chloro-6-(piperidin-l-ylcarbonyl)pyridin-3-yl]-5-fluoro-4-[2-methyl-l-(tetrahydro- 2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine hydrochloride; N-[5-Chloro-6-(piperidin-l-ylcarbonyl)pyridm-3-yl]-4-(l,2-dimethyl-lH-imidazol-5-yl)-5- fluoropyrimidin-2-amine hydrochloride;
N-[5-Chloro-6-(piperidin-l-ylcarbonyl)pyridin-3-yl]-5-fluoro-4-[l-methyl-2- (trifluoromethyl)- lH-imidazol-5-yl]pyrimidin-2-amine hydrochloride; and N-[5-Chloro-6-(piperidin-l-ylcarbonyl)pyridin-3-yl]-5-fluoro-4-[l-(tetrahydro-2H-pyran- 4-yl)-2-(trifluoromethyl)-lH-imidazol-5-yl]pyrimidin-2-amine hydrochloride; or other pharmaceutically acceptable salts or free bases thereof.
32. A compound selected from:
5-Fluoro-N-[6-(methylsulfonyl)pyridin-3-yl]-4-[2-methyl-l-(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl]pyrimidin-2-amine; 5-Fluoro-N- {5-[(4-methylpiperazin-l -yl)carbonyl]pyridin-2-yl} -4-[2-methyl-l -(tetrahydro-
2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-iV- {6-[(4-methylpiperazin- 1 -yl)carbonyl]pyridin-3 -yl} -4-[2-methyl- 1 -(tetrahydro-
2H-pyran-4-yl)-lH-imidazol-5-yl]pyrimidin-2-amine;
N-[6-(Azetidin-l-ylcarbonyl)pyridin-3-yl]-5-fluoro-4-[2-methyl-l-(tetrahydro-2H-pyran-4- yl)- lH-imidazol-5-yl]pyrimidin-2-amine;
(6-Ethoxy-pyridin-3-yl)-{5-fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4- yl]-pyrimidin-2-yl}-amine; {5-Fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-iniidazol-4-yl]-ρyrimidin-2-yl}-(2- methoxy-pyrimidin-5-yl)-amine; iV-Butan-2-yl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-
N-propyl-pyridine-2-carboxamide; (353-Difluoropyrrolidin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]-
(3 -methyl- 1 -piperidyl)methanone;
5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N-methyl-iV'- propan-2-yl-pyridine-2-carboxamide;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidm-2-yl]amino]pyridin-2-yl]-
[4-(4-fluorophenyl)- 1 -piperidyl]methanone;
(4-Ethylpiperazin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]methanone; (4-Butylpiperazin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]methanone;
N-Ethyl-5 -[ [5 -fluoro-4- [2-methyl-3 -(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl] amino]-iV- propan-2-yl-pyridine-2-carboxamide;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino3pyridin-2-yl]- (l-piperidyl)methanone;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]-
(4-propan-2-ylpiperazin-l-yl)methanone;
5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]aniino]-iV,N- dipropan-2-yl-pyridine-2-carboxamide; (2,6-Dimethyl-l-piperidyl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone;
5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N,iV- dipropyl-pyridine-2-carboxamide;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]- (4-methoxy- 1 -piperidyl)methanone;
N-Ethyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-iV- methyl-pyridine-2-carboxamide; [5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]-
(4-methyl- 1 -piperidyl)methanone;
(4-Ben2ylpiperazin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]ρyrimidin-
2-yl] amino]pyridin-2-yl]methanone; (4,4-Difluoro-l-piperidyl)-[5-[[5-fluoro-4-[2-meihyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone;
N-Benzyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N- propan-2-yl-pyridine-2-carboxamide;
5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N-methyl-N- (2-methylpropyl)pyridine-2-carboxamide;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrinύdin-2-yl]amino]pyridin-2-yl]-
(4-fluoro- 1 -piperidyl)methanone;
N-Benzyl-N-ethyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-carboxamide; (4-Butan-2-ylpiperazin-l-yl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone; iV-(Cyclopropylmethyl)-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]-N-propyl-pyridine-2-carboxamide;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]- [4-(4-fluorophenyl)piperazin- 1 -yljmethanone;
[5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]-
(4-propylpiperazin- 1 -yl)methanone;
N;,iV:-Diethyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl] amino]pyridine-2-carboxamide; N-(3-Dimethylamino-2,2-dimethyl-propyl)-5-[[5-fluoro-4-[2-methyl-3-(oxan-4- yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridine-2-carboxamide;
(3,5-Dimethyl-l-piperidyl)-[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone;
Methyl 5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-carboxylate;
Azetidin-l-yl-[3-chloro-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl] amino]pyridin-2-yl]methanone; [3-Chloro-5-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]-(4-methylpiperazin-l-yl)methanone;
[3 -Chloro-5-[ [5-fluoro-4- [3 -methyl-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]-(4-methylpiperazin-l-yl)methanone; N-[6-(Azetidin- 1 -ylcarbonyl)pyridin-3 -yl]-4-( 1 ,2-dimethyl- lH-imidazol-5-yl)-5- fluoropyrimidin-2-amine;
4-(l ,2-Dimethyl-lH-imidazol-5-yl)-5-fluoro-N- {6-[(4-methylpiperazin- 1 - yl)carbonyl]pyridin-3-yl}pyrimidin-2-amine;
N-[6-(Azetidin-l-ylcarbonyl)-5-chloropyridin-3-yl]-4-(l,2-dimethyl-lH-imidazol-5-yl)-5- fluoropyrimidin-2-amine;
N-{5-Chloro-6-[(4-methylpiperazin-l-yl)carbonyl]pyridin-3-yl}-4-(l,2-dimethyl-lH- imidazol-5-yl)-5-fluoropyrimidin-2-amine;
{5-Fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-[6-
(propan-2-ylsulfonyl)-pyridin-3-yl]-amine; (6-Ethanesulfonyl-pyridin-3-yl)-{5-fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H- imidazol-4-yl]-pyrimidin-2-yl}-amine;
5-[[5-Fluoro-4-[2-methyl-3-(oxan-4-yl)-2,4-dihydroimidazol-4-yl]pyrimidin-2-yl]amino]-
N-(2,2,2-trifluoroethyl)pyridine-2-sulfonamide;
N^-Dimethyl-5-[[4-[2-methyl-3-(oxan-4-yl)-2,4-dihydroimidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-sulfonamide; and
{5-Fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-[6-(4- methyl-piperazine- 1 -sulfonyl)-pyridin-3 -y 1] -amine; as a free base or a pharmaceutically acceptable salt thereof.
33. A pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 32 in association with pharmaceutically acceptable excipients, carriers or diluents.
34. A compound as defined in any one of claims 1 to 32 for use in therapy.
35. Use of a compound as defined in any one of claims 1 to 32 in the manufacture of a medicament for prevention and/or treatment of conditions associated with glycogen synthase kinase-3.
36. Use of a compound as defined in any one of claims 1 to 32 in the manufacture of a medicament for prevention and/or treatment of cognitive disorders.
37. The use according to claim 36, wherein the cognitive disorder is dementia, Cognitive Deficit in Schizophrenia (CDS), Mild Cognitive Impairment (MCI), Age-Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD) or Cognitive Impairement No Dementia (CIND).
38. The use according to claim 37, wherein the disease is Cognitive Deficit in Schizophrenia.
39. The use according to claim 37, wherein the dementia is associated with neurofibrillar tangle pathologies.
40. The use according to claim 37, wherein the dementia is Frontotemporal dementia (FTD), Frontotemporal dementia Parkinson's Type (FTDP), progressive supranuclear palsy (PSP), Pick's Disease, Niemann-Pick's Disease, corticobasal degeneration, traumatic brain injury (TBI) or dementia pugilistica.
41. The use according to claim 37, wherein the dementia is Alzheimer's Disease (AD), Down's syndrome, vascular dementia, Parldnson's Disease (PD), postencephelatic parkinsonism, dementia with Lewy bodies, HIV dementia, Huntington's Disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases (MND), Creuztfeld- Jacob's disease or prion diseases.
42. The use according to claim 41 wherein the dementia is Alzheimer's Disease.
43. The use according to claim 37, wherein the use is in the delay of the disease progression of Alzheimer's Disease.
44. Use of a compound as defined in any one of claims 1 to 32 in the manufacture of a medicament for prevention and/or treatment of attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD) or affective disorders.
45. The use according to claim 44, wherein the affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, or dysthymia.
46. Use of a compound as defined in any one of claims 1 to 32 in the manufacture of a medicament for prevention and/or treatment of Type I diabetes, Type II diabetes, diabetic neuropathy, alopecia, inflammatory diseases or cancer.
47. Use of a compound as defined in any one of claims 1 to 32 in the manufacture of a medicament for prevention and/or treatment of bone related disorders or conditions in mammals.
48. The use of a compound as defined in any one of claims 1 to 32 in the manufacture of a medicament for prevention and/or treatment of osteoporosis in mammals.
49. The use of a compound as described in any one of claims 1 to 32, in the manufacturing of a medicament for increasing bone formation in mammals.
50. The use of a compound as described in any one of claims 1 to 32, in the manufacturing of a medicament for increasing cancellous bone formation and/or new bone formation in mammals.
51. The use of a compound as described in any one of claims 1 to 32, in the manufacturing of a medicament for increasing bone mineral density in a mammal.
52. The use of a compound as described in any one of claims 1 to 32, in the manufacturing of a medicament for reducing the incidence of fracture in a mammal.
s 53. The use of a compound as described in any one of claims 1 to 32, in the manufacturing of a medicament for enhancing fracture healing in a mammal.
54. The use according to any one of claims 35 to 53, wherein said mammal is a human. o
55. A method of prevention and/or treatment of conditions associated with glycogen synthase kinase-3, comprising administering to a mammal, including human in need of such prevention and/or treatment, a therapeutically effective amount of a compound as defined in any one of claims 1 to 32. s
56. A method of prevention and/or treatment of cognitive disorders, comprising administering to a mammal, including human in need of such prevention and/or treatment, a therapeutically effective amount of a compound as defined in any one of claims 1 to 32.
57. The method according to claim 56, wherein the cognitive disorder is dementia,0 Cognitive Deficit in Schizophrenia (CDS), Mild Cognitive Impairment (MCI), Age- Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD) or Cognitive Impairement No Dementia (CIND).
58. The method according to claim 57, wherein the disease is Cognitive Deficit in5 Schizophrenia.
59. The method according to claim 57, wherein the dementia is associated with neurofibrillar tangle pathologies. 0
60. The method according to claim 57, wherein the dementia is Frontotemporal dementia (FTD), Frontotemporal dementia Parkinson's Type (FTDP), progressive supranuclear palsy (PSP), Pick's Disease, Niemann-Pick's Disease, corticobasal degeneration, traumatic brain injury (TBI) or dementia pugilistica.
61. The method according to claim 60, wherein the dementia is Alzheimer's Disease (AD), 5 Down syndrome, vascular dementia, Parkinson's Disease (PD), postencephelatic parkinsonism, dementia with Lewy bodies, HIV dementia, Huntington's Disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases (MND), Creuztfeld-Jacob's disease or prion diseases.
I0 62. The method according to claim 61, wherein the dementia is Alzheimer's Disease.
63. The method according to claim 61, wherein the treatment is in the delay of the disease progression of Alzheimer's Disease.
is 64. A method of prevention and/or treatment of attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD) or affective disorders, comprising administering to a mammal, including human in need of such prevention and/or treatment, a therapeutically effective amount of a compound as defined in any one of claims 1 to 32.
20 65. The method according to claim 64, wherein the affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, or dysthymia. 5
66. A method of prevention and/or treatment of Type I diabetes, Type II diabetes, diabetic neuropathy, alopecia, inflammatory diseases or cancer, comprising administering to a mammal, including human in need of such prevention and/or treatment, a therapeutically effective amount of a salt compound as defined in any one of claims 1 to 32. 0
67. A method of prevention and/or treatment of bone related disorders or conditions comprising administering to a mammal, in need of such prevention and/or treatment, a therapeutically effective amount of a saltcompound as defined in any one of claims 1 to 32.
68. A method of prevention and/or treatment of osteoporosis comprising administering to a mammal, in need of such prevention and/or treatment, a therapeutically effective amount of a compound as described in any one of claims 1 to 32.
69. A method of increasing bone formation comprising administering to a mammal, in need of such prevention and/or treatment, a therapeutically effective amount of a compound as described in any one of claims 1 to 32.
70. A method of increasing cancellous bone formation and/or new bone formation comprising administering to a mammal, in need of such prevention and/or treatment, a therapeutically effective amount of a compound as described in any one of claims 1 to 32.
71. A method of increasing bone mineral density comprising administering to a mammal, in need of such prevention and/or treatment, a therapeutically effective amount of a compound as described in any one of claims 1 to 32.
72. A method of reducing the incidence of fracture comprising administering to a mammal in need of such prevention and/or treatment, a therapeutically effective amount of a compound as described in any one of claims 1 to 32.
73. A method of enhancing fracture healing comprising administering to a mammal, in need of such prevention and/or treatment, a therapeutically effective amount of a compound as described in any one of claims 1 to 32.
74. A method according to any one of claims 55 to 73, wherein said mammal is a human.
75. A process for preparing a compound of formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, which process comprises: a) reacting a pyrrolidine of formula (II):
Figure imgf000105_0001
with a compound of formula (III):
Figure imgf000105_0002
wherein Y is a displaceable group; and
R1, R2, R3, R4, X1, X2, X3 and X4 are, unless otherwise specified, defined as in claim 1; and thereafter optionally: b) converting a compound of the formula (I) into another compound of formula (I); c) removing any protecting groups; and d) forming a pharmaceutically acceptable salt or in vivo hydroly sable ester.
76. A compound selected from:
Lithium 5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridine-2-carboxylate; Azetidin-l-yl-(3,5-dichloropyridin-2-yl)methanone;
(3,5-Dichloropyridin-2-yl)-(4-methylpiperazin-l-yl)methanone;
5-Bromo-pyridine-2-sulfonic acid (2,2,2-trifluoro-ethyl)-amide; l-(5-Bromo-pyridine-2-sulfonyl)-4-methyl-piperazine;
5-Bromo-pyridine-2-sulfonic acid dimethylamide; and 3 ,5-Dichloro~2-(piperidin- 1 -ylcarbonyl)pyridine.
77. Use of a compound according to claim 76, as an intermediate in the manufacture of a compound according to claim 1.
PCT/SE2007/000620 2006-06-27 2007-06-26 Imidazol-pyrimidine derivatives for treatment of diseases related to glycogen synthase kinase (gsk3) WO2008002244A2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
BRPI0713576-9A BRPI0713576A2 (en) 2006-06-27 2007-06-26 compound, pharmaceutical formulation, use of a compound, and methods for preventing and / or treating condition, disorder and disease, for enhancing bone formation, for enhancing spongy bone formation and / or new bone formation, for increasing density bone mineral, to reduce the incidence of fracture and to improve fracture healing, and process for preparing a compound
MX2008015720A MX2008015720A (en) 2006-06-27 2007-06-26 Imidazol-pyrimidine derivatives for treatment of diseases relates to glycogen synthase kinase 3 (gsk3).
AU2007265731A AU2007265731A1 (en) 2006-06-27 2007-06-26 Imidazol-pyrimidine derivatives for treatment of diseases related to glycogen synthase kinase (GSK3)
JP2009518044A JP2009542638A (en) 2006-06-27 2007-06-26 Imidazole-pyrimidine derivatives for the treatment of diseases associated with glycogen synthase kinase (GSK3)
EP07748281A EP2046782A4 (en) 2006-06-27 2007-06-26 Imidazolylpyrimidine derivatives for treatment of diseases related to glycogen synthase kinase (gsk3)
CA002655441A CA2655441A1 (en) 2006-06-27 2007-06-26 New compounds 384
IL195666A IL195666A0 (en) 2006-06-27 2008-12-02 Imidazol-pyrimidine derivatives for treatment of diseases related to glycogen synthase kinase (gsk3)
NO20090327A NO20090327L (en) 2006-06-27 2009-01-21 New connections 384

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US81675606P 2006-06-27 2006-06-27
US60/816,756 2006-06-27

Publications (3)

Publication Number Publication Date
WO2008002244A2 true WO2008002244A2 (en) 2008-01-03
WO2008002244A3 WO2008002244A3 (en) 2008-02-14
WO2008002244A8 WO2008002244A8 (en) 2008-10-09

Family

ID=38846127

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2007/000620 WO2008002244A2 (en) 2006-06-27 2007-06-26 Imidazol-pyrimidine derivatives for treatment of diseases related to glycogen synthase kinase (gsk3)

Country Status (20)

Country Link
US (1) US20080188502A1 (en)
EP (1) EP2046782A4 (en)
JP (1) JP2009542638A (en)
KR (1) KR20090024817A (en)
CN (1) CN101511825A (en)
AR (1) AR061652A1 (en)
AU (1) AU2007265731A1 (en)
BR (1) BRPI0713576A2 (en)
CA (1) CA2655441A1 (en)
CL (1) CL2007001881A1 (en)
CO (1) CO6140059A2 (en)
EC (1) ECSP088973A (en)
IL (1) IL195666A0 (en)
MX (1) MX2008015720A (en)
NO (1) NO20090327L (en)
RU (1) RU2008148902A (en)
TW (1) TW200815418A (en)
UY (1) UY30440A1 (en)
WO (1) WO2008002244A2 (en)
ZA (1) ZA200810484B (en)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
EP2046783A2 (en) * 2006-06-27 2009-04-15 AstraZeneca AB Imidazol-pyrimidine derivatives for treatment of diseases related to glycogen synthase kinase (gsk3)
WO2010103438A1 (en) 2009-03-11 2010-09-16 Pfizer Inc. Substituted indazole amides and their use as glucokinase activators
WO2010120237A1 (en) * 2009-04-15 2010-10-21 Astrazeneca Ab Imidazole substituted pyrimidines useful in the treatment of glycogen synthase kinase 3 related disorders such as alzheimer's disease
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2016008966A1 (en) 2014-07-17 2016-01-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for treating neuromuscular junction-related diseases
WO2016124557A1 (en) 2015-02-05 2016-08-11 Bayer Cropscience Aktiengesellschaft 2-(het)aryl-substituted condensed bicyclic heterocycle derivatives as pest control agents
WO2016207366A1 (en) 2015-06-26 2016-12-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of viral infections
US10799501B2 (en) 2015-11-05 2020-10-13 King's College Hospital Nhs Foundation Trust Combination of an inhibitor of PARP with an inhibitor of GSK-3 or DOT1L
EP3896066A2 (en) 2015-08-07 2021-10-20 Bayer CropScience Aktiengesellschaft 2-(het)aryl-substituted condensed heterocycle derivatives as pesticides

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2623374A1 (en) 2005-09-30 2007-04-05 Astrazeneca Ab Imidazo [1,2-a] pyridine having anti-cell-proliferation activity
AR058073A1 (en) * 2005-10-03 2008-01-23 Astrazeneca Ab IMIDAZOL 5-IL-PYRIMIDINE DERIVATIVES, OBTAINING PROCESSES, PHARMACEUTICAL COMPOSITIONS AND USES
TW200811169A (en) * 2006-05-26 2008-03-01 Astrazeneca Ab Chemical compounds
CN102731451B (en) * 2006-06-27 2015-07-29 武田药品工业株式会社 Fused ring compound
CN103724207B (en) * 2013-12-20 2016-07-06 北京智博高科生物技术有限公司 Phenylbenzyl ether derivative and its preparation method and application

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0021726D0 (en) * 2000-09-05 2000-10-18 Astrazeneca Ab Chemical compounds
JP4570955B2 (en) * 2002-07-09 2010-10-27 バーテクス ファーマスーティカルズ インコーポレイテッド Imidazoles with protein kinase inhibitory activity
EP1648887A1 (en) * 2003-07-30 2006-04-26 Cyclacel Limited Pyridinylamino-pyrimidine derivatives as protein kinase inhibitors
BRPI0415759A (en) * 2003-10-21 2006-12-19 Cyclacel Ltd pyrimidin-4-yl-3,4-thione compounds and their use in therapy
GB0402653D0 (en) * 2004-02-06 2004-03-10 Cyclacel Ltd Compounds
NZ555474A (en) * 2004-12-17 2010-10-29 Astrazeneca Ab 4-(4-(imidazol-4-yl) pyrimidin-2-ylamino) benzamides as CDK inhibitors
GB0504753D0 (en) * 2005-03-08 2005-04-13 Astrazeneca Ab Chemical compounds
AR058073A1 (en) * 2005-10-03 2008-01-23 Astrazeneca Ab IMIDAZOL 5-IL-PYRIMIDINE DERIVATIVES, OBTAINING PROCESSES, PHARMACEUTICAL COMPOSITIONS AND USES
TW200815417A (en) * 2006-06-27 2008-04-01 Astrazeneca Ab New compounds II

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of EP2046782A4 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2046783A2 (en) * 2006-06-27 2009-04-15 AstraZeneca AB Imidazol-pyrimidine derivatives for treatment of diseases related to glycogen synthase kinase (gsk3)
EP2046783A4 (en) * 2006-06-27 2010-08-04 Astrazeneca Ab Imidazol-pyrimidine derivatives for treatment of diseases related to glycogen synthase kinase (gsk3)
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2010103438A1 (en) 2009-03-11 2010-09-16 Pfizer Inc. Substituted indazole amides and their use as glucokinase activators
WO2010120237A1 (en) * 2009-04-15 2010-10-21 Astrazeneca Ab Imidazole substituted pyrimidines useful in the treatment of glycogen synthase kinase 3 related disorders such as alzheimer's disease
US8178529B2 (en) 2009-04-15 2012-05-15 Astrazeneca Ab Imidazole substituted pyrimidines
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2016008966A1 (en) 2014-07-17 2016-01-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for treating neuromuscular junction-related diseases
WO2016124557A1 (en) 2015-02-05 2016-08-11 Bayer Cropscience Aktiengesellschaft 2-(het)aryl-substituted condensed bicyclic heterocycle derivatives as pest control agents
WO2016207366A1 (en) 2015-06-26 2016-12-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of viral infections
EP3896066A2 (en) 2015-08-07 2021-10-20 Bayer CropScience Aktiengesellschaft 2-(het)aryl-substituted condensed heterocycle derivatives as pesticides
EP3896065A1 (en) 2015-08-07 2021-10-20 Bayer CropScience Aktiengesellschaft 2-(het)aryl-substituted condensed heterocycle derivatives as pesticides
US10799501B2 (en) 2015-11-05 2020-10-13 King's College Hospital Nhs Foundation Trust Combination of an inhibitor of PARP with an inhibitor of GSK-3 or DOT1L

Also Published As

Publication number Publication date
AU2007265731A1 (en) 2008-01-03
JP2009542638A (en) 2009-12-03
TW200815418A (en) 2008-04-01
WO2008002244A8 (en) 2008-10-09
WO2008002244A3 (en) 2008-02-14
CA2655441A1 (en) 2008-01-03
RU2008148902A (en) 2010-08-10
NO20090327L (en) 2009-02-09
ZA200810484B (en) 2009-08-26
UY30440A1 (en) 2008-01-31
KR20090024817A (en) 2009-03-09
CL2007001881A1 (en) 2008-02-08
MX2008015720A (en) 2008-12-19
CN101511825A (en) 2009-08-19
EP2046782A4 (en) 2010-10-13
EP2046782A2 (en) 2009-04-15
IL195666A0 (en) 2009-09-01
AR061652A1 (en) 2008-09-10
ECSP088973A (en) 2009-01-30
US20080188502A1 (en) 2008-08-07
BRPI0713576A2 (en) 2012-10-23
CO6140059A2 (en) 2010-03-19

Similar Documents

Publication Publication Date Title
WO2008002244A2 (en) Imidazol-pyrimidine derivatives for treatment of diseases related to glycogen synthase kinase (gsk3)
US20080188503A1 (en) New Compounds II
AU2006297890B2 (en) New pyrimidine derivatives and their use in therapy as well as the use of pyrimidine derivatives in the manufacture of a medicament for prevention and/or treatment of Alzheimer's disease
US20090018130A1 (en) Derivatives of 5-Aryl-1H-Pyrrolo [2, 3B] Pyridine-3-Carboxamide or 5-Aryl-1H-Pyrrolo [2, 3B] Pyridine-3-Carboxylic Acid
US20100234593A1 (en) Imidazo[4,5-B]Pyridine-7-Carboxamides 704
EP3684776A1 (en) Heterocyclyl substituted pyrrolopyridines that are inhibitors of the cdk12 kinase
US20080255106A1 (en) Novel 2-Phenyl-Imidazo[4,5-B]Pyridine Derivatives as Inhibitors of Glycogen Synthase Kinase for the Treatment of Dementia and Neurodegenerative Disorders
AU2004273771B2 (en) 3-heterocyclyl-indole derivatives as inhibitors of glycogen synthase kinase-3 (GSK-3)
US20110028489A1 (en) Pyrimidine Derivatives and Their Use for Treating Bone-Related Disorders
CN115583946A (en) Heterocyclic compounds and their use as CDK inhibitors

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200780032210.7

Country of ref document: CN

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

Ref document number: 07748281

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 195666

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 10118/DELNP/2008

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: MX/a/2008/015720

Country of ref document: MX

Ref document number: 12008502722

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 2655441

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 08134161

Country of ref document: CO

WWE Wipo information: entry into national phase

Ref document number: 2007265731

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2008122072

Country of ref document: EG

WWE Wipo information: entry into national phase

Ref document number: 2009518044

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2007265731

Country of ref document: AU

Date of ref document: 20070626

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 574372

Country of ref document: NZ

Ref document number: 1020097001642

Country of ref document: KR

Ref document number: 2007748281

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2008148902

Country of ref document: RU

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: a200813929

Country of ref document: UA

ENP Entry into the national phase

Ref document number: PI0713576

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20081226