WO2017046739A1 - Dérivés d'imidazolidinone comme inhibiteurs de perk - Google Patents

Dérivés d'imidazolidinone comme inhibiteurs de perk Download PDF

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WO2017046739A1
WO2017046739A1 PCT/IB2016/055506 IB2016055506W WO2017046739A1 WO 2017046739 A1 WO2017046739 A1 WO 2017046739A1 IB 2016055506 W IB2016055506 W IB 2016055506W WO 2017046739 A1 WO2017046739 A1 WO 2017046739A1
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methyl
pyrrolo
imidazolidin
amino
pyrimidin
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PCT/IB2016/055506
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Jeffrey Michael Axten
Nicolas Eric Faucher
Alain Claude-Marie Daugan
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Glaxosmithkline Intellectual Property (No.2) Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic 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
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to substituted imidazolidinone derivatives that are inhibitors of the activity of the protein kinase R (PKR)-like ER kinase, PERK.
  • PPKR protein kinase R
  • the present invention also relates to pharmaceutical compositions comprising such compounds and methods of using such compounds in the treatment of cancer, pre-cancerous syndromes and diseases/injuries associated with activated unfolded protein response pathways, such as Alzheimer's disease, neuropathic pain, spinal cord injury, traumatic brain injury,.
  • CTE chronic traumatic encephalopathy
  • the unfolded protein response is a signal transduction pathway that allows cells to survive stress caused by the presence of misfolded or unfolded proteins or protein aggregates (Walter and Ron, 2011), (Hetz, 2012).
  • UPR activating stress stimuli include hypoxia, disruption of protein glycosylation (glucose deprivation), depletion of luminal ER calcium, or changes in ER redox status, among others (Ma and Hendershot, 2004), (Feldman et al., 2005).
  • PPR protein kinase R
  • PERK protein kinase R
  • EIF2AK3 eukaryotic initiation factor 2A kinase 3
  • PKI pancreatic ER kinase
  • ATF6 activating transcription factor 6
  • PERK is a type I ER membrane protein containing a stress-sensing domain facing the ER lumen, a transmembrane segment, and a cytosolic kinase domain (Shi et al., 1998), (Harding et al., 1999), (Sood et al., 2000). Release of GRP78 from the stress- sensing domain of PERK results in oligomerization and autophosphorylation at multiple serine, threonine and tyrosine residues (Ma et al., 2001), (Su et al., 2008).
  • Phenotypes of PERK knockout mice include diabetes, due to loss of pancreatic islet cells, skeletal abnormalities, and growth retardation (Harding et al., 2001), (Zhang et al., 2006), (lida et al., 2007). These features are similar to those seen in patients with Wolcott-Rallison syndrome, who carry germline mutations in the PERK gene (Julier and Nicolino, 2010).
  • the major substrate for PERK is the eukaryotic initiation factor 2a (elF2a), which PERK phosphorylates at serine-51 (Marciniak et al., 2006) in response to ER stress or treatment with pharmacological inducers of ER stress such as thapsigargin and tunicamycin.
  • This site is also phosphorylated by other EIF2AK family members [(general control non- derepressed 2 (GCN2), PKR, and heme-regulated kinase (HRI)] in response to different stimuli.
  • GCN2 general control non- derepressed 2
  • PKR heme-regulated kinase
  • Phosphorylation of elF2a converts it to an inhibitor of the guanine nucleotide exchange factor (GEF) elF2B which is required for efficient turnover of GDP for GTP in the elF2 protein synthesis complex.
  • GEF guanine nucleotide exchange factor
  • the inhibition of elF2B by P-elF2a causes a general decrease in translation initiation and thus a reduction in global protein synthesis (Harding et al. 2002).
  • Paradoxically, translation of specific mRNAs is enhanced when the UPR is activated and elF2a is phosphorylated.
  • the transcription factor ATF4 has 5'-upstream open reading frames (uORFs) that normally represses ATF4 synthesis during normal global protein synthesis.
  • PERK when PERK is activated under stress and P-elF2a inhibits elF2B, the lower levels of ternary translation complex allows for selective enhanced translation of ATF4 (Jackson et al. 2010). Therefore, when ER stress ensues, PERK activation causes an increase in ATF4 translation, which transcriptionally upregulates downstream target genes such as CHOP (transcription factor C/EBP homologous protein). This transcriptional reprogramming modulates cell survival pathways and can lead to the induction of pro-apoptotic genes.
  • CHOP transcription factor C/EBP homologous protein
  • PERK and the UPR is associated with human neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), dementias, and prion diseases including Creutzfeldt-Jakob Disease (CJD), (Doyle et al. 201 1), (Paschen 2004), (Salminen et al. 2009), (Stutzbach et al. 2013).
  • CJD Creutzfeldt-Jakob Disease
  • a cell enduring ER stress may restore proteostasis and return to normal, or if the stress is insurmountable, sustained PERK activation may lead to cell death through ATF4/CHOP driven autophagy coupled with the inability to synthesize vital proteins because of the persistent translational repression.
  • Activated PERK and associated biological markers of PERK activation are detected in post-mortem brain tissue of Alzheimer's disease patients and in human prion disease (Ho et al. 2012), (Hoozemans et al, 2009) (Schberger et al. 2006).
  • P-elF2a the product of PERK activation correlates with levels of BACE1 in post-mortem brain tissue of Alzheimer's disease patients (O'Connor et al.
  • Tumor cells experience episodes of hypoxia and nutrient deprivation during their growth due to inadequate blood supply and aberrant blood vessel function (Brown and Wilson, 2004), (Blais and Bell, 2006). Thus, they are likely to be dependent on active UPR signaling to facilitate their growth.
  • mouse fibroblasts derived from PERK-/-, XBP1-/-, and ATF4-/- mice, and fibroblasts expressing mutant elF2a show reduced clonogenic growth and increased apoptosis under hypoxic conditions in vitro and grow at substantially reduced rates when implanted as tumors in nude mice (Koumenis et al., 2002), (Romero-Ramirez et al., 2004), (Bi et al., 2005).
  • Human tumor cell lines carrying a dominant negative PERK that lacks kinase activity also showed increased apoptosis in vitro under hypoxia and impaired tumor growth in vivo (Bi et al., 2005).
  • Human tumors including those derived from cervical carcinomas, glioblastomas (Bi et al., 2005), lung cancers (Jorgensen et al., 2008) and breast cancers (Ameri et al., 2004), (Davies et al., 2008) show elevated levels of proteins involved in UPR, compared to normal tissues. Therefore, inhibiting the unfolded protein response with compounds that block the activity of PERK and other components of the UPR is expected to have utility as anticancer agents. Recently, this hypothesis was supported by two small molecule inhibitors of PERK that were shown to inhibit the growth of human tumor xenografts in mice (Axten et al. 2012 and Atkins et al. 2013).
  • Inhibitors of PERK may be therapeutically useful for the treatment of a variety of human diseases such as Alzheimer's disease and frontotemporal dementias, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and other tauopathies such chronic traumatic encephalopathy (CTE) (Nijholt, D. A., et al. 2012), (Lucke-Wold, B. P., et al.
  • CTE chronic traumatic encephalopathy
  • Inhibitors of PERK may also be useful for effective treatment of cancers, particularly those derived from secretory cell types, such as pancreatic and neuroendocrine cancers, multiple myeloma, or for use in combination as a chemosensitizer to enhance tumor cell killing.
  • a PERK inhibitor may also be useful for myocardial infarction, cardiovascular disease, atherosclerosis (McAlpine et al., 2010, Civeiek et al.
  • a PERK inhibitor may also be useful in stem cell or organ transplantation to prevent damage to the organ and in the transportation of organs for transplantation (Inagi et al., 2014), (Cunard, 2015), (Dickhout et al., 2011), (van Galen, P., et al. (2014).
  • a PERK inhibitor is expected to have diverse utility in the treatment of numerous diseases in which the underlying pathology and symptoms are associated with dysregulaton of the unfolded protein response. References
  • PERK and GCN2 contribute to elF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway, Mol Biol Cell 16, 5493-501.
  • Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells, BMC Cancer 8, 229. Julier, C; Nicolino, M. (2010) Wolcott-Rallison syndrome Orphanet J. Rare Diseases 5 (29) 1-13. ht ⁇ p://www. oi rd .com/content/5/1 ;29 Liu, M. and S. C. Dudley, Jr.
  • XBP1 is essential for survival under hypoxic conditions and is required for tumor growth, Cancer Res 64, 5943- 7.
  • PPK pancreatic eukaryotic initiation factor-2alpha kinase
  • compositions that comprise a pharmaceutical carrier and compounds of Formula (I).
  • the invention is directed to substituted imidazolidinone derivatives and uses thereof. Specifically, the invention is directed to compounds according to Formula (I) and the use of compounds of Formula (I) in treating disease states.
  • the present invention also relates to the discovery that the compounds of Formula
  • This invention also relates to a method of treating cancer, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).
  • This invention also relates to a method of treating Alzheimer's disease which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).
  • This invention also relates to a method of treating Parkinson's disease, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).
  • This invention also relates to a method of treating amyotrophic lateral sclerosis, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).
  • This invention also relates to a method of treating Huntington's disease, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).
  • This invention also relates to a method of treating Creutzfeldt-Jakob Disease, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).
  • This invention also relates to a method of treating progressive supranuclear palsy
  • PSP which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).
  • This invention also relates to a method of treating dementia, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).
  • This invention also relates to a method of treating spinal cord injury, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).
  • This invention also relates to a method of treating traumatic brain injury, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).
  • This invention also relates to a method of treating ischemic stroke, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).
  • This invention also relates to a method of treating diabetes, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).
  • This invention also relates to a method of treating a disease state selected from:, myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).
  • This invention also relates to a method of using the compounds of Formula (I) in organ transplantation and in the transportation of organs for transplantation.
  • novel processes and novel intermediates useful in preparing the presently invented PERK inhibiting compounds are provided. Included in the present invention are pharmaceutical compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention.
  • Also included in the present invention are methods of co-administering the presently invented PERK inhibiting compounds with further active ingredients.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Alzheimer's disease.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Parkinson's disease.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of amyotrophic lateral sclerosis.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Huntington's disease.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Creutzfeldt-Jakob Disease.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of progressive supranuclear palsy (PSP).
  • PSP progressive supranuclear palsy
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of dementia.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of spinal cord injury.
  • the invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of traumatic brain injury.
  • the invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of diabetes.
  • the invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disease state selected from:, myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias.
  • a disease state selected from:, myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias.
  • the invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of chronic traumatic encephalopathy (CTE).
  • CTE chronic traumatic encephalopathy
  • the invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in organ transplantation and in the transportation of organs for transplantation.
  • a pharmaceutical carrier included in the present invention are pharmaceutical compositions that comprise a pharmaceutical carrier and a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also relates to a pharmaceutical composition as defined above for use in therapy.
  • This invention relates to novel compounds of Formula (I) and to the use of compoundsula (I) in the methods of the invention:
  • -6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C-
  • R is selected from:
  • heteroaryl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-
  • R is selected from:
  • Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-
  • R and R are each independently selected from hydrogen and C-
  • R4 and R5 taken together with the carbon atoms to which they are attached form a 3 or 4 member cycloalkyi, optionally substituted from 1 to 3 times by Ci_4alkyl;
  • R is selected from: hydrogen, Ci _4alkyl, -CF3, -C(H)F2, -CH2F, fluoro, chloro,
  • R 7 is selected from: hydrogen, Ci _4alkyl, -CF3, -C(H)F2, -CH2F, fluoro, chloro,
  • X is CR 1 00 or N
  • R 1 00 is selected from: hydrogen, -CH3, fluoro, chloro, bromo and iodo;
  • Y and Y are independently selected from: hydrogn, -CF3 and C-
  • Z is 0 or 1 ; and salts thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (I).
  • X is CR 100 , where R 1 00 is selected from: hydrogen, -CH3, fluoro, chloro, bromo and iodo.
  • X is N.
  • R is a substituted thieno[2,3-d]pyrimidine.
  • R is a substituted quinoline.
  • R is a substituted pyridine.
  • R is a substituted indazole.
  • R is a substituted quinazoline.
  • R is a substituted benzothiazole.
  • R is a substituted thienopyridine.
  • R is C-
  • R is selected from: pyrrolo[2,3d]pyrimidin-5 yl and pyrazolo[3,4d] pyrimidin-5-yl.
  • R is selected from: 5-yl pyrrolo[2,3d]pyrimidin-4-amine and 5-yl-pyrazolo[3,4d] pyrimidin-5-yl-4-amine.
  • R 1 0 is selected from:
  • R is selected from:
  • Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF 3 , -Ci-4alkylOC-
  • R and R are each independently selected from hydrogen and C-
  • R12 and R ⁇ 3 taken together with the carbon atoms to which they are attached form a 3 or 4 member cycloalkyi, optionally substituted from 1 to 3 times by C-
  • R is selected from: hydrogen, C-
  • R is selected from hydrogen and Ci_6alkyl
  • R 16 is selected from:
  • -6alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, C-
  • R is selected from: hydrogen and -CH3;
  • R is selected from: hydrogen, C-
  • 10 1 1 10 Y and Y are independently selected from: hydrogn, -CF3 and C-
  • X is CR 1 01 or N
  • R is selected from: hydrogen, fluoro and chloro; and salts thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of
  • X is CR , where R is selected from: hydrogen, fluoro and chloro.
  • X is N.
  • R 20 is selected from:
  • R is selected from:
  • -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-
  • R and R are each independently selected from hydrogen and C-
  • R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
  • R is selected from hydrogen and Ci-6alkyl
  • R is selected from:
  • -6alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, C-
  • R is selected from: hydrogen and -CH3;
  • R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
  • 21 22 21 Y and Y are independently selected from: hydrogn, -CF3 and Ci-4alkyl, or Y
  • X is CR 1 02 or N
  • R is selected from: hydrogen, fluoro and chloro; and salts thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (III).
  • X is CR , where R is selected from: hydrogen, fluoro and chloro.
  • R is selected from: hydrogen, fluoro and chloro.
  • X is N.
  • R 30 is selected from:
  • R is selected from:
  • -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-
  • R and R are each independently selected from hydrogen and C-
  • R32 and R ⁇ 3 taken together with the carbon atoms to which they are attached form a 3 or 4 member cycloalkyi, optionally substituted from 1 to 3 times by C-
  • R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
  • R is selected from:
  • -6alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, C-
  • R is selected from: hydrogen and -CH3;
  • R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
  • Y and Y are independently selected from: hydrogn, -CF3 and C-
  • X is CR 1 03 or N
  • R is selected from: hydrogen, fluoro and chloro; and salts thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (IV).
  • X is CR , where R is selected from: hydrogen, fluoro and chloro.
  • R is selected from: hydrogen, fluoro and chloro.
  • X is N.
  • salts, including pharmaceutically acceptable salts, of the compounds according to Formula (I) may be prepared. Indeed, in certain embodiments of the invention, salts including pharmaceutically-acceptable salts of the compounds according to Formula (I) may be preferred over the respective free or unsalted compound. Accordingly, the invention is further directed to salts, including pharmaceutically- acceptable salts, of the compounds according to Formula (I).
  • the salts, including pharmaceutically acceptable salts, of the compounds of the invention are readily prepared by those of skill in the art.
  • the compounds according to Formula (I) may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may be present in a substituent such as an alkyl group.
  • the stereochemistry of a chiral center present in a compound of Formula (I), or in any chemical structure illustrated herein if not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof.
  • compounds according to Formula (I) containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • the compounds according to Formula (I) may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula (I), or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula (I) whether such tautomers exist in equilibrium or predominately in one form.
  • the compounds of Formula (I) or salts, including pharmaceutically acceptable salts, thereof may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing vaiable amounts of water.
  • polymorphs may have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • Alkyl refers to a hydrocarbon chain having the specified number of "member atoms".
  • C-1-C5 alkyl refers to an alkyl group having from 1 to 6 member atoms.
  • Alkyl groups may be saturated, unsaturated, straight or branched. Representative branched alkyl groups have one, two, or three branches.
  • Alkyl includes methyl, ethyl, ethylene, propyl (n-propyl and isopropyl), butene, butyl (n-butyl, isobutyl, and t-butyl), pentyl and hexyl.
  • Alkoxy refers to an -O-alkyl group wherein “alkyl” is as defined herein. For example, C-
  • C4alkoxy refers to an alkoxy group having from 1 to 4 member atoms.
  • Representative branched alkoxy groups have one, two, or three branches. Examples of such groups include methoxy, ethoxy, propoxy, and butoxy.
  • Aryl refers to an aromatic hydrocarbon ring.
  • Aryl groups are monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring member atoms, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 member atoms, such as phenyl, naphthalene, tetrahydronaphthalene and biphenyl.
  • aryl is phenyl.
  • Bicycloheteroaryl refers to two fused aromatic rings containing from 1 to 6 heteroatoms as member atoms. Bicycloheteroaryl groups containing more than one heteroatom may contain different heteroatoms. Bicycloheteroaryl rings have from 6 to 1 1 member atoms.
  • Bicycloheteroaryl includes: 1 /-/-pyrrolo[3,2-c]pyridine, 1/-/-pyrazolo[4,3-c]pyridine, 1 H- pyrazolo[3,4-d]pyrimidine, 1 H-pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, thieno[3,2- c]pyridine, thieno[2,3-d]pyrimidine, furo[2,3-c]pyridine, furo[2,3-d]pyrimidine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, ben
  • Bicycloheteroaryl includes: 1 H-pyrazolo[3,4-d]pyrimidine, 1 H-pyrrolo[2,3- d] pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, thieno[3,2-c]pyridine, thieno[2,3-d]pyrimidine, furo[2,3-c]pyridine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imid
  • H-pyrazolo[3,4-d]pyrimidine 1 H-pyrrolo[2,3-d]pyrimidine, thieno[3,2-c]pyridine, thieno[2,3-d]pyrimidine, indazolyl, quinolinyl, quinazolinyl or benzothiazolyl.
  • 1 H- pyrrolo[2,3-d]pyrimidine 1 H-pyrrolo[2,3-d]pyrimidine.
  • Cycloalkyl refers to a saturated or unsaturated non aromatic hydrocarbon ring having from three to seven carbon atoms. Cycloalkyl groups are monocyclic ring systems. For example, C3-C7 cycloalkyl refers to a cycloalkyl group having from 3 to 7 member atoms. Examples of cycloalkyl as used herein include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptyl.
  • Heteroaryl refers to a monocyclic aromatic 4 to 8 member ring containing from 1 to 7 carbon atoms and containing from 1 to 4 heteroatoms, provided that when the number of carbon atoms is 3, the aromatic ring contains at least two heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms.
  • Heteroaryl includes: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl.
  • heteroaryl includes: pyrazole, pyrrole, isoxazole, pyridine, pyrimidine, pyridazine, and imidazole.
  • Heterocycloalkyl refers to a saturated or unsaturated non-aromatic ring containing 4 to 12 member atoms, of which 1 to 1 1 are carbon atoms and from 1 to 6 are heteroatoms. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups are monocyclic ring systems or a monocyclic ring fused with an aryl ring or to a heteroaryl ring having from 3 to 6 member atoms.
  • Heterocycloalkyl includes: pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, oxetanyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4- dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, 1 ,3oxazolidin-2-one, hexahydro-1 H- azepin, 4,5,6,7,tetrahydro-1 H-benzimidazol
  • Heteroatom refers to a nitrogen, sulphur or oxygen atom.
  • AIBN azobis(isobutyronitrile)
  • BINAP (2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl
  • BOP Benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate
  • CSF cesium fluoride
  • ATP adenosine triphosphate
  • BSA bovine serum albumin
  • C18 refers to 18-carbon alkyl groups on silicon in HPLC stationary phase
  • DIPEA Human's base, A/-ethyl-A/-(1-methylethyl)-2-propanamine); Dioxane (1 ,4-dioxane);
  • DMEDA ( ⁇ /, ⁇ /'-dimethylethylenediamine
  • DPPA diphenyl phosphoryl azide
  • EDC A/-(3-dimethylaminopropyl)-/ ⁇ /'ethylcarbodiimide
  • EDTA ethylenediaminetetraacetic acid
  • HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid);
  • HATU (0-(7-Azabenzotriazol-1-yl)-/ ⁇ /,/ ⁇ /,/ ⁇ /',A/'-tetramethyluronium hexafluorophosphate); HOAt (1-hydroxy-7-azabenzotriazole);
  • HMDS hexamethyldisilazide
  • Hunig's Base (A/,A/-Diisopropylethylamine);
  • KHMDS potassium hexamethyldisilazide
  • LAH lithium aluminum hydride
  • mCPBA m-chloroperbezoic acid
  • NaHMDS sodium hexamethyldisilazide
  • NBS (/V-bromosuccinimide
  • PE petroleum ether
  • TFA trifluoroacetic acid
  • the compounds according to Formula I are prepared using conventional organic synthetic methods. A suitable synthetic route is depicted below in the following general reaction schemes. All of the starting materials are commercially available or are readily prepared from commercially available starting materials by those of skill in the art.
  • a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006).
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • Substituted urea derivative B was prepared by reacting corresponding aniline A with chloroethylisocyanate using organic solvent preferably chloroform, the urea derivative B was reacted with base such as cesium carbonate to obtain A/-aryl cyclic urea intermediate C.
  • Disubstituted cyclic urea derivative D can be obtained by alkylation of intermediate C using substituted benzyl bromides or cycloalkyi bromides or alkyl halides in presence of base such as cesium carbonate or reacting with corresponding alcohol using Mitsunobu condition.
  • compounds F were prepared by boronate ester formation of bicycloheteroaryl E1 followed by Suzuki-Miyaura coupling with bromo aryl imidazolidinone D as described in general Scheme 2.
  • Scheme 2
  • r3 aryl or heteroaryl
  • Phenyl carbamate Z9 was prepared by reacting substituted aniline Z7 with phenyl carbonochloridate Z8 using base such as pyridine.
  • the intermediate Z8 was treated with methyl 2-amino-3-hydroxypropanoate Z10 in presence of base such as DMAP to give hydroxymethyl-imidazolidine-dione Z11.
  • Reduction was performed using sodiumborohydride and borontrifluoride ethyrate to give 4-hydroxymethyl imidazolidinone derivative Z12. Protection of hydroxyl group with TBDMS followed by alkylation using C1 gave trisubstituted imidazolidinone intermediate Z14.
  • Boronate ester formation followed by Suzuki-Miyaura reaction with heteroaryl bromide X gave intermediate Z16.
  • OTBDMS deprotection was performed to give compounds of the present invention Z17.
  • bicycloheteroaryl halide E1 used in the present invention are prepared by using methods and procedures described in Schemes 7 to 12 or procured from commercial sources.
  • Step 2 To a stirred solution of 6-bromoquinazolin-2-amine (0.75 g, 3.33 mmol, 1.0 equiv) in DCM/DMF (34 mL/2 mL) was added tert-butyl nitrite (0.6 mL, 4.99 mmol, 1.5 equiv), tetrabutylammonium chloride (0.37 g, 1.33 mmol, 0.4 equiv) and trimethylsillyl chloride (0.64 mL, 4.99 mmol, 1.5 equiv) at 0°C and stirred at room temperature for 15 min. The reaction mixture was heated to 50°C & stirred for 1 h.
  • reaction mixture was diluted with DCM (30 mL) and water (300 mL). Two layers were separated and aqueous layer extracted with DCM (40 mL). The organics were combined and dried over Na 2 S0 4 , filtered, and concentrated to give 6-bromo-2-chloroquinazoline (0.8 g, Crude). Crude product was used directly for next stage without purification.
  • LCMS (ES) m/z 243.0 [M+H] + .
  • Step 3 To a stirred solution of 6-bromo-2-chloroquinazoline (0.8 g, 3.3 mmol, 1.0 equiv) in THF (10 mL) was added methyl amine (2M in THF) (6.5 mL, 13.2 mmol, 4.0 equiv) in steel bomb and heated to 80°C for overnight. The reaction mixture was cooled to room temperature and concentrated to get crude compound. Crude product was purified by flash chromatography using Silica gel and compound was eluted with 30% EtOAc in Hexane. Fractions containing compound were concentrated to obtain 6-bromo-Ay-methylquinazolin-2-amine (0.21 g, 27%) as off white solid.
  • Step 1 To a stirred solution of 2,4-dichloro-7/-/-pyrrolo[2,3-c]pyrimidine (2 g, 10.638 mmol) in DMF (20 mL) was added 60 % NaH (0.63 g, 15.957 mmol, 1.5 equiv) at 0 °C and stirred for 30 min at room temperature. Methyl iodide (0.79 mL, 12.765 mol, 1.2 equiv) was added and allowed to stir at room temperature for 3 h.
  • H NMR 400 MHz, DMSO-d6) ⁇ ppm 3.84 (s, 3H), 7.24 (s, 1 H).
  • Step 3 A suspension of 5-bromo-2,4-dichloro-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidine (2.2 g, 7.831 mmol) in NH 4 OH (20 mL) and 1 ,4-dioxane (5 mL) was heated in a stainless steel autoclave at 95 °C for 18 h. The reaction mixture was cooled to room temperature and the suspension was filtered. The cake was washed with water (3 x 20 mL), and dried under vacuo to give 5-bromo-2-chloro-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine as an off white solid (2 g, 98 %).
  • Step 4 Run 1 ; To a stirred solution of 5-bromo-2-chloro-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4- amine (0.1 g, 0.383 mmol) in methanol (10 mL) was added 0.5 M sodium methoxide in methanol (3.8 mL, 1.915 mmol, 5 equiv) at room temperature. The reaction was stirred at 100 °C for overnight in a sealed tube. The reaction mixture was cooled to room temperature & concentrated. Water was added to the residue and extracted with dichloromethane (30 mL).
  • Run-2 To a stirred solution of 5-bromo-2-chloro-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.5 g, 1.915 mmol) in methanol (10 mL) was added 0.5 M sodium methoxide in methanol (19 mL, 9.578 mmol) at room temperature. The reaction was stirred at 100 °C for overnight in sealed tube. The reaction mixture was cooled to room temperature & concentrated. Water was added to the residue and extracted with dichloromethane (50 mL). The organic layer was dried over Na 2 S0 4 , filtered and evaporated to dryness.
  • Step 2 To a stirred solution of thieno[2,3-d]pyrimidin-4(1/-/)-one (3 g, 19.736 mmol) in acetic acid (30 mL) was added bromine (3 mL) at room temperature, and the reaction mixture was stirred for 2h. The reaction mixture was concentrated under reduced pressure. The residue was washed with water (2 x 10 mL) and dried to give 6-bromothieno[2,3-c]pyrimidin-4(1/-/)-one as light brown color solid (4.5 g, 98 %).
  • LCMS (ES) m/z 231.0, 233.0 [M+H] + .
  • H NMR 400 MHz, DMSO-d6) ⁇ ppm 7.53 (s, 1 H), 8.12 (s, 1 H), 12.61 (br. s., 1 H).
  • Step 4 To a stirred solution of 6-bromo-4-chlorothieno[2,3-c]pyrimidine (3 g, 12.048 mmol) in THF (120 mL) was added 2M LDA solution in THF/heptane/ethylbenzene (9 mL, 18.072 mmol) at -78 °C under nitrogen. The reaction mixture was stirred for 1 h at -78 °C, a mixture of 3.75 mL water and 15 mL THF was added slowly. The mixture was warmed to 0 °C, poured onto water (180 mL). The reaction mixture was extracted with dichloromethane (2 x 50 mL).
  • Step 5 A suspension of 5-bromo-4-chlorothieno[2,3-c]pyrimidine (1.7 g, 6.827 mmol) in NH 4 OH (60 mL) was heated in a stainless steel autoclave at 100 °C for 18 h. The reaction mixture was cooled to room temperature and filtered. The solid cake was washed with water (3 x 20 mL), and dried under vacuo to give 5-bromothieno[2,3-c]pyrimidin-4-amine as light yellow solid (1.3 g, 82 %).
  • LCMS (ES) m/z 230.0, 232.0 [M+H] + .
  • H NMR 400 MHz, DMSO- d6) ⁇ ppm 7.16 - 7.56 (br. s., 2H), 7.76 (s, 1 H), 8.31 (s, 1 H).
  • Step 1 To a stirred solution of 4-chloro-7/-/-pyrrolo[2,3-c]pyrimidine (6.0 g, 39.1 mmol, 1.0 equiv) in DMF (70 mL) was added NBS (6.95 g, 39.1 mmol, 1.0 equiv) slowly at room temperature. The reaction mixture was stirred for 2 h at room temperature. After consumption of the starting material, the reaction mixture was quenched with water, and the solid that formed was filtered and dried to give the 5-bromo-4-chloro-7/-/-pyrrolo[2,3-c]pyrimidine as off white solid (11.0 g, crude).
  • Step 2 To a stirred solution of 5-bromo-4-chloro-7/-/-pyrrolo[2,3-c]pyrimidine (3.2 g, 13.8 mmol, 1.0 equiv) in DMF (45 ml_) was added K 2 C0 3 (3.82 g, 27.6 mmol, 2.0 equiv) & 1 , 1- difluoro-2-iodoethane (1.33 ml_, 15.14 mmol, 1.1 equiv) slowly at room temperature. The reaction mixture was hated to 60 °C and stirred for 24 h. After consumption of the starting material, the reaction mixture was evaporated, water was added and then extracted with EtOAc.
  • Step 3 A solution of 5-bromo-4-chloro-7-(2,2-difluoroethyl)-7/-/-pyrrolo[2,3-c]pyrimidine (0.5 g, 1.7 mmol, 1.0 equiv) in aq. NH 4 OH (9.0 ml_) and 1 ,4-dioxane (3.0 ml_) in a sealed stainless steel autoclave at 100 °C was stirred for 16 h. After completion of the starting material, the reaction mixture was cooled to room temperature and the solid was filtered.
  • Step 1 To a stirred solution of methyl 3-bromobenzoate (3.0 g, 13.950 mmol, 1.0 equiv) in toluene (24 mL) and water (6 mL) (4: 1) was added cyclopropyl boronic acid (1.79 g, 20.900 mmol, 1.5 equiv), potassium phosphate (5.92 g, 27.900 mmol, 2.0 equiv) and tricyclohexylphosphine (0.39 g, 1.390 mmol, 0.1 equiv) at one portion and degassed with Ar gas for 5 min.
  • cyclopropyl boronic acid (1.79 g, 20.900 mmol, 1.5 equiv
  • potassium phosphate 5.92 g, 27.900 mmol, 2.0 equiv
  • tricyclohexylphosphine (0.39 g, 1.390 mmol, 0.1 equiv
  • Step 2 To a stirred solution of 3-cyclopropylbenzoate (2.0 g, 12.567 mmol, 1.0 equiv) in ethanol (20 mL) was added 2.0 M Lithium borohydride in THF (11.3 mL, 22.700 mmol, 2.0 equiv) at 0 °C and stirred the reaction mixture for 1 h at room temperature. After completion of the reaction, the reaction mixture was quenched with ice cold water (30 mL) and extracted with DCM (2 x 30 mL).
  • Step 3 To a stirred solution of (3-cyclopropylphenyl)methanol (1.0 g, 6.756 mmol, 1.0 equiv) in diethyl ether (20 mL) was added phosphorous tribromide (0.95 mL, 10.135 mmol, 1.5 equiv). The reaction mixture was stirred for 1 h at room temperature. After completion of the reaction, the reaction mixture was quenched with ice cold water (20 mL) and extracted with diethyl ether (2 x 20 mL).
  • Step 1 To a stirred solution of 2-bromo-3-fluoro-6-methylpyridine (5.0 g, 15.788 mmol, 1.0 equiv) in DMF (12 mL) was added copper cyanide (2.3 g, 15.788 mmol, 1.0 equiv) in one portion at room temperature and the reaction mixture was stirred for overnight at 110 °C. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water (80 mL) and extracted with ethyl acetate (2 ⁇ 150 mL). The organics were combined and dried over Na 2 S0 4 , filtered, and evaporated the solvent under reduced pressure to afford the crude product.
  • Step 3 To a stirred solution of 3-fluoro-6-methylpicolinic acid (2.0 g, 12.89 mmol, 1.0 equiv) in THF (20 mL) was added borane dimethylsulfide (6.11 mL, 64.462 mmol, 5.0 equiv) at 0 °C and stirred the reaction mixture for 2 h at room temperature. After completion of the reaction, the reaction mixture was quenched with methanol (20 mL) and evaporated the solvent under reduced pressure. The residue was extracted with ethyl acetate (2 ⁇ 50 mL). The organics were combined and dried over Na 2 S0 4 , filtered, and evaporated the solvent under reduced pressure to afford the crude product.
  • borane dimethylsulfide 6.11 mL, 64.462 mmol, 5.0 equiv
  • Step 4 To a stirred solution of (3-fluoro-6-methylpyridin-2-yl)methanol (0.3 g, 2.125 mmol, 1.0 equiv) in diethyl ether (15 mL) was added phosphorous tribromide (0.3 mL, 3.188 mmol, 1.5 equiv) at room temperature and stirred the reaction mixture for 1.5 h. After completion of the reaction, the reaction mixture was quenched with ice cold water (20 mL) and extracted with diethyl ether (2 x 10 mL).
  • Step 1 A stirred solution of 3-(difluoromethoxy)benzaldehyde (1.0 g, 5.81 mmol, 1 equiv), in MeOH (25 mL) was cooled to 0 °C, NaBH 4 (0.440 g, 11.62 mmol, 2.0 equiv) was slowly added in portion wise. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. After completion of starting material, the reaction mixture was evaporated and added water, extracted with DCM. The organic layer was washed with brine and dried over sodium sulfate and concentrated to give (3-(difluoromethoxy)phenyl)methanol as colorless liquid (1.0 g, crude).
  • Step 2 Run-1 ; To a stirred solution of (3-(difluoro methoxy)phenyl)methanol (0.5 g, 2.87 mmol, 1 equiv), in DCM (30 mL) was slowly added PPh 3 (1.131 g, 4.31 mmol, 1.5 equiv) and the reaction mixture was cooled to 0 °C, CBr 4 (1.43 g, 4.31 mmol, 1.5 equiv) was added. The reaction mixture was slowly warmed to room temperature and stirred for 3 h at room temperature. The reaction mixture was evaporated to give crude product. The crude product was purified by flash column chromatography using silica gel column, compound was eluted at 3 % EtOAc in Hexane.
  • Step 1 To a Suspension of 60% NaH (1 g, 26.200 mmol, 3 equiv) in 35 mL of toluene under argon, was slowly added diethyl malonate (4.19 g, 26.200 mmol, 3 equiv) in 5 mL of toluene. The reaction mixture was heated to reflux. After complete dissolution of the resulting malonate salt, dimethyl 4-chloropyridine-2, 6-dicarboxylate (2 g, 8.733 mmol, 1 equiv) was added. The reaction mixture was refluxed for 3 h. The hot supernatant solution was removed by decantation and 40 mL of 4N HCI was added to the residue.
  • Run-2 To a solution of (4-methylpyridine-2,6-diyl)dimethanol hydrochloride (1.5 g, 7.936 mmol) in 48% HBr in water (10 mL) was refluxed at 100°C for 1 h. The resulting mixture was cooled and basified with saturated sodium bicarbonate, and extracted with dichloromethane (2 x 100 mL). Organic layers were combined and dried over Na 2 S0 4 , filtered, and concentrated in vacuo to afford crude product. The crude product (run-1 and Run-2) was purified by flash column chromatography with silica gel cartridge using gradient elution of 0% to 5% MeOH in DCM.
  • Step 1 To a stirred solution of 3,5-dibromobenzoic acid (2 g, 7.168 mmol) in tetrahydrofuran (20 mL) was added borane dimethylsulfide (3.4 mL, 35.842 mmol, 5 eq.) at 0 °C, and the reaction mixture was stirred at room temperature for overnight. The reaction mixture was quenched with methanol at 0 °C and concentrated under vacuo to obtain (3,5- dibromophenyl)methanol as an off white solid (1.8 g, 94%).
  • Step 2 To a mixture of (3,5-dibromophenyl)methanol (1 g, 3.759 mmol, 1 equiv) and PdCI 2 (dppf).CH 2 Cl 2 complex (0.21 g, 0.263 mmol, 0.07 equiv) in 10 mL of dry THF at -70 °C was added 1 M diethyl zinc in hexane (15 mL). The resulting mixture was allowed to warm to room temperature, and stirred at 45 °C for overnight. To drive the reaction to completion, additional 11.3 mL of 1 M diethyl zinc in hexane was added with continued stirring at 45 °C for overnight.
  • reaction mixture was stirred for 5 min, tetrabromomethane (0.6 g, 1.829 mmol, 1.5 eqvi) was added, and the reaction mixture was stirred at room temperature under nitrogen atmosphere for overnight.
  • the reaction mixture was concentrated in vacuo to afford crude product.
  • the crude was purified by flash column chromatography with silica gel cartridge using gradient elution of 0 to 5% EtOAc in Hexane. The collected fractions with pure product were combined and concentrated in vacuo to afford 1-(bromomethyl)-3,5-diethylbenzene as colorless liquid (0.3 g, crude).
  • Step 1 Run 1 ; A mixture of methyl 5-bromo-2-fluorobenzoate (0.5 g, 2.145 mmol, 1 equiv), cyclopropylboronic acid (0.18 g, 2.145 mmol, 1 equiv) and cesium carbonate (1.74 g, 5.364 mmol, 2.5 equiv) in 10 mL of 1 ,4-dioxane and 2 mL of water was degassed with nitrogen for 10 min, PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.175 g, 0.214 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 100 °C for overnight in sealed vessel.
  • dppf PdCl 2 (dppf)-CH 2 Cl 2 adduct
  • Run 2 A mixture of methyl 5-bromo-2-fluorobenzoate (2 g, 8.583 mmol, 1 equiv), cyclopropylboronic acid (0.73 g, 8.583 mmol, 1 equiv) and cesium carbonate (6.9 g, 21.459 mmol, 2.5 equiv) in 20 mL of 1 ,4-dioxane and 5 mL of water was degassed with nitrogen for 10 min, PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.7 g, 0.858 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 100 °C for overnight in sealed vessel.
  • Step 2 To a stirred solution of methyl 5-cyclopropyl-2-fluorobenzoate (1.57 g, 8.092 mmol) in Ethanol (15 ml_) was added 2M lithium borohydride in THF (8 ml_, 16.185 mmol, 2 equiv) at room temperature, and the reaction mixture was stirred at room temperature for overnight.
  • reaction mixture was quenched with water, extracted with ethyl acetate (2 x 100 ml_).
  • Step 3 To a solution of (5-cyclopropyl-2-fluorophenyl)methanol (1.4 g, 8.433 mmol) in diethyl ether (10 ml_) was added phosphorus tribromide (1.2 ml_, 12.650 mmol, 1.5 equiv) at room temperature and the reaction was stirred at room temperature for 3 h. The reaction mixture was quenched with water, basified with saturated sodium bicarbonate & extracted with diethyl ether (2 x 100 ml_). Organic layers were combined and dried over Na 2 S0 4 , filtered, and concentrated in vacuo to afford 2-(bromomethyl)-4-cyclopropyl-1-fluorobenzene as light brown liquid (1 g, crude).
  • Step 1 To a stirred solution of methyl 6-(trifluoromethyl)nicotinaldehyde (2 g, 11.428 mmol) in
  • Step 2 To a solution of (6-(trifluoromethyl)pyridin-3-yl)methanol (1.8 g, 10.169 mmol) in 48% HBr in water (10 mL) was refluxed at 100 °C for 6h. The resulting mixture was concentrated and diluted with EtOAc (100 mL) washed with saturated sodium bicarbonate dried over Na 2 S0 4 , filtered, and concentrated in vacuo to afford crude product. The crude product was purified by flash column chromatography with silica gel cartridge using gradient elution of 0 to 20% EtOAc in hexane.
  • the compounds according to Formula (I) and pharmaceutically acceptable salts thereof are inhibitors of PERK. These compounds are potentially useful in the treatment of conditions wherein the underlying pathology is attributable to (but not limited to) activation of the UPR pathway, for example, neurodegenerative disorders, cancer, cardiovascular and metabolic diseases. Accordingly, in another aspect the invention is directed to methods of treating such conditions.
  • the present invention relates to a method for treating or lessening the severity of breast cancer, including inflammatory breast cancer, ductal carcinoma, and lobular carcinoma.
  • the present invention relates to a method for treating or lessening the severity of colon cancer.
  • the present invention relates to a method for treating or lessening the severity of pancreatic cancer, including insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, and glucagonoma.
  • the present invention relates to a method for treating or lessening the severity of skin cancer, including melanoma, including metastatic melanoma.
  • the present invention relates to a method for treating or lessening the severity of lung cancer including small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.
  • the present invention relates to a method for treating or lessening the severity of cancers selected from the group consisting of brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia,
  • the present invention relates to a method for treating or lessening the severity of pre-cancerous syndromes in a mammal, including a human, wherein the pre-cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplasia syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.
  • MGUS monoclonal gammapathy of unknown significance
  • MUS monoclonal gammapathy of unknown significance
  • myelodysplasia syndrome aplastic anemia
  • cervical lesions aplastic anemia
  • cervical lesions skin nevi (pre-melanoma)
  • PIN prostatic intraepith
  • the present invention relates to a method for treating or lessening the severity of neurodegenerative diseases/injury, such as Alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, Parkinson disease, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, and other diseases associated with UPR activation including: diabetes, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, fatty liver disease, liver steatosis, liver fibrosis chronic and acute diseases of the lung, lung fibrosis, chronic and acute diseases of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, frontotemporal dementias, tauopathies, Pick's disease, Neimann-Pick's disease,
  • the present invention relates to a method preventing organ damage during and after organ transplantation and in the transportation of organs for transplantation.
  • the method of preventing organ damage during and after organ transplantation will comprise the in vivo administration of a compound of Formula (I).
  • the method of preventing organ damage during the transportation of organs for transplantation will comprise adding a compound of Formula (I) to the solution housing the organ during transportation.
  • the compounds of this invention inhibit angiogenesis which is implicated in the treatment of ocular diseases. Nature Reviews Drug Discovery 4, 711-712 (September 2005).
  • the present invention relates to a method for treating or lessening the severity of ocular diseases/angiogenesis.
  • the disorder of ocular diseases can be: edema or neovascularization for any occlusive or inflammatory retinal vascular disease, such as rubeosis irides, neovascular glaucoma, pterygium, vascularized glaucoma filtering blebs, conjunctival papilloma; choroidal neovascularization, such as neovascular age-related macular degeneration (AMD), myopia, prior uveitis, trauma, or idiopathic; macular edema, such as post surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, macular edema secondary to diabetes, and macular edema secondary to retinovascular occlusive disease (i.e.
  • retinal vascular disease such as rubeosis irides, neovascular glaucoma, pterygium,
  • the neovascular age-related macular degeneration is wet age- related macular degeneration. In other embodiments, the neovascular age-related macular degeneration is dry age-related macular degeneration and the patient is characterized as being at increased risk of developing wet age-related macular degeneration.
  • the methods of treatment of the invention comprise administering an effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt, thereof to a patient in need thereof.
  • the invention also provides a compound according to Formula (I) or a pharmaceutically-acceptable salt thereof for use in medical therapy, and particularly in therapy for: cancer, pre-cancerous syndromes, Alzheimer's disease, neuropathic pain, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute diseases of the liver, fatty liver disease, liver steatosis, liver fibrosis, chronic and acute diseases of the lung, lung fibrosis, chronic and acute diseases
  • treating in reference to a condition means: (1) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • Prophylactic therapy is appropriate when a subject has, for example, a strong family history of cancer or is otherwise considered at high risk for developing cancer, or when a subject has been exposed to a carcinogen.
  • the term "effective amount” and derivatives thereof means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • the term "therapeutically effective amount” and derivatives thereof means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • patient or “subject” refers to a human or other animal.
  • patient or subject is a human.
  • the compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered by any suitable route of administration, including systemic administration.
  • Systemic administration includes oral administration, and parenteral administration.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • the compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Additionally, the compounds of Formula (I) or pharmaceutically-acceptable salts thereof may be administered as prodrugs.
  • a prodrug of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo.
  • Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound.
  • esters can be employed, for example methyl, ethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of cancer or pre-cancerous syndromes.
  • co-administration is meant either simultaneous administration or any manner of separate sequential administration of a PERK inhibiting compound, as described herein, and a further active agent or agents, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment.
  • further active agent or agents includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered orally.
  • any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention.
  • examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.
  • anti-microtubule agents such as
  • the pharmaceutically active compounds of the invention are used in combination with a VEGFR inhibitor, suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt thereof, which is disclosed and claimed in in International Application No. PCT/U S01/49367, having an International filing date of December 19, 2001 , International Publication Number WO02/059110 and an International Publication date of August 1 , 2002, the entire disclosure of which is hereby incorporated by reference, and which is the compound of Example 69.
  • a VEGFR inhibitor suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydroch
  • 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide can be prepared as described in International Application No. PCT/US01/49367.
  • 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino] ⁇ methylbenzenesulfonamide is in the form of a monohydrochloride salt. This salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001.
  • the present invention relates to the treatment of cancer and ocular diseases/angiogenesis, suitably age-related macular degeneration, which method comprises the administration of a compound of Formula (I) alone or in combination with pazopanib.
  • the cancer treatment method of the claimed invention includes the co-administration a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti- microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.
  • anti-neoplastic agent such as one selected from the group consisting of anti- microtubule agents, platinum coordination
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of neurodegenerative diseases/injury.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of diabetes.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of cardiovascular disease.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of ocular diseases.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful for preventing organ damage during and after organ transplantation and in the transportation of organs for transplantation.
  • the pharmaceutically active compounds within the scope of this invention are useful as PERK inhibitors in mammals, particularly humans, in need thereof.
  • the present invention therefore provides a method of treating cancer, neurodegeneration and other conditions requiring PERK inhibition, which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as PERK inhibitors.
  • the drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, topical, subcutaneous, intradermal, intraocular and parenteral.
  • a PERK inhibitor may be delivered directly to the brain by intrathecal or intraventricular route, or implanted at an appropriate anatomical location within a device or pump that continuously releases the PERK inhibitor drug.
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
  • the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • compositions are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
  • Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 500 mg/kg of active compound, preferably 0.001 - 100 mg/kg.
  • the selected dose is administered preferably from 1-6 times daily, orally or parenterally.
  • Preferred forms of parenteral administration include topically, rectally, transdermal ⁇ , by injection and continuously by infusion.
  • Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound.
  • Suitably oral dosage units for human administration preferably contain from 0.5 to 1 ,000 mg of active compound.
  • Oral administration which uses lower dosages, is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular PERK inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.
  • a compound of Formula (I) When administered to prevent organ damage in the transportation of organs for transplantation, a compound of Formula (I) is added to the solution housing the organ during transportation, suitably in a buffered solution.
  • the method of this invention of inducing PERK inhibitory activity in mammals, including humans comprises administering to a subject in need of such activity an effective PERK inhibiting amount of a pharmaceutically active compound of the present invention.
  • the invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as a PERK inhibitor.
  • the invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in therapy.
  • the invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating cancer, pre-cancerous syndromes, Alzheimer's disease, neuropathic pain, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, Parkinson disease, diabetes, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute diseases of the liver, fatty liver disease, liver steatosis, liver fibrosis, chronic and acute diseases of the lung, lung fibrosis, chronic and acute diseases of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, frontotemporal dementias, tauopathies, Pick's
  • the invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in preventing organ damage during the transportation of organs for transplantation. .
  • the invention also provides for a pharmaceutical composition for use as a PERK inhibitor which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the invention also provides for a pharmaceutical composition for use in the treatment of cancer which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for use in the treatment of cancer which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutically active compounds of the present invention can be coadministered with further active ingredients, such as other compounds known to treat cancer, or compounds known to have utility when used in combination with a PERK inhibitor.
  • the invention also provides a pharmaceutical composition comprising from 0.5 to 1 ,000 mg of a compound of Formula (I) or pharmaceutically acceptable salt thereof and from 0.5 to 1 ,000 mg of a pharmaceutically acceptable excipient.
  • Step 1 To a stirred solution of 4-bromo-3-fluoroaniline (500.0 g, 2.63 mol) in Chloroform (6 L) was added 1-chloro-2-isocyanatoethane (336.68 mL, 3.95 mol, 1.5 equiv) at room temperature. The reaction mixture was refluxed for 1 h and cooled to room temperature. The precipitated solid was filtered and washed with n-pentane to give 1-(4- bromofluorophenyl)-3-(2-chloroethyl) urea (610 g, 79 %) as a white solid.
  • Step 2 To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(2-chloroethyl)urea (610.0 g, 2.07 mol) in acetonitrile (7 L) was added Cs 2 C0 3 (1.35 kg, 4.13 mol, 2.0 equiv) at room temperature. The reaction mixture was refluxed for 12 h. The reaction mixture was cooled to room temperature and the solvents were evaporated. The crude product was diluted with ethyl acetate (1 L) and water (1 L). Two layers were separated and aqueous layer was extracted with ethyl acetate.
  • Step 3 To a stirred suspension of 60% NaH (2 g, 50.96 mmol, 1.2 equiv) in DMF (150 ml_) was added 1-(4-bromo-3-fluorophenyl)imidazolidin-2-one (1 1 g, 42.47 mmol, 1 equiv) at 0 °C, & stirred for 30 min and then 2-(bromomethyl)-1 ,4-difluorobenzene (9.7 g, 46.71 mmol, 1.1 equiv) was added at 0 °C. The reaction mixture was stirred for 3.5 h at room temperature and quenched with ice water.
  • Step 4 A mixture of 1-(4-bromo-3-fluorophenyl)-3-(2,5-difluorobenzyl)imidazolidin-2-one (10 g, 25.974 mmol, 1 equiv), bis(pinacolato)diboron (9.8 g, 38.961 mmol, 1.5 equiv) and potassium acetate (7.6 g, 77.922 mmol, 3 equiv) in 250 ml_ of 1 ,4-dioxane was degassed with nitrogen for 15 min, PdCl 2 (dppf)-CH 2 Cl 2 adduct (1.05 g, 1.298 mmol, 0.05 equiv) was added and the reaction mixture was stirred at 100 °C for overnight in sealed vessel.
  • Step 5 Run 1 ; A mixture of 1-(2,5-difluorobenzyl)-3-(3-fluoro-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)imidazolidin-2-one (0.5 g, 1.157 mmol, 1 equiv), 5-bromo- 7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-4-amine (0.31 g, 1.388 mmol, 1.2 equiv), K 3 P0 4 (0.49 g, 2.314 mmol, 2.0 equiv) and Pd 2 (dba) 3 (0.05 g, 0.057 mmol, 0.05 equiv) in 15 mL of 1 ,4- dioxane and 5 mL of water in a sealed tube was bubbled with nitrogen for 15 min, tri-(f- butyl)phosphonium tetrafluoroborate (0.03 g,
  • the reaction mixture was stirred for 16 h at 100°C in a sealed vessel.
  • the reaction was cooled to room temperature, 5-bromo-7-methyl-7/-/-pyrrolo[2,3- ⁇ pyrimidin-4-amine (260 mg, 1.16 mmol, 1.0 equiv), saturated aqueous NaHC0 3 (6 ml_) and PdCI 2 (dppf)-CH 2 CI 2 adduct (48 mg, 0.058 mmol, 0.05 equiv) were added and the reaction mixture was degassed with N 2 for 5 min.
  • the vessel was sealed and the reaction mixture was stirred for 16 h at 100°C.
  • Step 1 A stirred solution of 6-bromoquinolin-2(1 /-/)-one (1.0 g, 4.4 mmol, 1.0 equiv) in phosphorous oxychloride (15 mL) was heated to 100°C for 15 h. The solvent was completely evaporated and water was added to the residue. The precipitated solid was filtered and dried under vacuum to obtain 6-bromo-2-chloroquinoline (1.0 g, 92 %) as pink solid.
  • LCMS (ES) m/z 241.0, 243.0 [M+H] + .
  • Step 2 A suspension of 6-bromo-2-chloroquinoline (0.8 g, 3.3 mmol, 1.0 equiv.) in 15 mL methyl amine solution in THF was heated to 100°C in a stainless steel autoclave for 24 h. The reaction mixture was cooled to room temperature and evaporated completely to obtain crude product as a gummy solid.
  • Step 3 To a stirred solution of 1-(4-bromo-3-fluorophenyl) imidazolidin-2-one (500 mg, 1.92 mmol) in DMF (8 mL) was added sodium hydride (92 mg, 2.31 mmol, 1.2 equiv) at 0°C. The reaction mixture was stirred for 15 min. 1-(bromomethyl)-3, 5-dimethylbenzene (42 mg, 2.12 mmol, 1.1 equiv) in DMF (2 mL) was added drop wise and the reaction mixture was gradually allowed to warm to room temperature and stirred for 4 h.
  • Step 4 To a mixture of 6-bromo-/V-methylquinolin-2-amine (0.25 g, 1.05 mmol, 1 equiv) in 1 ,4-dioxane was added bis(pinacolato)diboron (0.27 g, 1.05 mmol, 1 equiv), and potassium acetate (0.31 g, 3.16 mmol, 3 equiv). The reaction mixture was degassed with N 2 for 5 min. PdCl 2 (dppf).CH 2 Cl 2 adduct (0.043 g, 0.05 mmol, 0.05 equiv) was added and degassed with N 2 for further 5 min. The reaction mixture was stirred for 3 h at 100°C in a sealed vessel.
  • Step 1 To a stirred solution of 4-bromoaniline (0.2 g, 1.16 mmol, 1.0 equiv) in acetic acid (2 mL) was added ethoxyethene (0.45 mL, 4.8 mmol, 3.0 equiv) and heated to 100°C & stirred for overnight. After completion of starting material, reaction mixture was concentrated. Crude product was neutralized with saturated NaHC0 3 solution and extracted with DCM (20 mL). The organics were combined and washed with brine solution, dried over Na 2 S0 4 , filtered, and concentrated to obtain crude product. Crude product was purified by flash chromatography on silica gel. The compound was eluted with 30% EtOAc in Hexane.
  • Step 2 To a mixture of 6-bromo-2-methylquinoline (0.5 g, 2.25 mmol, 1.0 equiv), bis(pinacolato)diboron (0.68 g, 2.7 mmol, 1.2 equiv), and potassium acetate (0.55 g, 5.62 mmol, 2.5 equiv) was added 1 ,4-dioxane (15 mL), and the mixture was degassed with N 2 for 10 min. PdCl 2 (dppf).CH 2 Cl 2 complex (0.183 g, 0.22 mmol, 0.1 equiv) was added and again degassed with N 2 for 10 min. The reaction mixture was stirred for 3 h at 100°C in a sealed vessel.
  • Step 1 To a stirred solution of 4-bromo-3-fluoroaniline (5 g, 26.31 mol) in EtOAc (50 mL) was added pyridine (2.3mL, 28.94 mol, 1.1 equiv) and phenyl carbonochloridate (3.6MI, 28.94 mmol, 1.1 equiv) at 0°C. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was washed with water (2 x 50 mL), organic solvent was dried over sodium sulphate, filtered and concentrated to obtain crude product.
  • Step 2 To a stirred solution of phenyl (4-bromo-3-fluorophenyl)carbamate (5.5 g, 17.74 mmol) in dichloromethane (60 ml_) was added methyl 2-amino-3-hydroxypropanoate (3.16 g, 26.61 mmol, 1.5 equiv) and dimethyl amino pyridine (5.4 g, 44.35 mmol, 2.5 equiv) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was washed with 5 % HCI (50 ml_) and water (50 ml_), organic solvent was separated and dried over sodium sulphate, filtered & concentrated to obtain crude product.
  • methyl 2-amino-3-hydroxypropanoate 3.16 g, 26.61 mmol, 1.5 equiv
  • dimethyl amino pyridine 5.4 g, 44.35 mmol, 2.5 equiv
  • Step 3 To a stirred solution of NaBH 4 (0.25g, 6.60 mmol) in THF (15 ml_) was added BF 3 -OEt 2 (3.25 ml_, 26.4 mmol, 4 equiv) at 0 °C & stirred for 15 min. A solution of 3-(4- bromo-3-fluorophenyl)-5-(hydroxymethyl) imidazolidine-2,4-dione (1g, 3.3mmol) in THF (5 ml_) was added to the reaction mixture and stirred for 30 min. The reaction mixture warmed to room temperature and stirred for overnight. The reaction mixture was quenched with MeOH and 1 N HCI slowly over 15 min. The reaction mixture was concentrated to obtain crude product.
  • Step 4 To a stirred solution of 1-(4-bromo-3-fluorophenyl)-4-(hydroxymethyl) imidazolidin-2-one (0.45g, 1.55 mmol) in DMF (10 ml_) was added Imidazole (0.075 g, 1.71 mmol, 0.05 equiv), dimethyl amino pyridine (0.019 g, 0.155 mmol, 1 equiv) and TBDMS-Chloride (0.258 g, 1.71 mmol, 1.1 equiv) and resulted mixture was stirred at room temperature for 12 h. Reaction mixture was concentrated to obtain crude product.
  • Step 5 To a stirred solution of 1-(4-bromo-3-fluorophenyl)-4-(((tertbutyldimethylsilyl)oxy)- methyl)imidazolidin-2-one (0.25g, 0.62 mmol) in DMF (10 mL) was cooled to 0°C, NaH (0.027 g, 0.68 mmol, 1.1 equiv) was added and stirred for 15 min at 0°C. 2- (bromomethyl)-4,6-dimethylpyridine (0.136 g, 0.68 mmol, 1.1 equiv) was added and the resulted mixture was stirred at room temperature for 1 h.
  • Step 6 A mixture of 1-(4-bromo-3-fluorophenyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3- ((4,6-dimethylpyridin-2-yl)methyl)imidazolidin-2-one (0.3 g, 0.57 mmol, 1 equiv), bis(pinacolato)diboron (0.15 g, 0.57 mmol, 1.0 equiv) and potassium acetate (0.167 g, 1.71 mmol, 3 equiv) in 10 mL of 1 ,4-dioxane was degassed with nitrogen for 15 min.
  • Step 7 A mixture of 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((4,6-dimethylpyridin-2- yl)methyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)imidazolidin- 2-one (0.3 g, 0.52 mmol, 1 equiv), 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.12 g, 0.52 mmol, 1 equiv), K 3 PO4 (0.22 g, 1.04 mmol, 2.0 equiv) and Pd 2 (dba) 3 (0.024 g, 0.026 mmol, 0.05 equiv) in 12 mL of 1 ,4-dioxane and 4 mL of water in a sealed tube was bubbled with nitrogen for 15 min.
  • Tri-(f-butyl)phosphonium tetrafluoroborate (0.015 g, 0.052 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 100°C for 6h in a sealed vessel. The reaction mixture was cooled to room temperature, filtered through celite and the filtrate was concentrated in vacuo to afford crude product. The crude product was purified by flash column chromatography with 24 g silica gel cartridge using gradient elution of 0-3 % MeOH in DCM.
  • Step 8 Run1 : To a stirred solution of 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin- 5-yl)-3-fluorophenyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((4,6-dimethylpyridin-2- yl)methyl)imidazolidin-2-one (0.02 g, 0.03 mmol, 1 equiv) in THF (5 mL) was added tetra butyl ammonium fluoride (0.084 mL, 0.084 mmol, 2.5 equiv, 1 M in THF) at 0°C.
  • Run 2 To a stirred solution of 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3- fluorophenyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((4,6-dimethylpyridin-2- yl)methyl)imidazolidin-2-one (0.13 g, 0.22 mmol, 1 equiv) in THF (10 mL) was added tetra butyl ammonium fluoride (0.55 mL 1 M in THF, 0.55 mmol, 2.5 equiv) at 0°C. The reaction mixture was stirred at room temperature for 1 h.
  • Step 1 To a stirred solution of 1 H-pyrrole-2-carbaldehyde (2.0 g, 21.3 mmol, 1 equiv), in DMF (45 mL) was added K 2 C0 3 (5.88 g, 42.6 mmol, 2 equiv) at room temperature. The reaction mixture was cooled to 0°C, and added Ethyl Iodide (2.05 mL, 25.53 mmol, 1.2 equiv) slowly at 0°C. The reaction mixture was stirred for 16 h at room temperature. After completion of starting material, the reaction mixture was quenched with water and extracted with EtOAc.
  • Step 2 To a stirred solution of 1 -ethyl- 1/-/-pyrrole-2-carbaldehyde (2.6 g, 21.1 1 mmol, 1 equiv), in MeOH (35 mL) was added NaBH 4 (1.6 g, 42.22 mmol, 2.0 equiv) slowly in portion wise at 0°C. After the addition, the reaction mixture was slowly warmed to room temperature and stirred for 3h at room temperature. The reaction mixture was evaporated; water was added to the residue and extracted with DCM. The organic layer was washed with brine and dried over sodium sulfate & concentrated to give (1-ethyl-1 H- pyrrol-2-yl) methanol as brown oil (1.7 g, crude).
  • Step 3 To a stirred solution of 1-(4-bromo-3-fluorophenyl)imidazolidin-2-one (1.65 g, 6.4 mmol, 1 equiv), in THF (50 mL) was added (1-ethyl-1 H-pyrrol-2-yl)methanol (0.8 g, 6.4 mmol, 1 equiv) and PPh 3 (3.36 g, 12.8 mmol, 2 equiv) at room temperature. DEAD (2.0 mL, 12.8 mmol, 2 equiv) was added slowly to the reaction mixture at 0°C. The reaction mixture was stirred for 3h at room temperature.
  • Step 4 To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-((1 -ethyl- 1 /-/-pyrrol-2- yl)methyl)imidazolidin-2-one (0.250 g, 0.683 mmol, 1.0 equiv) in dioxane (10 mL), was added bis(pinacolato)diboron (0.174 g, 0.683 mmol, 1.0 equiv), potassium acetate (0.209 g, 2.05 mmol, 3.0 equiv), and degassed with Argon for 10 min.
  • Step 1 To a stirred solution of 4-chloro-7/-/-pyrrolo[2,3-d]pyrimidine (4 g, 26.143 mmol) in THF (40 mL) was added potassium tertiary butoxide (3.8 g, 33.986 mmol, 1.3 equiv) at 0°C. The reaction mixture was allowed to stir at room temperature for 20 min. Methyl iodide (2.4 mL, 39.215 mol, 1.5 equiv) was added at 0°C to the reaction mixture and stirred for 4h at room temperature.
  • Step 2 To a stirred solution of 4-chloro-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidine (3.6 g, 21.556 mmol) in dimethyl formamide (50 mL) was added /V-iodosuccinimide (4.8 g, 21.556 mmol) in one portion at room temperature and the reaction mixture was stirred overnight. Ice water (100 mL) was added to the reaction mixture and the resulting precipitate was filtered, washed with water (100 mL) and dried under vacuum to obtain 4- chloro-5-iodo-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidine as off white solid (5.2 g, crude).
  • Step 3 To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(2,5- difluorobenzyl)imidazolidin-2-one (1.0 g, 2.6 mmol, 1.0 equiv), was added bis(pinacolato)diboron (0.66 g, 2.6 mmol, 1.0 equiv), & potassium acetate (0.764 g, 7.8 mmol, 3.0 equiv), and the reaction mixture was degassed with Argon for 10 min, PdCl 2 (dppf).CH 2 Cl 2 complex (0.106 g, 0.13 mmol, 0.05 equiv) was added and again degassed with Argon for 10 min.
  • bis(pinacolato)diboron (0.66 g, 2.6 mmol, 1.0 equiv)
  • & potassium acetate 0.764 g, 7.8 mmol, 3.0 equiv
  • the reaction mixture was stirred for 5h at 100°C in a sealed vessel.
  • the reaction mixture was cooled to room temperature.
  • 4-chloro-5-iodo-7- methyl-7/-/-pyrrolo[2,3-d]pyrimidine (0.762 g, 2.6 mmol, 1.0 equiv) and saturated aqueous NaHC0 3 (8.0mL) were added and Argon gas was bubbled through the mixture for 10 min.
  • PdCl 2 (dppf).CH 2 Cl 2 complex (0.106 g, 0.13 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100°C.
  • the reaction mixture was cooled to room temperature & filtered through celite.
  • Step 4 To a stirred solution of 1-(4-(4-chloro-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3- fluorophenyl)-3-(2,5-difluorobenzyl)imidazolidin-2-one (0.1 10 g, 89% purity by LCMS)) in MeOH (10 mL) was added 10% Pd/C (0.015 g, contains 50% moisture) and the mixture was degassed using nitrogen and then replaced with H 2 bladder. The reaction mixture was stirred for 16 h at room temperature. After consumption of the starting material, the reaction mixture was filtered through celite bed. The solvent was concentrated to give crude product.
  • Step 5 To a stirred solution of 4-chloro-5-iodo-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidine (0.6 g, 2.045 mmol, 1.0 equiv) in 1 ,4-dioxane (7.0 mL) and water (7.0 mL) was added NaOH pellets (0.408 g, 10.222 mmol, 5.0 equiv) and stirred for 5 min. The reaction mixture was heated to 100°C and stirred for 4 h. The reaction mixture was concentrated; the residue was diluted with water and acidified with 1 N HCI.
  • Step 6 To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(2,5- difluorobenzyl)imidazolidin-2-one (0.5 g, 1.3 mmol, 1.0 equiv) in DMF (15 mL) was added bis(pinacolato)diboron (0.33 g, 1.3 mmol, 1.0 equiv), and potassium acetate (0.382 g, 3.9 mmol, 3.0 equiv), and the mixture was degassed with Argon for 10 min.
  • Step 1 3-Oxabicyclo[3.1.0]hexane-2,4-dione (5.5 g, 49mmol, 1.0 equiv) was taken in H 2 0 (40 mL) and heated to 80 °C for overnight. The reaction mixture was concentrated under reduced pressure and co-distilled the water traces with toluene to get dry cyclopropane- 1 ,2-dicarboxylic acid (6.0 g, 94 %) as white solid.
  • Step 2 Cyclopropane-1 ,2-dicarboxylic acid (3.5 g, 26.9 mmol, 1.0 equiv) and PCI 5 (16.82 g, 80.7 mmol, 3.0 equiv) were mixed and heated to 90 °C for 6h. The reaction mixture was cooled to room temperature and filtered to remove the excess PCI 5 and washed with Et 2 0. Filtrate was concentrated under reduced pressure to give cyclopropane-1 ,2- dicarbonyl dichloride (3.5 g, crude) as colorless oil.
  • H NMR 400 MHz, DMSO) ⁇ ppm 1.60 - 1.64 (m, 1 H), 1.76 - 1.79 (m, 1 H), 2.87 - 2.90 (m, 2H).
  • Step 3 Caution - acyl azides are dangerous and potentially explosive. For saftey, all experiements involving acyl azides should be performed with appropriate protection and blast shielding.
  • Cyclopropane- 1 ,2-dicarbonyl dichloride (3.5 g, 21 mmol, 1.0 equiv) in acetone (30 mL) was added dropwise with stirring to a cooled (ice-salt bath) aqueous solution (30 mL) of NaN 3 (4.09 g, 62 mmol, 3.0 equiv)). After complete addition, the reaction the reaction mixture was stirred at 0 °C for 3h. The reaction mixture was diluted with cold water and extracted with Et 2 0 (3 x 100 mL).
  • Step 4 Caution - acyl azides are dangerous and potentially explosive. For saftey, all experiements involving acyl azides should be performed with appropriate protection and blast shielding. Cyclopropane-1 ,2-dicarbonylazide (2.6 g, 14.4 mmol, 1.0 equiv) in toluene was heated to 100°C for 15h. The disappearance of starting material was monitored by TLC and the reaction mixture was concentrated to give 1 ,2- diisocyanatocyclopropane (2.6 g, crude), which is used directly for next stage without purification.
  • Step 6 Run 1 ; To a mixture of tert-butyl 3-oxo-2,4-diazabicyclo[3.1.0]hexane-2- carboxylate and 2,4-diazabicyclo[3.1.0]hexan-3-one (0.2 g, 1.0 mmol, 1.0 equiv) in DMF (5.0 mL) was added NaH(60 % in oil) (0.04g, 1.1 mmol, 1.1 equiv) at 0 °C and stirred for 30 min. 2,5-Difluorobenzylbromide (0.15 mL, 1.1 mmol, 1.1 equiv) was added and stirred for 2h at 0°C.
  • reaction mixture was quenched with ice water and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water, brine solution & dried over Na 2 S0 4 , filtered, and concentrated under reduced pressure to get crude product. Crude product was purified by flash chromatography on silica gel and compound was eluted with 20% EtOAc in Hexane. Fractions containing desired product were concentrated to give tert-butyl 4-(2,5- difluorobenzyl)-3-oxo-2,4-diazabicyclo[3.1.0]hexane-2-carboxylate (0.1g, 31.2%) as white solid.
  • Step 8 To a stirred solution of 2-(2,5-difluorobenzyl)-2,4-diazabicyclo[3.1.0]hexan-3-one (0.3 g, 1.34 mmol, 1.0 equiv) and 1-bromo-2-fluoro-4-iodobenzene (0.484 g, 1.60 mmol, 1.2 equiv) in EtOAc (20 mL) was added cesium fluoride (0.51 g, 3.35 mmol, 2.5 equiv), ⁇ , ⁇ ' -dimethylethylenediamine (0.029 mL, 0.268 mmol, 0.2 equiv) and Cul (0.051 g, 0.268 mmol, 0.2 equiv) and the resulting mixture was stirred for 15h at room temperature.
  • cesium fluoride (0.51 g, 3.35 mmol, 2.5 equiv
  • ⁇ , ⁇ ' -dimethylethylenediamine 0.029 mL,
  • Step 9 To a mixture of 2-(4-bromo-3-fluorophenyl)-4-(2,5-difluorobenzyl)-2,4- diazabicyclo[3.1.0]- hexan-3-one (0.28 g, 0.7 mmol, 1.0 equiv), bis(pinacolato)diboron (0.22 g, 0.846 mmol, 1.2 equiv), and potassium acetate (0.173 g, 1.76 mmol, 2.5 equiv) was added 1 ,4-dioxane (10 ml_), and the mixture was degassed with N 2 for 10 minutes.
  • Step 10 2-(2,5-Difluorobenzyl)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)-2,4-diazabicyclo[3.1.0]hexan-3-one (0.19 g, 0.43 mmol, 1.0 equiv), 5-bromo-7- methyl-7/-/-pyrrolo[2,3-d]pyrimidin-4-amine (0.097 g, 0.43 mmol, 1.0 equiv) and potassium phosphate (0.183 g, 0.86 mmol, 2 equiv) in 1 ,4-dioxane: water (10 ml_ : 3.0 ml_) was degassed with N 2 for 15 minutes, added Pd 2 (dba) 3 ( 0.0196 g, 0.022 mmol, 0.05 equiv) & Tri-tert-butylphosphonium tetra
  • reaction mixture was further degassed for 5 minutes.
  • the vial was sealed and the reaction mixture was heated to 100°C and stirred for 5h.
  • the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was dried over Na 2 S0 4 , concentrated to obtain crude compound.
  • Crude product was purified by flash column chromatography using silica gel column and compound was eluted at 2% MeOH in DCM.
  • Example 99 PERK Enzyme Assay Compounds of the invention were assayed for PERK enzyme inhibitory activity with modifications to previously reported conditions (Axten et al. J. Med. Chem., 2012, 55, 7193-7207). Briefly, various concentrations of compounds (maximum 1 % DMSO) were dispensed into 384-well plates containing GST-PERK enzyme. After 30-60 minutes of compound pre-incubation, ATP and biotin-elF2a were added and after 60 minutes the reaction was quenched. After 2 hrs, a fluorescence plate reader was used to measure inhibition and IC50s were calculated.
  • Assay Buffer contains HEPES (pH7.5) 10mM, CHAPS 2mM, MgCI2 5mM and DTT 1 mM in water
  • Detection Buffer contains HEPES (pH7.5) 10mM and CHAPS 2mM in water
  • the activity of compounds in the PERK enzyme assay was determined at PERK Enzyme (500 ⁇ ATP) IC50 (nM).
  • An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table 3, below.
  • Example 101 Injectable Parenteral Composition
  • An injectable form for administering the present invention is produced by stirring 1.7% by weight of 1-(3,5-Dimethylbenzyl)-3-(3-fluoro-4-(2-(methylamino)quinolin-6- yl)phenyl)imidazolidin-2-one (Compound of Example 2) in 10% by volume propylene glycol in water.
  • sucrose, calcium sulfate dihydrate and a PERK inhibitor as shown in Table 4 below are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid;, screened and compressed into a tablet.
  • Examples 1 to 91 were tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 ⁇ ATP) IC50 (nM) value: ⁇ 8 ⁇ against PERK, except for Examples 2, 3, 6 to 8, 11 , 12, 20, 35, 38, 43, 46, 50, 57, 66, 69, 87, and 88, which exhibited IC50 > 10 ⁇ .
  • Example 74 The compound of Example 74 was tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 ⁇ ATP) IC50 (nM) value of 526.6 against PERK.

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Abstract

L'invention concerne des dérivés d'imidazolidinone substitués. L'invention concerne spécifiquement des composés de formule I (I), dans laquelle R1, R2, R3, R4, R5, R6, R7, X, Y1, Y2 sont tels que définis dans la description. Les composés de l'invention sont des inhibiteurs de PERK et peuvent être utiles dans le traitement du cancer, des syndromes précancéreux, tels que la maladie d'Alzheimer, de la douleur neuropathique, des lésions de la moelle épinière, d'une lésion cérébrale traumatique, de l'accident vasculaire cérébral ischémique, de l'accident vasculaire cérébral, de la maladie de Parkinson, du diabète, du syndrome métabolique, des troubles métaboliques, la maladie de Huntington, de la maladie de Creutzfeldt-Jakob, de l'insomnie familiale fatale, du syndrome de Gerstmann-Sträussler-Scheinker, et des maladies à prions apparentées, de la sclérose latérale amyotrophique, de la paralysie supranucléaire progressive, de l'infarctus du myocarde, des maladies cardio-vasculaires, de l'inflammation, de la fibrose d'organes, des maladies chroniques et aiguës du foie, de la stéatose hépatique, de la fibrose du foie, des maladies chroniques et aiguës du poumon, de la fibrose pulmonaire, des maladies chroniques et aiguës du rein, de la fibrose rénale, de l'encéphalopathie traumatique chronique (CTE), de la neurodégénérescence, des démences, des démences fronto-temporales, des tauopathies, de la maladie de Pick, de la maladie de Pick-Neimann, l'amyloïdose, de la déficience cognitive, l'athérosclérose, des maladies oculaires, des arythmies, dans la transplantation d'organe et dans le transport d'organes en vue d'une transplantation. Par conséquent, l'invention concerne en outre des compositions pharmaceutiques comprenant un composé de l'invention. L'invention concerne par ailleurs des procédés d'inhibition de l'activité de PERK et le traitement de troubles associés à celle-ci au moyen d'un composé de l'invention ou d'une composition pharmaceutique comprenant un composé de l'invention.
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