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WO2017046738A1 - Triazolone compounds as perk inhibitors - Google Patents

Triazolone compounds as perk inhibitors Download PDF

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Publication number
WO2017046738A1
WO2017046738A1 PCT/IB2016/055505 IB2016055505W WO2017046738A1 WO 2017046738 A1 WO2017046738 A1 WO 2017046738A1 IB 2016055505 W IB2016055505 W IB 2016055505W WO 2017046738 A1 WO2017046738 A1 WO 2017046738A1
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Prior art keywords
disease
4alkyl
triazol
pyrrolo
cancer
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Ceased
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PCT/IB2016/055505
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French (fr)
Inventor
Jeffrey Michael Axten
Nicolas Eric Faucher
Alain Claude-Marie Daugan
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GlaxoSmithKline Intellectual Property No 2 Ltd
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GlaxoSmithKline Intellectual Property No 2 Ltd
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to substituted triazolone derivatives that are inhibitors of the activity of the protein kinase R (PKR)-like ER kinase, PERK.
  • PLR 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,, ischemic stroke, stroke, Parkinson's 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 ste
  • 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.
  • 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.
  • XBP1 is essential for survival under hypoxic conditions and is required for tumor growth, Cancer Res 64, 5943- 7.
  • compositions that comprise a pharmaceutical carrier and compounds of Formula (I).
  • the invention is directed to substituted triazolone 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.
  • R , R 2 , R 3 , R 4 , R 5 , X, Y, Y 1 , and Z are as defined below.
  • the present invention also relates to the discovery that the compounds of Formula (I) are active as inhibitors of PERK.
  • 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).
  • PSP progressive supranuclear palsy
  • 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.
  • 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.
  • 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 compounds of Formula (I) in the methods of the invention:
  • substituted bicycloheteroaryl and said substituted heteroaryl are substituted with from one to five substituents independently selected from:
  • -6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C-
  • Ci-4alkyl -OH, - NH 2 , cycloalkyl, -COOH, -CF 3 , -N0 2 and
  • Ci-4alkyl independently selected from: Ci-4alkyl, 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:
  • -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-
  • R is selected from: hydrogen, C-
  • R is selected from: hydrogen, C-
  • 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).
  • R is hydrogen
  • X is CH.
  • R is selected from: hydrogen, methyl, -CF3, fluoro and chloro.
  • R is selected from: hydrogen, methyl, -CF3, fluoro and chloro. 2
  • R is phenyl optionally substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo,
  • Ci-4alkyl Ci-4alkyl, Ci -4alkyloxy, -OH, -COOH, -CF 3 , -Ci-4alkylOCi-4alkyl, -N0 2 , cycloalkyl, -OC(H)F 2 , -C(H)F 2 , -OCH 2 F, -CH 2 F, -OCF 3 , -NH 2 and -CN.
  • Y and Y are hydrogen.
  • X is CR 1 00 , 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]pyrimidinyl.
  • R is selected from: substituted pyrrolo[2,3d]pyrimidin-5-yl and substituted pyrazolo[3,4d] pyrimidin-5-yl.
  • R is selected from: 4-amino-7-methyl- 7H-pyrrolo[2,3-d]pyrimidin-5-yl and 4-amino-1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl.
  • 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, C-
  • R is selected from: hydrogen, C-
  • R is selected from:
  • Ci-6alkyl diCi -4alkylaminoC-
  • R is selected from:
  • Ci_4alkyl independently selected from: Ci_4alkyl, Ci-4alkyloxy, -OH,
  • -6alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, Ci-4alkyloxy, -OH, -CF3 -COOH, -NO2, -NH 2 and -CN;
  • R is selected from: hydrogen and -CH3;
  • R is selected from: hydrogen, C-
  • X is CR or N
  • R is selected from: hydrogen, fluoro and chloro; and 10 1 1
  • Y and Y are independently selected from: hydrogen, -CF3 and C-
  • Y and Y are taken together with the carbon to which they are attached to form a C3-C6 cycloalkyl; and salts thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (II). 101 101
  • X is CR , where R is selected from: hydrogen, fluoro and chloro.
  • X is N.
  • R 20 is selected from:
  • phenyl optionally substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci-4alkyl,
  • R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
  • R is selected from:
  • R is selected from:
  • R is selected from: hydrogen and -CH3;
  • R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
  • X is CR or N
  • R is selected from: hydrogen, fluoro and chloro
  • Y and Y are independently selected from: hydrogen, -CF3 and C-
  • Y and Y are taken together with the carbon to which they are attached to form a C3-C6 cycloalkyl; and salts thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (III).
  • X is CH.
  • R is hydrogen
  • R is hydrogen
  • R is phenyl optionally substituted with from 1 or 2 substituents independently selected from: fluoro and methyl, suitably methyl.
  • Y and Y are hydrogen.
  • R and R are hydrogen.
  • R is selected from: methyl and cyclopropyl, suitably methyl.
  • X is CR , where R is selected from: hydrogen, fluoro and chloro.
  • X is N.
  • phenyl optionally substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl,
  • R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
  • R is selected from:
  • R is selected from: hydrogen and -CH3;
  • R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
  • X is CR 1 03 or N
  • R is selected from: hydrogen, fluoro and chloro
  • Y and Y are independently selected from: hydrogen, CF3 and C-
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (IV).
  • X is CH.
  • R is hydrogen
  • R is hydrogen.
  • R is phenyl optionally substituted with from 1 or 2 substituents independently selected from: fluoro and methyl, suitably methyl.
  • Y and Y are hydrogen.
  • R is hydrogen
  • R is selected from: methyl and cyclopropyl, suitably methyl.
  • X is CR , where 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).
  • 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.
  • the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically acceptable 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.
  • -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]pyridinyl, 1 /-/-pyrazolo[4,3- c] pyridinyl, 1 H-pyrazolo[3,4-d]pyrimidinyl, 1 H-pyrrolo[2,3-d]pyrimidinyl, 7H-pyrrolo[2,3- d] pyrimidinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, furo[2,3-c]pyridinyl, furo[2,3- d]pyrimidinyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl,
  • Bicycloheteroaryl includes: 1 H-pyrazolo[3,4-d]pyrimidinyl, 1 H-pyrrolo[2,3- d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, furo[2,3-c]pyridinyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothi
  • 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: pyrazolyl, pyrrolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and imidazolyl.
  • Heterocycloalkyl refers to a saturated or unsaturated non-aromatic ring containing 4 to 12 member atoms, of which 1 to 11 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-onyl, hexahydro-1 H-azepinyl, 4,5,6,7,tetrahydro-1 H-benzimi
  • Heteroatom refers to a nitrogen, sulphur or oxygen atom.
  • ACN Aceonitrile
  • AIBN Azobis(isobutyronitrile)
  • BOP Benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate
  • CSF Chemical fluoride
  • ATP Addenosine triphosphate
  • Bis-pinacolatodiboron (4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1 ,3,2-dioxaborolane); BSA (Bovine serum albumin);
  • DIPEA Human's base, /V-ethyl-/V-(1-methylethyl)-2-propanamine
  • DMEDA (A/./V -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)-/V,A/,A/',A/'-tetramethyluronium hexafluorophosphate);
  • HOBt (1-Hydroxybenzotriazole
  • HMDS Hexamethyldisilazide
  • Hunig's Base (A/,A/-Diisopropylethylamine);
  • KHMDS Lithyl hexamethyldisilazide
  • LAH Lithium aluminum hydride
  • LDA Lithium diisopropylamide
  • LHMDS Lithium hexamethyldisilazide
  • mCPBA m-Chloroperbezoic acid
  • NBS (/V-bromosuccinimide
  • PE Petroleum ether
  • 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.
  • aryl hydrazine B was prepared by reacting corresponding aniline A with concentrated HCI, sodium nitrite and stannous chloride.
  • Aryl hydrazine B was reacted with concentrated HCI and 2-oxo acetic acid to obtain corresponding arylhydrazino acetic acid C.
  • Triazolone intermediate D was obtained by reacting intermediate C with TEA and DPPA followed by treatment with a suitable base such as sodium hydroxide. Alkylation of triazolone intermediate D with substituted benzyl, cycloalkyl, or alkyl bromides afforded compound E.
  • the 3-substitutted triazolones of formula N were generally prepared according to Scheme 2.
  • Ethyl acetimidate hydrochloride I was reacted with Ethylchloroformate in presence of base such as DIPEA to give ethyl /V-ethoxycarbonylacetimidate J.
  • Ethoxycarbonylacetimidate J was reacted with aryl hydrazine J1 in presence of base such as triethyl amine to give A/-aryl-3-methyl-triazolone intermediate K.
  • Alkylation of triazolone K followed by boronate ester formation and Suzuki-Miyaura coupling were performed similar to the general Scheme 1 to give compounds of formula N.
  • 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 precancerous 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.
  • the precancerous 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
  • 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, neuropathic pain, 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-
  • 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, 71 1-712 (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,
  • retinal neovascularization due to diabetes such as retinal vein occlusion, uveitis, ocular ischemic syndrome from carotid artery disease, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, or Eale's Disease; and genetic disorders, such as VonHippel- Lindau syndrome.
  • 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 of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, frontotemporal dementias, tauopathies, Pick's
  • 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.
  • therapeutically effective amount 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. Suitably the 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.
  • 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/US01/49367, having an International filing date of December 19, 2001 , International Publication Number WO02/0591 10 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 monohydrochlor
  • 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- 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.
  • Pazopanib is implicated in the treatment of cancer and ocular diseases/angiogenesis.
  • 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 complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor t
  • 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'
  • 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.
  • the pharmaceutically active compounds of the present invention can be co-administered 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-chloro-1 H-pyrazolo[3,4-d]pyrimidine (2.5 g, 16.23 mmol, 1 equiv) in DCM (30 ml_) was added NBS (3.4 g, 19.48 mmol, 1.2 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for O/N. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate evaporated to obtain crude which was purified over silica gel flash column chromatography.
  • Step 2 To a stirred solution of 3-bromo-1 ,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.3 g, 6.04 mmol, 1 equiv) in Pyridine (30 mL) was added cyclopropyl boronic acid (1.03 g, 12.09 mmol, 2 equiv) and copper acetate (2.18 g , 12.09 mmol, 2 equiv) at room temperature. The reaction mixture was stirred for 2h at 90°C. The reaction mixture was quenched with water and extracted with ethyl acetate.
  • Step 3 To a stirred solution of 3-bromo-1-cyclopropyl-1 ,5-dihydro-4H-pyrazolo[3,4- d]pyrimidin-4-one (1.2 g, 4.70 mmol, 1 equiv) in dichloro ethane (20 mL) was added DMF (1.2 mL) and POCI 3 (1.5 mL) at room temperature. The reaction mixture was stirred for O/N at 80°C. The reaction mixture was quenched with cold Sat. NaHC03 solution (0-5°C) and extracted in ethyl acetate. The organic layer was dried over sodium sulphate, filtered and evaporated to obtain crude product, which was purified over silica gel flash column chromatography.
  • Step 4 To a stirred solution of 3-bromo-4-chloro-1-cyclopropyl-1 H-pyrazolo[3,4- d]pyrimidine (0.4 g, 1.46 mmol, 1 equiv) in 1 ,4-dioxane (5 mL) was added NH 4 OH (10 mL) at room temperature. The reaction mixture was heated at 100°C in an autoclave for O/N. The reaction mixture was cooled and the solids formed were filtered to obtain 3-bromo-1- cyclopropyl-1 H-pyrazolo[3,4-d]pyrimidin-4-amine (0.23 g, 61 %) as off white solid.
  • Step 1 Run1 : To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 26.14 mmol, 1 equiv) in Pyridine (40 mL) was added cyclopropyl boronic acid (4.4 g, 52.28 mmol, 2 equiv) and copper acetate (9.4 g , 52.28 mmol, 2 equiv) at room temperature. The reaction mixture was stirred for O/N at 90°C. The reaction mixture was quenched with water and extracted in ethyl acetate. The organic layer was dried over sodium sulphate evaporated to obtain crude product, which was purified over silica gel flash column chromatography.
  • cyclopropyl boronic acid 4.4 g, 52.28 mmol, 2 equiv
  • copper acetate 9.4 g , 52.28 mmol, 2 equiv
  • Run 2 To a stirred suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 16.276 mmol, 1.0 eq), cyclopropyl boronic acid (2.8 g, 32.55 mmol, 2 eq ), sodium Carbonate (3.45 g, 32.5 mmol, 2 eq) in dichloroethne (50 mL) was added a suspension of Cu(OAc)2 (2.95 g, 16.3 mmol, 1.0 eq), and Bipy (2.54 g, 16.3 mmol, 1.0 eq) in hot dichloro ethane (20 mL). The reaction mixture was heated to reflux and stirred for overnight.
  • reaction was monitored by TLC for completion.
  • the reaction mixture was cooled to room temperature and filtered through celite. The celite bed was thoroughly washed with dichloro ethane. The filtrate was then washed with 1 N HCI, the two layers were separated. The Aq. Phase was extracted with DCM and the combined organic layers were washed with brine, dried over Na2S04, filtered, evaporated and purified by Flash column chromatography. The desired product was eluted in 12% EtOAc in hexane. Fractions containing the desired product were combined and concentrated to afford the desired product 4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine as off-white solid (1.85 g, 53%).
  • Step 2 To a stirred solution of 4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (0.67 g, 3.47 mmol, 1 equiv) in DCM (20 mL) was added NBS (0.61 g, 3.47 mmol, I .Oequiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate evaporated to obtain 5-bromo-4-chloro-7- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (0.7 g, 75%) as an pale yellow solid.
  • Step 1 To a stirred solution of 4 4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (2.5 g, 16.17 mmol, 1 equiv) in DMF (50 mL) was added NBS (3.2 g, 17.78 mmol, 1.1 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 3h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate evaporated to obtain 3-bromo-4-chloro-1 H-pyrazolo[3,4- d]pyrimidine (3.5 g, crude) as pale yellow solid.
  • Step 2 To a stirred solution of 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (3.5 g, 15.02 mmol, 1 equiv) in DMF (60 mL) was added sodium hydride (0.72 g, 18.02 mmol, 1.2 equiv) at 0°C. The reaction mixture was stirred for 15 min at 0°C. Methyl iodide (1.12 mL, 18.02 mmol, 1.2 equiv) was added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 3h. The reaction mixture was quenched with ice water and extracted in ethyl acetate.
  • Step 3 To a stirred solution of 3-bromo-4-chloro-1-methyl-1 H-pyrazolo[3,4-d]pyrimidine (2.0 g, 8.09 mmol, 1 equiv) in 1 ,4-dioxane (10 mL) was added NH 4 OH (30 mL) at room temperature. The reaction mixture was heated at 100°C in an autoclave for O/N.
  • Step 1 To a stirred solution of 4-bromo-3-fluoroaniline (150 g, 0.789 mol, 1 equiv) in Concentrated HCI (756 ml) was added a solution of NaN0 2 (56.3g, 0.827 mol, 1.05 equiv) in water (390 ml_) at -10 °C and reaction mixture was stirred for 30 min, SnCI 2 .2H 2 0 (343 g, 2.95 mol, 3.7 equiv) solution in Concentrated HCI (582 ml_) was added. The resulting mixture was warmed to room temperature and stirred for 1 h.
  • Step 2 To a stirred suspension of (4-bromo-3-fluorophenyl)hydrazine hydrochloride (154 g, 0.641 mol, 1 equiv) in Water (1.54 L) was added Concentrated HCI (121.66 ml_) followed by the addition of 50 % aqueous 2-oxo acetic acid (52 g, 0.705 mol, 1.1 equiv) portion wise. The mixture turned to orange and stirred at room temperature for 3 hours. The precipitate was filtered off and washed with water. The orange solid was dissolved in ethyl acetate and washed with water. The organic phase was dried over Na 2 S0 4 , filtered and evaporated to dryness.
  • Step 3 To a stirred suspension of (£)-2-(2-(4-bromo-3-fluorophenyl)hydrazono)acetic acid (74 g, 0.284 mol, 1 equiv) in toluene (740 ml_) was added Et 3 N (39.91 ml_, 0.284 mol, 1 equiv) and DPPA (61.65 ml_, 0.284 mol, 1 equiv). The mixture was slowly heated at reflux with stirring for 5 hours. The reaction was cooled and 1 N NaOH solution (1.0 L) and water (2.0 L) were added. The aqueous phase was washed with Et 2 0 and then acidified with 1 N HCI solution to pH 2.
  • Step 4 To a stirred suspension of 60% NaH (2 g, 50.387 mmol, 1.3 equiv) in DMF (50 ml_) was added 1-(4-bromo-3-fluorophenyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (10 g, 38.759 mmol, 1 equiv) at 0 °C, then stirred for 30 min and 2-(bromomethyl)-1 ,4-difluorobenzene (9.6g, 46.511 mmol, 1.2 equiv) was added at 0 °C. The reaction mixture was stirred for 2.5h at room temperature and quenched with ice water.
  • Step 5 Boronate ester isolation: A mixture of 1-(4-bromo-3-fluorophenyl)-4-(2,5- difluorobenzyl)-1/-/-1 ,2,4-triazol-5(4/-/)-one (11.2 g, 39.436 mmol, 1 equiv), bis(pinacolato)diboron (15 g, 59.154 mmol, 1.5 equiv) and potassium acetate (1 1.59 g, 118.309 mmol, 3 equiv) in 250 ml_ of 1 ,4-dioxane was degassed with nitrogen for 15 min, PdCI2(dppf)-CH 2 CI 2 adduct (1.6 g, 1.971 mmol, 0.05 equiv) was added and the reaction mixture was stirred at 100 °C for overnight in sealed vessel.
  • Step 1 To a stirred suspension of 1-(4-bromo-3-fluorophenyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (0.5 g , 1.94 mmol, 1 equiv) in DMF (30 mL) , at 0°C under N 2 atmosphere , 60% NaH (0.078 g, 1.94 mmol, 1 equiv) was added portion wise, then stirred for 20 minutes. A solution of (bromomethyl)benzene in THF was added and the reaction mixture was stirred for 2 h at room temperature, after completion of the reaction the reaction mixture was quenched with ice water, extracted with EtOAc (2 x 30 mL).
  • Step 2 To a stirred solution of 4-benzyl-1-(4-bromo-3-fluorophenyl)-1/-/-1 ,2,4-triazol-5(4/-/)- one (0.520 g, 1.494 mmol, 1.0 equiv), was added bis(pinacolato)diboron (0.130 g, 1.494 mmol, 1.0 equiv), potassium acetate (0.440 g, 1.494 mmol, 3.0 equiv), and the mixture was degassed with Argon for 10 min, PdCI 2 (dppf)-CH 2 CI 2 adduct (0.061 g, 0.075 mmol,0.05 equiv) was added and again degassed with Argon for 10 min.
  • the reaction mixture was stirred for 5h at 100 °C in a sealed vessel.
  • the reaction mixture was cooled to room temperature, 5-bromo-7-methyl-7/-/- pyrrolo[2,3-d]pyrimidin-4-amine (0.340 g, 1.494 mmol, 1.0 equiv) and saturated aqueous NaHC0 3 (5 mL) was added to the reaction mixture and Argon gas was bubbled through the mixture for 10 min.
  • PdCI 2 (dppf)-CH 2 CI 2 adduct (0.061 g, 0.075 mmol,0.05 equiv ) was added to the reaction mixture, the vessel was sealed and the reaction mixture was stirred overnight at 100 °C .
  • Step 1 To a stirred solution of ethyl acetimidate hydrochloride in DCM was added DIPEA at 0°C and stirred for 30 min, then added ethylchloroformate dropwise into the reaction mixture and allowed the reaction mixture to stir at room temperature for 3h. The reaction mixture was filtered through celite and filtrate was concentrated to give ethyl N- ethoxycarbonylacetimidate (3.8 g crude) as pale yellow oil.
  • Step 2 Ethyl /V-ethoxycarbonylacetimidate (0.8 g, 4.96 mmol, 1.2 equiv), (4-bromo-3- fluorophenyl)hydrazine hydrochloride (1.0 g, 4.14mmol, 1.0 equiv) and Et 3 N (0.7 mL, 4.96 mmol, 1.2 equiv) were taken in toluene and stirred for 1 h at 45°C, then heated to 100°C & stirred for overnight.
  • Step 3 To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-methyl-1 /-/-1 ,2,4-triazol- 5(4/-/)-one (0.16g, 0.585 mmol, 1.0 equiv) in DMF (10.0 ml_) was added NaH (60 % in oil) (0.015g, 0.647 mmol, 1.1 equiv) at 0°C and stirred for 30 min. 2,5-Difluorobenzylbromide (0.08 ml_, 0.647 mmol, 1.1 equiv) was added and continued stirring for another 2h at 0°C.
  • Step 4 To a mixture of 1-(4-bromo-3-fluorophenyl)-4-(2,5-difluorobenzyl)-3-methyl-1 /-/- 1 ,2,4-triazol-5(4/-/)-one (0.13 g, 0.33 mmol, 1.0 equiv), bis(pinacolato)diboron (0.099 g, 0.39 mmol, 1.2 equiv), and potassium acetate (0.081 g, 0.825 mmol, 2.5 equiv) was added 1 ,4-dioxane (10 ml_), and the mixture was degassed with N 2 for 10 minutes.
  • Step 5 A mixture of 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-3-methyl-1 /-/-1 ,2,4-triazol-5(4/-/)-one (0.1 g, 0.215 mmol, 1.0 equiv), 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.048 g, 0.215 mmol, 1.0 equiv) and potassium phosphate (0.091 g, 0.43 mmol, 2 equiv) in 1 ,4-dioxane: water (4 mL: 1 mL) was degassed with N 2 for 15 minute.
  • Step 1 To a stirred solution of (2,5-difluorophenyl)methanamine (5.0 g, 34.9 mmol, 1 equiv) in pyridine (20 mL) was added phenyl carbonochloridate (4.9 mL, 38.4 mmol, 1.1 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. The solvents were completely evaporated and 1 M hydrazine solution in THF (20 mL) was added and the mixture was heated to 50°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature and solvents were completely evaporated to obtain crude product which was extracted in to ethyl acetate.
  • Step 2 To a stirred solution of A/-(2,5-difluorobenzyl)hydrazinecarboxamide (3.3 g, 16.41 mmol, 1 equiv) in THF (30 mL) was added ethyl formate (2.0 mL, 24.6 mmol, 1.5 equiv) at room temperature and heated to 50 °C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature and solvents were completely evaporated to obtain crude product. The product was extracted in to ethyl acetate.
  • Step 3 To a stirred solution of A/-(2,5-difluorobenzyl)-2-formylhydrazinecarboxamide (2.0 g, 8.73 mmol, 1 equiv) in 3N NaOH (20 ml_) was refluxed for 12 hours. The reaction mixture was allowed to cool to room temperature and neutralized with 6N HCI solution. The crude product was extracted in 5% MeOH : DCM solution.
  • Step 4 To a stirred solution of 4-(2,5-difluorobenzyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (1.0 g, 4.73 mmol, 1.0 equiv), 5-bromo-2-iodopyridine (1.6 g, 5.68 mmol, 1.2 equiv), and CsF (2.2 g, 14.2 mmol, 3.0 equiv) in EtOAc (25 ml_) was added DM EDA (0.05 ml_, 0.47 mmol, 0.1 equiv) followed by Cul (0.05 g, 0.23 mmol, 0.05 equiv). The reaction mixture was stirred at room temperature for 24 h.
  • Step 5 To a stirred solution of 1-(5-bromopyridin-2-yl)-4-(2,5-difluorobenzyl)-1 /-/-1 ,2,4- triazol-5(4/-/)-one (0.1 g, 0.27 mmol, 1 equiv) in 1 ,4-dioxane (6 ml_) was added bis(pinacolato)diboron (0.07 g, 0.27 mmol, 1 equiv), and potassium acetate (0.08 g, 8.1 mmol, 3 equiv). The reaction mixture was degassed with N 2 for 15 minutes.
  • Step 1 To a stirred solution of 4-chloro-7/-/-pyrrolo[2,3-c]pyrimidine (5.0 g, 32.56 mmol, 1 equiv) in DMF (50 mL) was added 60% sodium hydride (1.5 g, 39.07 mmol, 1.2 equiv) at 0°C and stirred for 15 min followed by addition of (2-(chloromethoxy)ethyl)trimethylsilane (5.7 mL, 32.56 mmol, 1.0 equiv) at same temperature. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice water. The crude product was extracted in to ethyl acetate.
  • Step 2 Run-1 : To a stirred solution of 4-chloro-7-((2-(trimethylsilyl) ethoxy) methyl)-7/-/- pyrrolo [2,3-d]pyrimidine (1.0 g, 3.52 mmol, 1.0 equiv), in THF (20 mL) was added LDA (1.9 mL, 3.82 mmol, 1.1 equiv) at -78°C under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 15 minutes. Methyl iodide (1.1 mL, 17.96 mmol, 5.1 equiv) was added at -78°C and the reaction mixture was stirred at the same temperature for 1 h.
  • LDA 1.9 mL, 3.82 mmol, 1.1 equiv
  • Run-2 To a stirred solution of 4-chloro-7-((2-(trimethylsilyl) ethoxy) methyl)-7/-/-pyrrolo [2,3-c]pyrimidine (7.0 g, 25.06 mmol, 1.0 equiv), in THF (150 mL) was added LDA (14 mL, 27.56 mmol, 1.1 equiv) at -78°C under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 15 minutes. Methyl iodide (9.4 mL, 150.41 mmol, 5.1 equiv) was added at -78°C and the reaction mixture was stirred at the same temperature for 1 h.
  • Step 3 Run-1 : To a stirred suspension of 4-chloro-6-methyl-7-((2- (trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-c]pyrimidine (2.0 g , 6.71 mmol, 1 equiv) in DCM (20 mL) was added TFA (3.0 g, 26.84 mmol, 4.0 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 h at room temperature. The reaction mixture was quenched with sat. NaHC0 3 solution at 0°C and extracted in to ethyl acetate.
  • Run-2 To a stirred suspension of 4-chloro-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)- 7/-/-pyrrolo[2,3-c]pyrimidine (5.0 g , 16.77 mmol, 1 equiv) in DCM (75 mL) was added TFA (7.6 g, 67.14 mmol, 4.0 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 h at room temperature. The reaction mixture was quenched with sat. NaHC0 3 solution at 0°C and extracted in to ethyl acetate.
  • Step 4 Run-1 : To a stirred solution of (4-chloro-6-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-7- yl)methanol (0.1 g, 0.50 mmol, 1.0 equiv) in THF (5 mL) was added borontrifluoride diethyl ether (0.25 mL, 2.52 mmol, 5.0 equiv. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was quenched with sat. NH 4 CI solution and extracted with ethyl acetate.
  • Run-2 To a stirred solution of (4-chloro-6-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-7-yl)methanol (4.0 g, 20.24 mmol, 1.0 equiv) in THF (50 mL) was added borontrifluoride diethyl etherate (10.7 mL, 101.2 mmol, 5.0 equiv. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was quenched with Sat. NH 4 CI solution and extracted with ethyl acetate.
  • Step 5 Run-1 : To a stirred solution of 4-chloro-6-methyl-7/-/-pyrrolo[2,3-c]pyrimidine (0.1 g, 0.59 mmol, 1.0 equiv), in DMF (5m L) was added 60% sodium hydride (0.035 g, 0.89 mmol, 1.5 equiv) at 0°C and stirred for 15 min at same temperature. Methyl iodide (0.101 g, 0.71 mmol, 1.2 equiv) was added to the reaction mixture at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate.
  • Run-2 To a stirred solution of 4-chloro-6-methyl-7/-/-pyrrolo[2,3-c]pyrimidine (3.0 g, 17.64 mmol, 1.0 equiv), in DMF (50mL) was added 60% sodium hydride (1.0 g, 26.94 mmol, 1.5 equiv) at 0°C and stirred for 15 min at same temperature. Methyl iodide (3.06 g, 21.55 mmol, 1.2 equiv) was added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice waterand extracted with ethyl acetate.
  • Step 6 Run-1 : To a stirred solution of 4-chloro-6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrimidine (0.05 g, 0.27 mmol, 1 equiv) in DCM (5 mL) was added NBS (0.029 g, 0.16 mmol, 0.6 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2h. The reaction mixture was quenched with water and extracted with ethyl acetate.
  • Run-2 To a stirred solution of 4-chloro-6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrimidine (0.6 g, 3.31 mmol, 1 equiv) in DCM (10 mL) was added NBS (0.38 g, 2.15 mmol, 0.6 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2h. The reaction mixture was quenched with water and extracted in to ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain 5-bromo-4-chloro-6,7- dimethyl-7/-/-pyrrolo[2,3-c]pyrimidine (0.65 g, crude) as pale yellow solid.
  • Step 7 To a stirred solution of 5-bromo-4-chloro-6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrirTiidine ( 0.6 g, 2.5 mmol, 1 equiv) in 1 ,4-dioxane (5 ml_) was added NH 4 OH (10 ml_) at room temperature. The reaction mixture was heated to 100°C in an autoclave and stirred for 16h. The reaction mixture was cooled and the solids formed were filtered to obtain 5- bromo-6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.3 g, 50%) as pale yellow solid.
  • Step 8 To a stirred solution of 1 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (0.4 g, 0.92 mmol, 1 equiv) in 1 ,4-dioxane (30 mL) was added 5-bromo-6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.2 g, 0.83 mmol, 0.9 equiv), tripotassium phosphate (0.39 g, 1.85 mmol, 2.0 equiv) and water (7mL).
  • the reaction mixture was degassed with N 2 for 15 minutes.
  • Pd 2 (dba) 3 (0.04 g, 0.046 mmol, 0.05 equiv) and (t-Bu) 3 HPBF 4 (0.026 g, 0.098 mmol, 0.1 equiv) was added and degassed with N 2 for 5 minutes.
  • the reaction mixture was stirred for 10 h at 100 °C in a sealed vessel.
  • the reaction mixture was cooled to room temperature and evaporated to obtain crude product.
  • the crude product was purified over silica gel flash column chromatography. The compound eluted out in 3% MeOH:DCM along with some impurity and was purified by preparative HPLC.
  • Step 1 To a stirred solution of 5-bromo-4-chloro-67-dimethyl-7/-/-pyrrolo[2,3-c]pyrirTiidine (1.0 g, 3.83 mmol, 1 equiv) in DCM (10 ml_) was added NBS (0.81 g, 4.59 mmol, 1.2 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with water (20 ml_) and extracted in to ethyl acetate (2 ⁇ 50 ml_).
  • Step 2 To a stirred solution of 5-bromo-6-(bromomethyl)-4-chloro-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidine (1.0 g, 2.94 mmol, 1 equiv) in DCM (15 ml_) was added potassium carbonate (0.49 g, 3.53 mmol, 1.2 equiv) and dimethyl amine (2.94 ml_, 2.94 mmol, 1 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for overnight. The reaction mixture was quenched with cold water (30 ml_) and extracted in DCM (3 ⁇ 20 ml_).
  • Step 3 To a stirred solution of 1-(5-bromo-4-chloro-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin- 6-yl)-A/,A/-dimethylmethanamine ( 0.65 g, 2.14 mmol, 1 equiv) in 1 ,4-Dioxane (5 mL) was added NH 4 OH (5 mL) at RT. The reaction mixture was heated at 100°C in an autoclave for over night.
  • Step 4 To a stirred solution of 1 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (0.5 g, 1.16 mmol, 1 equiv) in 1 ,4-dioxane (10 mL) was added 5-bromo-6-((dimethylamino)methyl)-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-4-amine (0.2 g, 0.83 mmol, 1.0 equiv), sodium bicarbonate (0.194 g, 2.32 mmol, 2.0 equiv) and water (4mL).
  • reaction mixture was degassed with N 2 for 15 minutes.
  • Pd(PPh 3 ) 4 (0.067 g, 0.058 mmol, 0.05 equiv) was added and degassed with N 2 for further 5 minutes.
  • the reaction mixture was stirred for 2 h at 100 °C under microwave.
  • the reaction was cooled to room temperature and evaporated to obtain crude product which was purified over silica gel flash column chromatography. The compound eluted out in 2.8% MeOH:DCM.
  • Step 1 To a stirred suspension of 2-(4-bromo-3-fluorophenyl)-2,4-dihydro-3H-1 ,2,4- triazol-3-one (0.74 g , 2.87 mmol, 1 equiv) in DMF (15 mL) at 0°C under N 2 atmosphere, 60% NaH (0.138 g, 3.44 mmol, 1.2 equiv) was added portion wise, then stirred for 20 minutes. A solution of 1-(bromomethyl)-3,5-dimethylbenzene (0.628 g, 3.154 mmol, 1.1 equiv) in DMF was added and the reaction mixture was stirred for 1 h at room temperature.
  • Step 2 To a stirred solution of 2-(4-bromo-3-fluorophenyl)-4-(3,5-dimethylbenzyl)-2,4- dihydro-3H-1 ,2,4-triazol-3-one (0.6 g, 1.595 mmol, 1.0 equiv) in Dioxane, were added bis(pinacolato)diboron (0.410 g, 1.595 mmol, 1.0 equiv), and potassium acetate (0.470 g, 4.785 mmol, 3.0 equiv), and the mixture was degassed with argon for 15 minutes and then PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.065 g, 0.07975 mmol, 0.05 equiv) was added and again degassed with argon for 10 minutes.
  • bis(pinacolato)diboron (0.410 g, 1.595 mmol, 1.0 equiv)
  • potassium acetate 0.470 g
  • the reaction mixture was stirred for 5 hours at 100 °C in a sealed vessel.
  • the reaction mixture was monitored by LCMS for completion, then the reaction was cooled down to room temperature and 5-bromo-7-methyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine (0.362 g, 1.595 mmol, 1.0 equiv) and saturated aqueous NaHC0 3 (6 mL) was added, and argon gas was bubbled through the reaction mixture for 15 minutes and PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.065 g, 0.07975 mmol, 0.05 equiv ) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C.
  • Step 1 To a stirred solution of 2,5-dimethylbenzaldehyde (3.0 g, 22.3 mmol, 1 equiv) in MeOH (30 mL) was added sodium borohydride (1.0 g, 26.86 mmol, 1.2 equiv) in two lots at 0°C. The reaction mixture was stirred for 2h at 0°C. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was dried over Na2S04, concentrated under reduced vacuum to afford (2,5- dimethylphenyl)methanol (3.0 g, crude) as pale yellow liquid .
  • Step 2 To a stirred solution of (2,5-dimethylphenyl)methanol (3.0 g, 22.05 mmol, 1 equiv) in DCM (30 mL) was added Phosphorous tribromide (1.3 mL, 13.23 mmol, 0.6 equiv) at 0°C. The reaction mixture was stirred for 2h at 0°C. The reaction mixture was quenched with water and extracted with EtOAc . The combined organic layer was dried over Na2S04, concentrated under reduced vacuum to afford 2-(bromomethyl)-1 ,4- dimethylbenzene (4.5 g, crude) as pale yellow liquid.
  • H NMR 400 MHz, CDCI 3 ) ⁇ ppm 2.30 (s, 3H), 2.36 (s, 3H), 4.49 (s, 2H), 7.01-7.07 (m, 2H), 7.12 (s, 1 H).
  • Step 3 To a stirred suspension of 2-(4-bromo-3-fluorophenyl)-2,4-dihydro-3H-1 ,2,4- triazol-3-one (3.0 g , 1 1.62 mmol, 1 equiv) in DMF (50 mL) was added 60% NaH (0.55 g, 13.95 mmol, 1.2 equiv) at 0°C and the mixture was stirred for 30 min at 0°C. 2- (bromomethyl)-1 ,4-dimethylbenzene (2.8 g, 13.95 mmol, 1.2 equiv) was added to the reaction mixture at 0°C. The reaction mixture was stirred for 2.5 h at room temperature.
  • Step 4 To a stirred solution of 2-(4-bromo-3-fluorophenyl)-4-(2,5-dimethylbenzyl)-2,4- dihydro-3H-1 ,2,4-triazol-3-one (2.0 g, 5.31 mmol, 1.0 equiv) in Dioxane (100 ml_), was added bis(pinacolato)diboron (2.0 g, 7.97 mmol, 1.5 equiv) and potassium acetate (1.6 g, 15.95 mmol, 3.0 equiv) at room temperature. The mixture was degassed with Argon for 10 minutes.
  • Step 5 To a stirred solution 4-(2,5-dimethylbenzyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one (0.18 g, 0.42 mmol, 1 equiv) in 1 ,4-Dioxane (30 ml_) was added 3-bromo-1-cyclopropyl-1 H-pyrazolo[3,4- d]pyrimidin-4-amine (0.08 g, 0.31 mmol, 0.75 equiv), tripotassium phosphate (0.18 g, 0.85 mmol, 2.0 equiv) and water (0.5ml_). The reaction mixture was degassed with argon for 10 minutes.
  • Compound 30 is prepared generally according to the above Schemes and the procedures described for Examples 1 to 7, 9, 22, 27 and 28.
  • 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
  • Enzyme Preparation 4X Enzyme Solution was prepared immediately prior to adding to compound plates.
  • 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.
  • An injectable form for administering the present invention is produced by stirring 1.7% by weight of 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)- 4-benzyl-1 H-1 ,2,4-triazol-5(4H)-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.
  • the compounds of Examples 1 to 29 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: ⁇ 5 ⁇ against PERK.
  • the compound of Example 2 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 568 against PERK.
  • Example 9 The compound of Example 9 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 6.4 against PERK.
  • Example 22 The compound of Example 22 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 6.5 against PERK.
  • Example 1 1 The compound of Example 1 1 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 89.4 against PERK.
  • Example 15 The compound of Example 15 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 1435 against PERK.
  • Example 23 The compound of Example 23 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 51 against PERK.
  • Example 27 The compound of Example 27 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 54.8 against PERK.
  • Example 28 The compound of Example 28 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 36.9 against PERK.
  • Example 29 The compound of Example 29 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 269.1 against PERK. While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

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Abstract

The invention is directed to substituted triazolidinone derivatives. Specifically, the invention is directed to compounds according to Formula I: (I) wherein R1, R2, R3, R4, R5, X, Y, Y1, and Z are as defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, pre-cancerous syndromes, as 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-Sträussler-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 disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

Description

TRIAZOLONE COMPOUNDS AS PERK INHIBITORS
FIELD OF THE INVENTION
The present invention relates to substituted triazolone derivatives that are inhibitors of the activity of the protein kinase R (PKR)-like ER kinase, PERK. 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,, ischemic stroke, stroke, Parkinson's 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 disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation.
BACKGROUND OF THE INVENTION
The unfolded protein response (UPR) 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). Environmental stresses that perturb protein folding and maturation in the endoplasmic reticulum (ER) also can lead to activation of the UPR (Feldman et al., 2005), (Koumenis and Wouters, 2006). 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). These perturbations result in disruption of ER redox homeostasis and the accumulation of unfolded or mis-folded proteins in the ER. Cellular responses include transcriptional reprogramming to increase the level of chaperone proteins to enhance protein re-folding, degradation of the mis- folded proteins, and translational arrest to decrease the burden of client proteins entering the ER (Ron, D. 2002), (Harding et al., 2002). These pathways also regulate cell survival by modulating apoptosis (Ma and Hendershot, 2004), (Feldman et al., 2005), and autophagy (Rouschop et al. 2010), and can trigger cell death under conditions of prolonged ER stress (Woehlbier and Hetz, 201 1).
Three ER membrane proteins have been identified as primary effectors of the UPR: protein kinase R (PKR)-like ER kinase [PERK, also known as eukaryotic initiation factor 2A kinase 3 (EIF2AK3), pancreatic ER kinase, or pancreatic elF2a kinase (PEK)], inositol-requiring gene 1 α/β (IRE1), and activating transcription factor 6 (ATF6) (Ma and Hendershot, 2004), (Hetz, 2012). Under normal conditions these proteins are held in the inactive state through binding of the ER chaperone GRP78 (BiP) to their luminal sensor domain. Accumulation of unfolded proteins in the ER leads to release of GRP78 from these sensors resulting in activation of these UPR effectors (Ma et al., 2002), (Hetz, 2012).
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.
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. As a result, 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. For example, the transcription factor ATF4 has 5'-upstream open reading frames (uORFs) that normally represses ATF4 synthesis during normal global protein synthesis. However, 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.
The activation of 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). The common hallmark of all these diseases is the presence of malformed/misfolded or aggregated protein deposits (e.g tau tangles, Lewy bodies, a-synuclein, Αβ plaques, mutant prion proteins) believed to contribute to the underlying disease pathophysiology, neuron loss, and cognitive decline (Prusiner, 2012), (Doyle et al. 2011). The fate of a cell (e.g a neuron) enduring unfolded or misfolded protein stress is under control of PERK. 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) (Unterberger et al. 2006). Furthermore, 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. 2008). Recently, the small molecule PERK inhibitor GSK2606414 was shown to provide a neuroprotective effect and prevent clinical signs of disease in prion infected mice (Moreno et al. 2013), consistent with previous results derived from genetic manipulation of the UPR/PERK/elF2a pathway (Moreno et al. 2012). Involvement of the pathway in ALS (Kanekura et. al., 2009 and Nassif et. al. 2010), spinal cord injury (Ohri et al. 201 1) and traumatic brain injury (Tajiri et al. 2004) is also reported. Taken together these data suggest that the UPR and PERK represent a promising node of drug intervention as a means to halt or reverse the clinical progression and associated cognitive impairments of a wide range of neurodegenerative diseases.
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. Consistent with this, 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). In these studies, activation of the UPR was observed in regions within the tumor that coincided with hypoxic areas. These areas exhibited higher rates of apoptosis compared to tumors with intact UPR signaling. Further evidence supporting the role of PERK in promoting tumor growth is the observation that the number, size, and vascularity of insulinomas arising in transgenic mice expressing the SV40- T antigen in the insulin- secreting beta cells, was profoundly reduced in PERK mice compared to wild-type control (Gupta et al., 2009). Activation of the UPR has also been observed in clinical specimens. 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).
Loss of endoplasmic reticulum homeostasis and accumulation of misfolded proteins can contribute to a number of disease states (Wek and Cavener 2007), (Zhang and Kaufman 2006). 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. 2016), spinal cord injury, traumatic brain injury, stroke, Creutzfeldt-Jakob Disease (CJD) and related prion diseases, such as fatal familial insomnia (FFI), Gerstmann-Straussler-Scheinker Syndrome, and vanishing white matter (VWM) disease. 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. 2009, Liu and Dudley 2016), arrhythmias, and kidney disease (Dickhout et al., 2011 , Cybulsky, A. V., et al. 2005). 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.
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Zhang, W., Feng, D., Li, Y., lida, K., McGrath, B., and Cavener, D. R. (2006). PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is reguired for postnatal glucose homeostasis, Cell Metab 4, 491-7.
Zhang, K. and R. J. Kaufman (2006). The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology 66(2 Suppl 1): S102-109 It is an object of the instant invention to provide novel compounds that are inhibitors of PERK.
It is also an object of the present invention to provide pharmaceutical compositions that comprise a pharmaceutical carrier and compounds of Formula (I).
It is also an object of the present invention to provide a method for treating neurodegenerative diseases, cancer, and other diseases/injuries associated with activated unfolded protein response pathways such as: 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 disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation that comprises administering novel inhibitors of PERK activity.
SUM MARY OF THE INVENTION
The invention is directed to substituted triazolone 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.
Figure imgf000015_0001
wherein R , R2, R3, R4, R5, X, Y, Y1 , and Z are as defined below.
The present invention also relates to the discovery that the compounds of Formula (I) are active as inhibitors of PERK.
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. In a further aspect of the invention there is provided novel processes and novel intermediates useful in preparing the presently invented PERK inhibiting compounds.
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).
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.
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).
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.
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.
DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel compounds of Formula (I) and to the compounds of Formula (I) in the methods of the invention:
Figure imgf000019_0001
is selected from:
bicycloheteroaryl,
substituted bicycloheteroaryl,
heteroaryl, and
substituted heteroaryl,
where said substituted bicycloheteroaryl and said substituted heteroaryl are substituted with from one to five substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
C-|-6alkyl,
C-|-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyloxy,
Ci-4alkyl, -OH, - NH2, cycloalkyl, -COOH, -CF3, -N02 and
-CN,
-OH,
hydroxyC-|-6alkyl,
-COOH, tetrazole,
cycloalkyl,
oxo,
-OC-| -6alkyl,
-CF3,
-CF2H,
-CFH2,
-Ci-6alkylOCi-4alkyl,
-CONH2,
-CON(H)Ci-3alkyl,
-CH2CH2N(H)C(0)OCH2aryl,
diCi-4alkylaminoC-|-4alkyl, aminoCi-6alkyl,
-CN,
heterocycloalkyi,
heterocycloalkyi substituted with from 1 to 4 substituents
independently selected from: Ci-4alkyl, C-|-4alkyloxy, -OH,
-COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02, -NH2 and -CN,
-N02,
-NH2,
-N(H)Ci-3alkyl, and -N(Ci-3alkyl)2;
2
R is selected from:
aryl,
aryl substituted with form one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci-4alkyl, cycloalkyl,
C-|-4alkyloxy, -OH, -COOH, -CF3, -C-|-4alkylOCi-4alkyl, -N02, -NH2, -OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, and -CN, heteroaryl,
heteroaryl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, cycloalkyl,
Ci-4alkyloxy, -OH, -COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02,
-NH2 ,-OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, and -CN, bicycloheteroaryl,
bicycloheteroaryl substituted with from one to five substituents
independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl,
Ci-4alkyloxy, -OH, -COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02,
-NH2, cycloalkyl ,-OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, and -CN, and
cycolalkyl;
3
R is selected from:
hydrogen,
-NH2,
-N(H)Ci.3alkyl,
-N(Ci.3alkyl)2,
-OH,
cycloalkyl,
Ci-6alkyl, and
C-|-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH, -CF3, -Ci-4alkylOC-|-4alkyl, -N02, -NH2 and -CN;
4
R is selected from: hydrogen, C-|-4alkyl, -CF3, -C(H)F2, -CH2F, fluoro, chloro, bromo and iodo;
5
R is selected from: hydrogen, C-|-4alkyl, -CF3, -C(H)F2, -CH2F, fluoro, chloro, bromo and iodo; X is CR1 00 or N,
where R1 00 is selected from: hydrogen, -CH3, fluoro, chloro, bromo and iodo;
Y and Y are independently selected from: hydrogn, -CF3 and C-|-4alkyl, or Y and
Y are taken together with the carbon to which they are attached to form a
C3-C6 cycloalkyl; and
Z is 0 or 1 ; and salts thereof.
This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (I).
Suitably, in the compounds of Formula (I), z is 0.
3
Suitably, in the compounds of Formula (I), R is hydrogen.
Suitably, in the compounds of Formula (I), X is CH.
4
Suitably, in the compounds of Formula (I), R is selected from: hydrogen, methyl, -CF3, fluoro and chloro.
5
Suitably, in the compounds of Formula (I), R is selected from: hydrogen, methyl, -CF3, fluoro and chloro. 2
Suitably, in the compounds of Formula (I), R is phenyl optionally substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo,
Ci-4alkyl, Ci -4alkyloxy, -OH, -COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02, cycloalkyl, -OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, -NH2 and -CN.
Suitably, in the compounds of Formula (I), Y and Y are hydrogen.
Suitably, in the compounds of Formula (I), X is CR1 00, where R1 00 is selected from: hydrogen, -CH3, fluoro, chloro, bromo and iodo.
Suitably, in the compounds of Formula (I), X is N.
Suitably, in the compounds of Formula (I), R is a substituted thieno[2,3- d]pyrimidinyl.
Suitably, in the compounds of Formula (I), R is selected from: substituted pyrrolo[2,3d]pyrimidin-5-yl and substituted pyrazolo[3,4d] pyrimidin-5-yl.
Suitably, in the compounds of Formula (I), R is selected from: 4-amino-7-methyl- 7H-pyrrolo[2,3-d]pyrimidin-5-yl and 4-amino-1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl.
Included in the presently invented compounds of Formula (I) are compounds of Formula (II):
Figure imgf000023_0001
wherein: R1 0 is selected from:
aryl,
aryl substituted with form one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-| -4alkyloxy, -OH,
-COOH, -CF3, -Ci-4alkylOC-|-4alkyl, -N02, -NH2, cycloalkyl,
-OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, and -CN, cycloalkyl,
heteroaryl, and
heteroaryl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy,
-OH, -COOH, -CF3, -Ci -4alkylOC-|-4alkyl, -N02, -NH2, cycloalkyl, -OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, and -CN;
1 1
R is selected from:
hydrogen,
-NH2,
-N(H)Ci.3alkyl,
-N(Ci-3alkyl)2,
-OH,
cycloalkyl,
C-|-6alkyl, and
Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH, -CF3, -Ci -4alkylOC-|-4alkyl, -N02, -NH2 and -CN;
12
R is selected from: hydrogen, C-|-4alkyl, -CF3, -C(H)F2, -CH2F, fluoro and
chloro;
13
R is selected from:
hydrogen,
Ci-6alkyl, diCi -4alkylaminoC-|-4alkyl, and aminoCi -6alkyl;
14
R is selected from:
hydrogen,
cycloalkyl,
heterocycloalkyl,
heterocycloalkyl substituted with from 1 to 4 substituents
independently selected from: Ci_4alkyl, Ci-4alkyloxy, -OH,
-COOH, -CF3, -Ci-4alkylOCi_4alkyl, -N02, -NH2 and -CN,
Ci-6alkyl, and
C-|-6alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, Ci-4alkyloxy, -OH, -CF3 -COOH, -NO2, -NH2 and -CN;
15
R is selected from: hydrogen and -CH3;
16
R is selected from: hydrogen, C-|-4alkyl, -CF3, -C(H)F2, -CH2F, fluoro and
chloro;
101
X is CR or N,
101
where R is selected from: hydrogen, fluoro and chloro; and 10 1 1
Y and Y are independently selected from: hydrogen, -CF3 and C-|-4alkyl, or
1
Y and Y are taken together with the carbon to which they are attached to form a C3-C6 cycloalkyl; and salts thereof.
This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (II). 101 101
Suitably, in the compounds of Formula (II), X is CR , where R is selected from: hydrogen, fluoro and chloro.
Suitably, in the compounds of Formula (II), X is N.
Included in the presently invented compounds of Formula (I) are compounds of Formula (III):
Figure imgf000026_0001
wherein:
R20 is selected from:
phenyl optionally substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci-4alkyl,
Ci-4alkyloxy, -OH, -COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02, cycloalkyl, -OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, -NH2 and -CN, and
cycloalkyl;
21
R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
22
R is is selected from:
hydrogen,
C-|-6alkyl, diCi -4alkylaminoC-|-4alkyl, and aminoC-| -6alkyl;
23
R is selected from:
hydrogen,
cycloalkyl, heterocycloalkyl,
heterocycloalkyl substituted with from 1 to 4 substituents
independently selected from: C-|-4alkyl, C-|-4alkyloxy, -OH,
-COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02, -NH2 and -CN, and
Ci-6alkyl;
24
R is selected from: hydrogen and -CH3;
25
R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
102
X is CR or N,
102
where R is selected from: hydrogen, fluoro and chloro; and 20 21
Y and Y are independently selected from: hydrogen, -CF3 and C-|-4alkyl,
1
or Y and Y are taken together with the carbon to which they are attached to form a C3-C6 cycloalkyl; and salts thereof.
This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (III).
Suitably, in the compounds of Formula (III), X is CH.
21
Suitably, in the compounds of Formula (III), R is hydrogen.
25
Suitably, in the compounds of Formula (III), R is hydrogen.
20
Suitably, in the compounds of Formula (III), R is phenyl optionally substituted with from 1 or 2 substituents independently selected from: fluoro and methyl, suitably methyl. 20 21
Suitably, in the compounds of Formula (III), Y and Y are hydrogen.
22 24
Suitably, in the compounds of Formula (III), R and R are hydrogen.
23
Suitably, in the compounds of Formula (III), R is selected from: methyl and cyclopropyl, suitably methyl.
102 102
Suitably, in the compounds of Formula (III), X is CR , where R is selected from: hydrogen, fluoro and chloro.
Suitably, in the compounds of Formula (III), X is N.
Included in the presently invented compounds of Formula (I) are compounds of Formula (IV):
Figure imgf000028_0001
is selected from:
phenyl optionally substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl,
Ci_4alkyloxy, -OH, -COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02, cycloalkyl, -OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, -NH2 and -CN, and
cycloalkyl; 31
R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
32
R is selected from:
hydrogen,
cycloalkyl,
heterocycloalkyl,
heterocycloalkyl substituted with from 1 to 4 substituents
independently selected from: C-|-4alkyl, C-|-4alkyloxy, -OH,
-COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02, -NH2 and -CN, and
Ci-6alkyl;
33
R is selected from: hydrogen and -CH3;
34
R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
X is CR1 03 or N,
103
where R is selected from: hydrogen, fluoro and chloro;
30 31
Y and Y are independently selected from: hydrogen, CF3 and C-|-4alkyl, or Y and Y are taken together with the carbon to which they are attached to form a C3-C6 cycloalkyl; and salts thereof.
This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (IV).
Suitably, in the compounds of Formula (IV), X is CH.
Suitably, in the compounds of Formula (IV), R is hydrogen.
Suitably, in the compounds of Formula (IV), R is hydrogen. Suitably, in the compounds of Formula (IV), R is phenyl optionally substituted with from 1 or 2 substituents independently selected from: fluoro and methyl, suitably methyl.
30 31
Suitably, in the compounds of Formula (IV), Y and Y are hydrogen.
33
Suitably, in the compounds of Formula (IV), R is hydrogen.
32
Suitably, in the compounds of Formula (IV), R is selected from: methyl and cyclopropyl, suitably methyl.
103 103
Suitably, in the compounds of Formula (IV), X is CR , where R is selected from: hydrogen, fluoro and chloro.
Suitably, in the compounds of Formula (IV), X is N.
Included in the presently invented compounds of Formula (I) are:
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-benzyl- 1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-3-methyl-1 H-1 ,2,4-triazol-5(4H)-one;
4-(4-amino-5-(4-(4-(2,5-difluorobenzyl)-5-oxo-4,5-dihydro-1 H-1 ,2,4-triazol-1-yl)-2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1 , 1-dimethylpiperidin-1-ium iodide;
1-(5-(4-Amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)pyridin-2-yl)-4-(2,5- difluorobenzyl)-1/-/-1 ,2,4-triazol-5(4/-/)-one; 1-(4-(4-Amino-67-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-1/-/-1 ,2,4-triazol-5(4/-/)-one;
1-(4-(4-Amino-6-((dimethylamino)methyl)-7-methyl-7H-pyrrolo[2,3-(^pyrimidin-5- yl)-3-fluorophenyl)-4-(2,5-difluorobenzyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one;
1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(3,5- difluorobenzyl)-1/-/-1 ,2,4-triazol-5(4H)-one ;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pynmidin-5-yl)-3-fluorophenyl)-4-(3,5- dimethylbenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(3,5- dimethylbenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4- (cyclopentylmethyl)-l H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-4-(2,5- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-benzyl-1 H-1 ,2,4- triazol-5(4H)-one;
1-(4-(4-amino-1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-4-benzyl-1 H- 1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-4-(2,5- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(3- chloro-2-fluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,3- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one; 1-(4-(4-amino-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- fluorophenyl)-4-(2,5-difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-4-(2,5- dimethylbenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- dimethylbenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-27-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- dimethylbenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrirnidin-5-yl)-3-fluorophenyl)-4-(2,3,6- trifluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrirnidin-5-yl)-3-fluorophenyl)-4-(3- chloro-2-fluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
2-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrirnidin-5-yl)-3-fluorophenyl)-4-(5- chloro-2-fluorobenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one;
2-(4-(4-amino-1-cyclopropyl-1 H-pyrazolo[3,4-d]pyrirnidin-3-yl)-3-fluorophenyl)-4- (2,5-dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-onedihydro-3H-1 ,2,4-triazol-3-one;
2-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4- (2,5-dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one;
2-(4-(4-amino-1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorophenyl)-4-(2,5- dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one; and
1-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4- (2,5-difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one; and salts thereof including pharmaceutically acceptable salts thereof.
The skilled artisan will appreciate that 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. Where 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. Thus, 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. For compounds of the invention that are in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable 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. The skilled artisan will further appreciate that certain compounds of Formula (I) or salts, including pharmaceutically acceptable salts thereof that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." Polymorphs 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. The skilled artisan will appreciate that different 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.
Definitions
"Alkyl" refers to a hydrocarbon chain having the specified number of "member atoms". For example, 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. Suitably 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]pyridinyl, 1 /-/-pyrazolo[4,3- c] pyridinyl, 1 H-pyrazolo[3,4-d]pyrimidinyl, 1 H-pyrrolo[2,3-d]pyrimidinyl, 7H-pyrrolo[2,3- d] pyrimidinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, furo[2,3-c]pyridinyl, furo[2,3- d]pyrimidinyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5-c]pyridinyl, imidazo[4.5- b]pyridinyl, furopyridinyl and napthyridinyl.
Suitably "Bicycloheteroaryl" includes: 1 H-pyrazolo[3,4-d]pyrimidinyl, 1 H-pyrrolo[2,3- d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, furo[2,3-c]pyridinyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5-c]pyridinyl, imidazo[4.5- b]pyridinyl, furopyrimidinyl and napthyridinyl. Suitably 1 H-pyrazolo[3,4-d]pyrimidinyl, 1 H- pyrrolo[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, indazolyl, quinolinyl, quinazolinyl or benzothiazolyl. Suitably 1 H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl or 1 H-pyrrolo[2,3-d]pyrimidinyl. Suitably 1 H-pyrrolo[2,3- d]pyrimidinyl.
"Cycloalkyl", unless otherwise defined, 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.
"Halo" refers to the halogen radicals fluoro, chloro, bromo, and iodo. "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. Suitably, "heteroaryl" includes: pyrazolyl, pyrrolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and imidazolyl.
"Heterocycloalkyl" refers to a saturated or unsaturated non-aromatic ring containing 4 to 12 member atoms, of which 1 to 11 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-onyl, hexahydro-1 H-azepinyl, 4,5,6,7,tetrahydro-1 H-benzimidazolyl, piperidinyl, 1 ,2,3,6-tetrahydro-pyridinyl and azetidinyl.
"Heteroatom" refers to a nitrogen, sulphur or oxygen atom.
As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification: Ac (Acetyl);
Ac20 (Acetic anhydride);
ACN (Acetonitrile);
AIBN (Azobis(isobutyronitrile));
BINAP (2,2'-Bis(diphenylphosphino)-1 ,1 '-binaphthyl);
BMS (Borane - dimethyl sulphide complex);
Bn (Benzyl);
Boc (Tert-Butoxycarbonyl);
Boc20 (Di-te/f-butyl dicarbonate);
BOP (Benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate);
CAN (Cerric ammonium nitrate);
Cbz (Benzyloxycarbonyl);
CSI (Chlorosulfonyl isocyanate);
CSF (Cesium fluoride);
DABCO (1 ,4-Diazabicyclo[2.2.2]octane);
DAST (Diethylamino)sulfur trifluoride);
DBU (1 ,8-Diazabicyclo[5.4.0]undec-7-ene);
DCC (Dicyclohexyl Carbodiimide);
DCE (1 ,2-Dichloroethane);
DCM (Dichloromethane);
DDQ (2,3-Dichloro-5,6-dicyano-1 ,4-benzoquinone);
ATP (Adenosine triphosphate);
Bis-pinacolatodiboron (4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1 ,3,2-dioxaborolane); BSA (Bovine serum albumin);
C18 (Refers to 18-carbon alkyl groups on silicon in HPLC stationary phase)
CH3CN (Acetonitrile) Cy (Cyclohexyl);
DCM (Dichloromethane);
DIPEA (Hunig's base, /V-ethyl-/V-(1-methylethyl)-2-propanamine);
Dioxane (1 ,4-Dioxane);
DMAP (4-Dimethylaminopyridine);
DME (1 ,2-Dimethoxyethane);
DMEDA (A/./V -Dimethylethylenediamine);
DMF (/V,A/-Dimethylformamide);
DMSO (Dimethylsulfoxide);
DPPA (Diphenyl phosphoryl azide);
EDC (A/-(3-Dimethylaminopropyl)-/\/'ethylcarbodiimide);
EDTA (Ethylenediaminetetraacetic acid);
EtOAc (Ethyl acetate);
EtOH (Ethanol);
Et20 (Diethyl ether);
HEPES (4-(2-Hydroxyethyl)-1-piperazine ethane sulfonic acid);
HATU (0-(7-Azabenzotriazol-1-yl)-/V,A/,A/',A/'-tetramethyluronium hexafluorophosphate);
HOAt (1-Hydroxy-7-azabenzotriazole);
HOBt (1-Hydroxybenzotriazole);
HOAc (Acetic acid);
HPLC (High pressure liquid chromatography);
HMDS (Hexamethyldisilazide);
Hunig's Base (A/,A/-Diisopropylethylamine);
I PA (Isopropyl alcohol);
Indoline (2, 3-Dihydro-1 /-/-indole) ;
KHMDS (Potassium hexamethyldisilazide) ;
LAH (Lithium aluminum hydride) ; LDA (Lithium diisopropylamide) ;
LHMDS (Lithium hexamethyldisilazide)
MeOH (Methanol);
MTBE (Methyl tert-butyl ether);
mCPBA (m-Chloroperbezoic acid);
NaHMDS (Sodium hexamethyldisilazide);
NBS (/V-bromosuccinimide);
PE (Petroleum ether);
Pd2(dba)3 (Tris(dibenzylideneacetone)dipalladium(O);
Pd(dppf)CI2.DCMComplex ([1 ,1 - Bis(diphenylphosphino)ferrocene]dichloropalladium(ll).dichloromethane complex);
PyBOP (Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate);
PyBrOP (Bromotripyrrolidinophosphonium hexafluorophosphate);
RPHPLC (Reverse phase high pressure liquid chromatography);
RT (Room temperature);
Sat. (Saturated)
SFC (Supercritical fluid chromatography);
SGC (Silica gel chromatography);
SM (Starting material);
TCL (Thin layer chromatography);
TEA (Triethylamine);
TEMPO (2,2,6,6-Tetramethylpiperidine 1-oxyl, free radical);
TFA (Trifluoroacetic acid); and
THF (Tetrahydrofuran).
All references to ether are to diethyl ether and brine refers to a saturated aqueous solution of NaCI.
Compound Preparation 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 scheme. All of the starting materials are commercially available or are readily prepared from commercially available starting materials by those of skill in the art.
The skilled artisan will appreciate that if 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). In some instances, 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.
As used in the Schemes, "x" and "r" groups represent corresponding positional groups on any of Formulas I to IV. As used in the Schemes, compounds of formula G and M1 represent all corresponding R substituents of Formula (I). All such substituents can be prepared generally as described in the Schemes.
Compounds of the invention were generally prepared according to Schemes 1 to 3. Substituted aryl hydrazine B was prepared by reacting corresponding aniline A with concentrated HCI, sodium nitrite and stannous chloride. Aryl hydrazine B was reacted with concentrated HCI and 2-oxo acetic acid to obtain corresponding arylhydrazino acetic acid C. Triazolone intermediate D was obtained by reacting intermediate C with TEA and DPPA followed by treatment with a suitable base such as sodium hydroxide. Alkylation of triazolone intermediate D with substituted benzyl, cycloalkyl, or alkyl bromides afforded compound E. After conversion to the boronate ester F, palladium catalyzed Suzuki- Miyaura reaction with the bicycloheteroaryl bromide G produced the compound H, which represents the structure of the compounds of the invention. In some examples of the invention, boronate ester formation and Suzuki-Miyaura reaction were performed in-situ and in some examples the boronate ester was isolated and purified prior to the suzuki- miyaura reaction. Corresponding alkyl or aryl or cycloalkyl bromides used were commercially available. The bicycloheteroaryl bromides G were prepared as per the literature procedures described in J. Med. Chem., 2012, 55 (16), pp 7193-7207 and J. Med. Chem., 2015, 58 (3), pp 1426-1441. Generally, bicycloheteroaryl halides G1 can be prepared similarly and used to make compounds of the invention represented as H.
Scheme 1 ,
Figure imgf000042_0001
= H, F, Me, CI = H, F, Me, CI
x1 = CH, N r3 = Substituted aryl or heteroaryl
or cycloalkyl
x1 = CH, N
Figure imgf000042_0002
r1 = H, F, Me, CI r4 = Me, iPr = H, F, Me, CI
r3 = Substituted aryl or heteroaryl r5 = H, Me r3 = Substituted aryl or heteroaryl or cycloalkyl x2 :■ CH, N or cycloalkyl
x1 = CH, N x1 , x2 = CH, N
i-Pr
Figure imgf000042_0003
G1
x2 = CH, CH-r5, N
x3 = S, O, N-r4
x4 = N, CH
x5 = CI, Br, I
r4 = H, optionally substituted
alkyl or cycloalkyl
r5 = H, Me
The 3-substitutted triazolones of formula N were generally prepared according to Scheme 2. Ethyl acetimidate hydrochloride I was reacted with Ethylchloroformate in presence of base such as DIPEA to give ethyl /V-ethoxycarbonylacetimidate J. Ethoxycarbonylacetimidate J was reacted with aryl hydrazine J1 in presence of base such as triethyl amine to give A/-aryl-3-methyl-triazolone intermediate K. Alkylation of triazolone K followed by boronate ester formation and Suzuki-Miyaura coupling were performed similar to the general Scheme 1 to give compounds of formula N.
Scheme 2
Figure imgf000043_0001
Figure imgf000043_0002
Compounds with a pyridyl linker were generally prepared according to Scheme 3. Substituted hydrazinecarboxamide Z2 was made in two steps by reacting benzyl amine Z with phenyl carbonochloridate Z1 followed by hydrazine hydrate. Z2 was formylated with ethylformate Z3 to give the intermediate Z4. The triazolone was formed by treating Z4 under basic conditions. Arylation of Z5 with bromoiodopyridine Z6 gave the disubstituted triazolone Z7. After conversion to the boronate ester Z8, palladium catalyzed Suzuki- Miyaura reaction with the bicycloheteroaryl bromide G produced compounds of formula H1 , which represents the structure of the compounds of the invention. Scheme 3
Figure imgf000044_0001
Z4 Z5
Z2
Figure imgf000044_0002
r = Substituted aryl or heteroaryl or cycloalkyl
Methods of Use
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.
Suitably, 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.
Suitably the present invention relates to a method for treating or lessening the severity of colon cancer. Suitably 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.
Suitably the present invention relates to a method for treating or lessening the severity of skin cancer, including melanoma, including metastatic melanoma.
Suitably 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.
Suitably 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, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers and testicular cancer.
Suitably 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 precancerous 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.
Suitably 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, neuropathic pain, 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, amyloidosis cognitive impairment, atherosclerosis, ocular diseases, and arrhythmias.
Suitably 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, 71 1-712 (September 2005). Suitably the present invention relates to a method for treating or lessening the severity of ocular diseases/angiogenesis. In embodiments of methods according to the invention, the disorder of ocular diseases, including vascular leakage 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. branch and central retinal vein occlusion); retinal neovascularization due to diabetes, such as retinal vein occlusion, uveitis, ocular ischemic syndrome from carotid artery disease, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, or Eale's Disease; and genetic disorders, such as VonHippel- Lindau syndrome.
In some embodiments, 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 of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, frontotemporal dementias, tauopathies, Pick's disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. Thus, in further aspect, the invention is directed to the use of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disorder characterized by activation of the UPR, such as cancer.
By the term "treating" and derivatives thereof as used herein, 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.
The skilled artisan will appreciate that "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.
As used herein, 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. Furthermore, 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.
As used herein, "patient" or "subject" refers to a human or other animal. Suitably the 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. In addition, 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. As used herein, 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. Where a - COOH or -OH group is present, pharmaceutically acceptable 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.
By the term "co-administration" as used herein 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. The term further active agent or agents, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if 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.
Typically, 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), 6th 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. Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented PERK inhibiting compounds are chemotherapeutic agents.
Suitably, 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/US01/49367, having an International filing date of December 19, 2001 , International Publication Number WO02/0591 10 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. 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/U S01/49367.
Suitably, 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- 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.
5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide is sold commercially as the monohydrochloride salt and is known by the generic name pazopanib and the trade name Votrient®.
Pazopanib is implicated in the treatment of cancer and ocular diseases/angiogenesis. Suitably 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.
In one embodiment, 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.
Suitably, 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.
Suitably, 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.
Suitably, 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.
Suitably, 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.
Suitably, 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.
Compositions
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. Suitably, 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.
The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. 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. Similarly, 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. When a liquid carrier is used, 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.
The pharmaceutical 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. When treating a human patient in need of a PERK inhibitor, 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.
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 disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, ocular diseases, and arrhythmias.
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.
In addition, the pharmaceutically active compounds of the present invention can be co-administered 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.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. EXAMPLES
The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
Intermediate Examples 3 to 5 provide the synthetic methods and corresponding experimental procedures to prepare the bicycloheteroaryl bromide intermediates C6, C9, and C13 used in the Examples.
Intermediate Example 1 : 3-bromo-1-cyclopropyl-1 H-pyrazolo[3,4-d]pyrimidin-4-amine (C6)
Figure imgf000056_0001
C6
Step 1 : To a stirred solution of 4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (2.5 g, 16.23 mmol, 1 equiv) in DCM (30 ml_) was added NBS (3.4 g, 19.48 mmol, 1.2 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for O/N. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate evaporated to obtain crude which was purified over silica gel flash column chromatography. The compound eluted out in 15% ethyl acetate in n-hexane to afford 3-bromo-1 ,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.3 g, crude) as pale yellow solid. H NMR (400 MHz, DMSO-d6) δ ppm - 8.02 (s, 1 H), 12.18 (s, 1 H), 14.00 (br.s, 1 H)
Step 2: To a stirred solution of 3-bromo-1 ,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.3 g, 6.04 mmol, 1 equiv) in Pyridine (30 mL) was added cyclopropyl boronic acid (1.03 g, 12.09 mmol, 2 equiv) and copper acetate (2.18 g , 12.09 mmol, 2 equiv) at room temperature. The reaction mixture was stirred for 2h at 90°C. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate evaporated to obtain crude product, which was purified over silica gel flash column chromatography. The compound eluted out in 2% MeOH in DCM to afford 3- bromo-1-cyclopropyl-1 ,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.2 g, crude) as pale yellow solid. LCMS (ES) m/z = 255.0, 257.0 [M+H. ]+. H NMR (400 MHz, DMSO-d6) δ ppm - 0.16 (m, 1 H), 0.30 (m, 1 H), 0.32 (m, 1 H), 0.37-0.40 (m, 1 H), 2.54 (s, 1 H), 7.21 (s, 1 H), 7.65 (br.s, 1 H)
Step 3: To a stirred solution of 3-bromo-1-cyclopropyl-1 ,5-dihydro-4H-pyrazolo[3,4- d]pyrimidin-4-one (1.2 g, 4.70 mmol, 1 equiv) in dichloro ethane (20 mL) was added DMF (1.2 mL) and POCI3 (1.5 mL) at room temperature. The reaction mixture was stirred for O/N at 80°C. The reaction mixture was quenched with cold Sat. NaHC03 solution (0-5°C) and extracted in ethyl acetate. The organic layer was dried over sodium sulphate, filtered and evaporated to obtain crude product, which was purified over silica gel flash column chromatography. The compound eluted out in 15% EtOAc in n-Hexane to afford 3-bromo- 4-chloro- 1 -cyclopropyl- 1 H-pyrazolo[3,4-d]pyrimidine (0.4 g, 31 %) as off white solid. LCMS (ES) m/z = 273.1 , 275.1 [M+H. ]+. H NMR (400 MHz, CDCI3) δ ppm - 1.20-1.23 (m, 2H), 1.35 (s, 2H), 3.84-3.88 (m, 1 H), 8.77 (s, 1 H)
Step 4: To a stirred solution of 3-bromo-4-chloro-1-cyclopropyl-1 H-pyrazolo[3,4- d]pyrimidine (0.4 g, 1.46 mmol, 1 equiv) in 1 ,4-dioxane (5 mL) was added NH4OH (10 mL) at room temperature. The reaction mixture was heated at 100°C in an autoclave for O/N. The reaction mixture was cooled and the solids formed were filtered to obtain 3-bromo-1- cyclopropyl-1 H-pyrazolo[3,4-d]pyrimidin-4-amine (0.23 g, 61 %) as off white solid. LCMS (ES) m/z = 254.0, 256.0 [M+H. ]+. H NMR (400 MHz, DMSO-d6) δ ppm - 1.02 (d, J=5.6 Hz, 2H), 1.10 (s, 2H), 3.68-3.78 (m, 1 H), 6.20-8.10 (br.s, 2H), 8.19 (s, 1 H)
Intermediate Example 2: 5-bromo-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C9)
Figure imgf000058_0001
Step 1 : Run1 : To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 26.14 mmol, 1 equiv) in Pyridine (40 mL) was added cyclopropyl boronic acid (4.4 g, 52.28 mmol, 2 equiv) and copper acetate (9.4 g , 52.28 mmol, 2 equiv) at room temperature. The reaction mixture was stirred for O/N at 90°C. The reaction mixture was quenched with water and extracted in ethyl acetate. The organic layer was dried over sodium sulphate evaporated to obtain crude product, which was purified over silica gel flash column chromatography. The compound eluted out in 20% EtOAc in n-Hexane to afford 4-chloro- 7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (0.7 g, 14%) as off white solid. LCMS (ES) m/z = 194.1 [M+H. ]+. H NMR (400 MHz, CDCI3) δ ppm - 1.06-1.10 (m, 2H), 1.14-1.21 (m, 2H), 3.50-3.55 (m, 1 H), 6.54 (d, J=3.6 Hz, 1 H), 7.23 (d, J=3.6 Hz, 1 H), 8.67 (s, 1 H)
Run 2: To a stirred suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 16.276 mmol, 1.0 eq), cyclopropyl boronic acid (2.8 g, 32.55 mmol, 2 eq ), sodium Carbonate (3.45 g, 32.5 mmol, 2 eq) in dichloroethne (50 mL) was added a suspension of Cu(OAc)2 (2.95 g, 16.3 mmol, 1.0 eq), and Bipy (2.54 g, 16.3 mmol, 1.0 eq) in hot dichloro ethane (20 mL). The reaction mixture was heated to reflux and stirred for overnight. The reaction was monitored by TLC for completion. The reaction mixture was cooled to room temperature and filtered through celite. The celite bed was thoroughly washed with dichloro ethane. The filtrate was then washed with 1 N HCI, the two layers were separated. The Aq. Phase was extracted with DCM and the combined organic layers were washed with brine, dried over Na2S04, filtered, evaporated and purified by Flash column chromatography. The desired product was eluted in 12% EtOAc in hexane. Fractions containing the desired product were combined and concentrated to afford the desired product 4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine as off-white solid (1.85 g, 53%).
Step 2: To a stirred solution of 4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (0.67 g, 3.47 mmol, 1 equiv) in DCM (20 mL) was added NBS (0.61 g, 3.47 mmol, I .Oequiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate evaporated to obtain 5-bromo-4-chloro-7- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (0.7 g, 75%) as an pale yellow solid. LCMS (ES) m/z = 272.5, 274.5 [M+H. ]+. H NMR (400 MHz, DMSO-d6) δ ppm - 1.02-1.04 (m, 4H), 3.62-3.63 (m, 1 H), 7.95 (s, 1 H), 8.66 (s, 1 H)
Step 3: To a stirred solution of 5-bromo-4-chloro-7-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidine ( 0.7 g, 2.57 mmol, 1 equiv) in 1 ,4-dioxane (5 mL) was added NH4OH (10 mL) at room temperature. The reaction mixture was heated at 100°C in an autoclave for 16h. The reaction mixture was cooled and the solids formed were filtered to obtain 5- bromo-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.63 g, 96%) as off white solid. LCMS (ES) m/z = 253.0, 255.0 [M+H. ]+. H NMR (400 MHz, DMSO-d6) δ ppm - 0.97 (s, 4H), 3.45-3.51 (m, 1 H), 6.64 (br.s, 2H), 7.33 (s, 1 H), 8.09 (s, 1 H)
Intermediate Example 3: 3-bromo-1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-4-amine (C13)
Figure imgf000059_0001
C10 C11 C12 C13
Step 1 : To a stirred solution of 4 4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (2.5 g, 16.17 mmol, 1 equiv) in DMF (50 mL) was added NBS (3.2 g, 17.78 mmol, 1.1 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 3h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate evaporated to obtain 3-bromo-4-chloro-1 H-pyrazolo[3,4- d]pyrimidine (3.5 g, crude) as pale yellow solid. LCMS (ES) m/z = 233.4, 235.4 [M+H. ]+. H NMR (400 MHz, DMSO-d6) δ ppm - 8.82 (s, 1 H), 14.80 (br.s, 1 H)
Step 2: To a stirred solution of 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (3.5 g, 15.02 mmol, 1 equiv) in DMF (60 mL) was added sodium hydride (0.72 g, 18.02 mmol, 1.2 equiv) at 0°C. The reaction mixture was stirred for 15 min at 0°C. Methyl iodide (1.12 mL, 18.02 mmol, 1.2 equiv) was added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 3h. The reaction mixture was quenched with ice water and extracted in ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain crude product, which was purified over silica gel flash column chromatography. The compound eluted out in 30% EtOAc in n-Hexane. Fractions obtained were concentrated to give 3-bromo-4-chloro-1-methyl-1 H-pyrazolo[3,4- d]pyrimidine (2.0 g, 57%) as pale yellow solid. LCMS (ES) m/z = 247.4, 249.4 [M+H. ]+. H NMR (400 MHz, DMSO-d6) δ ppm - 4.03 (s, 3H), 8.88 (s, 1 H) Step 3: To a stirred solution of 3-bromo-4-chloro-1-methyl-1 H-pyrazolo[3,4-d]pyrimidine (2.0 g, 8.09 mmol, 1 equiv) in 1 ,4-dioxane (10 mL) was added NH4OH (30 mL) at room temperature. The reaction mixture was heated at 100°C in an autoclave for O/N. The reaction mixture was cooled and the solids formed were filtered to obtain 3-bromo-1- methyl-1 H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0 g, 45%) as pale yellow crystalline solid. LCMS (ES) m/z = 228.0, 230.0 [M+H. ]+. H NMR (400 MHz, DMSO-d6) δ ppm -3.84 (s, 3H), 6.42-7.20 (br.s, 2H), 7.34-8.52 (br.s, 2H), 8.19 (s, 1 H)
Example 1
1 -(4-(4-Amino-7-methyl-7H-pyrrolor2,3-dlpyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one
Figure imgf000060_0001
Figure imgf000061_0002
Figure imgf000061_0003
Step 1 : To a stirred solution of 4-bromo-3-fluoroaniline (150 g, 0.789 mol, 1 equiv) in Concentrated HCI (756 ml) was added a solution of NaN02 (56.3g, 0.827 mol, 1.05 equiv) in water (390 ml_) at -10 °C and reaction mixture was stirred for 30 min, SnCI2.2H20 (343 g, 2.95 mol, 3.7 equiv) solution in Concentrated HCI (582 ml_) was added. The resulting mixture was warmed to room temperature and stirred for 1 h. The resulting cream color suspension was filtered under vacuum and washed with diethyl ether and dried under vacuum to obtain desired product (4-bromo-3-fluorophenyl)hydrazine hydrochloride as off white solid (155 g, 82 % yield). H NMR (400 MHz, DMSO-d6) δ ppm 6.76-6.78 (d, J = 8.0 Hz, 1 H), 7.01 (d, J = 1 1 Hz, 1 H), 7.56 (t, J = 8.24 Hz, 1 H), 8.73 (br.s, 1 H), 10.46 (br.s, 3H).
Step 2: To a stirred suspension of (4-bromo-3-fluorophenyl)hydrazine hydrochloride (154 g, 0.641 mol, 1 equiv) in Water (1.54 L) was added Concentrated HCI (121.66 ml_) followed by the addition of 50 % aqueous 2-oxo acetic acid (52 g, 0.705 mol, 1.1 equiv) portion wise. The mixture turned to orange and stirred at room temperature for 3 hours. The precipitate was filtered off and washed with water. The orange solid was dissolved in ethyl acetate and washed with water. The organic phase was dried over Na2S04, filtered and evaporated to dryness. Triturating in diisopropyl ether to give desired product (E)-2- (2-(4-bromo-3-fluorophenyl)hydrazono)acetic acid as light yellow powder (75 g, 45.18 % yield). LCMS (ES) m/z = 259, 260.83 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 6.85- 6.87 (m, 1 H), 7.07 - 7.10 (m, 1 H), 7.15 (s, 1 H), 7.53-7.57 (m, 1 H), 1 1.37 (s, 1 H), 12.54 (br.s, 1 H). Step 3: To a stirred suspension of (£)-2-(2-(4-bromo-3-fluorophenyl)hydrazono)acetic acid (74 g, 0.284 mol, 1 equiv) in toluene (740 ml_) was added Et3N (39.91 ml_, 0.284 mol, 1 equiv) and DPPA (61.65 ml_, 0.284 mol, 1 equiv). The mixture was slowly heated at reflux with stirring for 5 hours. The reaction was cooled and 1 N NaOH solution (1.0 L) and water (2.0 L) were added. The aqueous phase was washed with Et20 and then acidified with 1 N HCI solution to pH 2. The precipitate was filtered, washed with water, dissolved in 5% methanol in DCM, washed with a saturated NaCI solution. The organic phase is dried over Na2S04, filtered and evaporated to dryness. Triturating in iPr20 gave 1-(4-bromo-3- fluorophenyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one as light yellow powder (33.0 g, 45.20 % yield). LCMS (ES) m/z = 255.89, 257.90 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 7.71 - 7.80 (m, 2H), 7.89 (dd, J = 2.08, 10.8 Hz, 1 H), 8.19 (s, 1 H), 12.16 (s, 1 H).
Step 4: To a stirred suspension of 60% NaH (2 g, 50.387 mmol, 1.3 equiv) in DMF (50 ml_) was added 1-(4-bromo-3-fluorophenyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (10 g, 38.759 mmol, 1 equiv) at 0 °C, then stirred for 30 min and 2-(bromomethyl)-1 ,4-difluorobenzene (9.6g, 46.511 mmol, 1.2 equiv) was added at 0 °C. The reaction mixture was stirred for 2.5h at room temperature and quenched with ice water. The precipitate was filtered, washed with water and dried to obtain 1-(4-bromo-3-fluorophenyl)-4-(2,5-difluorobenzyl)- 1H-1 ,2,4-triazol-5(4H)-one as off white powder (13.2 g, 88 % yield). LCMS (ES) m/z = 384.0, 386.0 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 4.87 (s, 2H), 6.99 - 7.12 (m, 2H), 7.12 - 7.17 (m, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 7.59 (s, 1 H), 7.73 (dd, J = 1.6, 8.8 Hz, 1 H), 7.86 (dd, J = 2, 10.4 Hz, 1 H).
Step 5: Boronate ester isolation: A mixture of 1-(4-bromo-3-fluorophenyl)-4-(2,5- difluorobenzyl)-1/-/-1 ,2,4-triazol-5(4/-/)-one (11.2 g, 39.436 mmol, 1 equiv), bis(pinacolato)diboron (15 g, 59.154 mmol, 1.5 equiv) and potassium acetate (1 1.59 g, 118.309 mmol, 3 equiv) in 250 ml_ of 1 ,4-dioxane was degassed with nitrogen for 15 min, PdCI2(dppf)-CH2CI2 adduct (1.6 g, 1.971 mmol, 0.05 equiv) was added and the reaction mixture was stirred at 100 °C for overnight in sealed vessel. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude was purified by flash column chromatography with 80 g silica gel cartridge using gradient elution of 10% EtOAc in hexane to 50% EtOAc in hexane. The collected fractions with pure product were combined and concentrated in vacuo to afford 4-(2,5-difluorobenzyl)-1-(3-fluoro-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1/-/-1 ,2,4-triazol-5(4/-/)-one (8.1 g) as off white solid. LC-MS (ES) m/z = 432.2 [M+H]+.
Step 6: Suzuki-Miyaura reaction:
Run1 : A mixture of 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (2 g, 4.640 mmol, 1 equiv), 5-bromo- 7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (1 g, 4.640 mmol, 1 equiv), K3P04 (1.96 g, 9.280 mmol, 2.0 equiv) and Pd2(dba)3 (0.21 g, 0.232 mmol, 0.05 equiv) in 60 ml_ of 1 ,4- dioxane and 20 ml_ of water in a sealed tube was bubbled with nitrogen for 10 min, tri-(t- butyl)phosphonium tetrafluoroborate (0.134 g, 0.464 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 100 °C for overnight in a sealed vessel. After completion of reaction mixture, the mixture was cooled to room temperature, filtered through Celite and the filtrate was concentrated in vacuo to afford crude product (3 g, crude). LC-MS (ES) m/z = 452.1 [M+H]+.
Run 2: A mixture of 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (5 g, 11.60 mmol, 1 equiv), 5-bromo- 7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (2.6 g, 1 1.60 mmol, 1 equiv), K3P04 (4.9 g, 23.201 mmol, 2.0 equiv) and Pd2(dba)3 (0.53 g, 0.58 mmol, 0.05 equiv) in 100 ml_ of 1 ,4- dioxane and 30 ml_ of water in a 250 ml_ sealed tube was bubbled with nitrogen for 15 min, tri-(t-butyl)phosphonium tetrafluoroborate (0.336 g, 1.160 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 100 °C overnight in a sealed vessel. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through Celite and the filtrate was concentrated in vacuo to afford crude product. The crude was purified by flash column chromatography with 80 g silica gel cartridge using gradient elution of 0 to 2% MeOH in DCM and the desired product eluted at 2% MeOH in DCM. The collected fractions with pure product were combined and concentrated in vacuo. The solid product was triturated with diether (3 x 30ml_) and dried to afford 1-(4- (4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-difluorobenzyl)- 1/-/-1 ,2,4-triazol-5(4/-/)-one as off white solid (5.43 g, 74 % yield, combined yield of run 1 and run 2). LC-MS (ES) m/z = 452.1 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3H), 4.95 (s, 2H), 6.02 (br.s, 2H), 7.21 - 7.33 (m, 4H), 7.47 (t, J = 8.4 Hz, 1 H), 7.80 - 7.83 (m, 2H), 8.13 (s, 1 H), 8.36 (s, 1 H). 99.72% of purity by HPLC @ 254 nM.
Example 2
1 -(4-(4-Amino-7-methyl-7H-pyrrolor2,3-dlpyrimidin-5-yl)-3-fluorophenyl)-4-benzyl-
1 HA .2.4-triazol-5(4H)-one
Figure imgf000063_0001
Figure imgf000064_0001
Step 1 : To a stirred suspension of 1-(4-bromo-3-fluorophenyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (0.5 g , 1.94 mmol, 1 equiv) in DMF (30 mL) , at 0°C under N2 atmosphere , 60% NaH (0.078 g, 1.94 mmol, 1 equiv) was added portion wise, then stirred for 20 minutes. A solution of (bromomethyl)benzene in THF was added and the reaction mixture was stirred for 2 h at room temperature, after completion of the reaction the reaction mixture was quenched with ice water, extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine solution and dried over Na2S04 and concentrated. The crude material was purified by flash column chromatography using silicagel column, compound was eluted at 21-23 % EtOAc:Hexane to obtain desired product 4-benzyl-1-(4-bromo-3- fluorophenyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one as light yellow solid (0.52 g, 65.3% yield). LCMS (ES) m/z = 348.0, 350.0 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 4.88 (s , 2 H), 7.29 - 7.39 (m , 5H ), 7.72 - 7.74 (m , 1 H), 7.79 (t , J = 7.6 Hz, 1 H), 7.87 - 7.90 (m , 1 H ), 8.42 (s, 1 H).
Step 2: To a stirred solution of 4-benzyl-1-(4-bromo-3-fluorophenyl)-1/-/-1 ,2,4-triazol-5(4/-/)- one (0.520 g, 1.494 mmol, 1.0 equiv), was added bis(pinacolato)diboron (0.130 g, 1.494 mmol, 1.0 equiv), potassium acetate (0.440 g, 1.494 mmol, 3.0 equiv), and the mixture was degassed with Argon for 10 min, PdCI2(dppf)-CH2CI2 adduct (0.061 g, 0.075 mmol,0.05 equiv) was added and again degassed with Argon for 10 min. The reaction mixture was stirred for 5h at 100 °C in a sealed vessel. The reaction mixture was cooled to room temperature, 5-bromo-7-methyl-7/-/- pyrrolo[2,3-d]pyrimidin-4-amine (0.340 g, 1.494 mmol, 1.0 equiv) and saturated aqueous NaHC03 (5 mL) was added to the reaction mixture and Argon gas was bubbled through the mixture for 10 min. PdCI2(dppf)-CH2CI2 adduct (0.061 g, 0.075 mmol,0.05 equiv ) was added to the reaction mixture, the vessel was sealed and the reaction mixture was stirred overnight at 100 °C . The reaction mixture was cooled to room temperature and filtered through celite, the filtrate was dried over Na2S04 and concentrated. The crude material was purified by flash column chromatography using silicagel column using 4-5 % MeOH in DCM as an eluent to obtain 1-(4-(4- amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-benzyl-1 /-/-1 ,2,4-triazol- 5(4/-/)-one as off white solid (0.044 g, 7.1 %). LCMS (ES) m/z = 416.2 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (s, 3H), 4.91 (s, 2H), 6.03 (br.s, 2H), 7.33 - 7.41 (m, 6H), 7.48 (t, J = 9.2 Hz, 1 H), 7.84 (t, J = 6.0 Hz, 2H), 8.14 (s, 1 H), 8.42 (s, 1 H). 99.79% of purity by HPLC @ 254 nM. Example 3
1 -(4-(4-Amino-7-methyl-7H-pyrrolor2,3-dlpyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-3-methyl-1 H-1 ,2,4-triazol-5(4H)-one
Figure imgf000065_0001
Step 1 : To a stirred solution of ethyl acetimidate hydrochloride in DCM was added DIPEA at 0°C and stirred for 30 min, then added ethylchloroformate dropwise into the reaction mixture and allowed the reaction mixture to stir at room temperature for 3h. The reaction mixture was filtered through celite and filtrate was concentrated to give ethyl N- ethoxycarbonylacetimidate (3.8 g crude) as pale yellow oil. HNMR(CDCI3, 400MHz) 1.18 - 1.32 (m, 6H), 2.08 (s, 3H), 4.1 1 - 4.22 (m, 4H).
Step 2: Ethyl /V-ethoxycarbonylacetimidate (0.8 g, 4.96 mmol, 1.2 equiv), (4-bromo-3- fluorophenyl)hydrazine hydrochloride (1.0 g, 4.14mmol, 1.0 equiv) and Et3N (0.7 mL, 4.96 mmol, 1.2 equiv) were taken in toluene and stirred for 1 h at 45°C, then heated to 100°C & stirred for overnight. The reaction mixture was concentrated under reduced pressure and crude product was purified by flash chromatography on silica gel and compound was eluted with 50% EtOAc/Hexane to give 1-(4-bromo-3-fluorophenyl)-3-methyl-1 /-/-1 ,2,4- triazol-5(4H)-one (0.18 g, 16 %) as off white solid. LC-MS (ES) m/z = 272.0, 274.0 (M+H)+. H NMR (400 MHz, DMSO-d6) δ ppm 2.15 (s, 3H), 7.66 - 7.85 (m, 3H), 11.94 (s, 1 H).
Step 3: To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-methyl-1 /-/-1 ,2,4-triazol- 5(4/-/)-one (0.16g, 0.585 mmol, 1.0 equiv) in DMF (10.0 ml_) was added NaH (60 % in oil) (0.015g, 0.647 mmol, 1.1 equiv) at 0°C and stirred for 30 min. 2,5-Difluorobenzylbromide (0.08 ml_, 0.647 mmol, 1.1 equiv) was added and continued stirring for another 2h at 0°C. After completion of starting material, the reaction mixture was quenched with ice cold water. The solid obtained was filtered, washed with pentane and dried to give 1-(4-bromo- 3-fluorophenyl)-4-(2,5-difluorobenzyl)-3-methyl-1 H-1 ,2,4-triazol-5(4H)-one (0.14g, 61 %) as off white solid. LC-MS (ES) m/z = 398.0, 400.0 (M+H)+. H NMR (400 MHz, CDCI3) δ ppm 2.27 (s, 3H), 4.88 (s, 2H), 6.97 - 7.25 (m, 3H), 7.55 (t, J = 7.6 Hz, 1 H), 7.26 - 7.53 (m, 1 H), 7.85 - 7.88 (m, 1 H).
Step 4: To a mixture of 1-(4-bromo-3-fluorophenyl)-4-(2,5-difluorobenzyl)-3-methyl-1 /-/- 1 ,2,4-triazol-5(4/-/)-one (0.13 g, 0.33 mmol, 1.0 equiv), bis(pinacolato)diboron (0.099 g, 0.39 mmol, 1.2 equiv), and potassium acetate (0.081 g, 0.825 mmol, 2.5 equiv) was added 1 ,4-dioxane (10 ml_), and the mixture was degassed with N2 for 10 minutes. PdCl2(dppf).CH2Cl2 complex (0.027 g, 0.03 mmol, 0.1 equiv) was added and again the mixture was degassed with N2 for 10 minutes. The reaction mixture was stirred for 15 hours at 100 °C in a sealed vessel. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to give crude product. Crude product was purified by flash chromatography on silica gel and compound was eluted with 25% EtOAc/Hexane to give 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-3-methyl-1 /-/-1 ,2,4-triazol-5(4/-/)-one (0.1 1g, 69%) as off white solid. LC-MS (ES) m/z = 446.2 [M+H]+.
Step 5: A mixture of 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-3-methyl-1 /-/-1 ,2,4-triazol-5(4/-/)-one (0.1 g, 0.215 mmol, 1.0 equiv), 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.048 g, 0.215 mmol, 1.0 equiv) and potassium phosphate (0.091 g, 0.43 mmol, 2 equiv) in 1 ,4-dioxane: water (4 mL: 1 mL) was degassed with N2 for 15 minute. Pd2(dba)3 (0.009 g, 0.01 1 mmol, 0.05 equiv) & tri-tert-butylphosphonium tetrafluoroborate (0.006 g, 0.0215 mmol, 0.1 equiv) were added and the reaction mixture was again degassed for 5 minutes. The vial was sealed and the reaction mixture was heated to 100 °C & stirred for 5h. The reaction mixture was cooled to room temperature and filtered through celite and filtrate was dried over Na2S04 & concentrated to obtain crude compound. Crude product was purified by flash column chromatography using silica gel column chromatography using 2% MeOH : DCM as mobile phase. Fractions containing pure product was concentrated to give 1-(4- (4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-difluorobenzyl)- 3-methyl-1 H-1 ,2,4-triazol-5(4H)-one (0.045g, 43 %) as off white solid. LCMS (ES) m/z = 466.2 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H), 3.72 (s, 3H), 4.95 (s, 2H), 6.01 (br. S., 2H), 7.17 - 7.26 (m, 2H), 7.27 - 7.33 (m, 2H), 7.46 (t, J = 8.4 Hz, 1 H), 7.80 - 7.83 (m, 2H), 8.13 (s, 1 H).
Example 4
4-(4-Amino-5-(4-(4-(2,5-difluorobenzyl)-5-oxo-4,5-dihvdro-1 H-1 ,2,4-triazol-1-yl)-2- fluorophenyl)-7H-pyrrolor2,3-c/lpyrimidin-7-yl)-1 ,1-dimethylpiperidin-1-ium iodide
Figure imgf000067_0001
17 4
1-(4-(4-Amino-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-<^pyrimidin-5-yl)-3-fluorophenyl)- 4-(2,5-difluorobenzyl)-1/-/-1 ,2,4-triazol-5(4/-/)-one (0.1g, 0.187 mmol, 1.0 equiv) in MeOH (2 mL) was added methyl iodide (0.018 mL, 0.280 mmol, 1.5 equiv) in a sealed tube and stirred for overnight at room temperature. The reaction mixture was cooled to room temperature. The solid was filtered, washed with MeOH and dried to give 4-(4-amino-5- (4-(4-(2,5-difluorobenzyl)-5-oxo-4,5-dihydro-1 /-/-1 ,2,4-triazol-1-yl)-2-fluorophenyl)-7/-/- pyrrolo[2,3-d]pyrimidin-7-yl)-1 , 1-dimethylpiperidin-1-ium iodide (0.075g, 60%) as off white solid. LCMS (ES) m/z- 549.3(M+H)+-127. H NMR (DMSO-d6, 400MHz) 2.06 - 2.10 (m, 2H), 2.47 -2.50 (m, 2H), 3.16 (s, 3H), 3.23 (s, 3H), 3.56 - 3.67 (m, 4H), 4.91 - 4.95 (m, 3H), 6.12 (br. S., 2H), 7.22 - 7.34 (m, 3H), 7.49 (t, J = 8.4 Hz, 1 H), 7.69 (s, 1 H), 7.82 - 7.86 (m, 2H), 8.14 (s, 1 H), 8.38 (s, 1 H).
Example 5 l-(5-(4-Amino-7-methyl-7H-pyrrolo[2 -dlpyrimidin-5-yl)pyridin-2-yl)-4-(2,5-difluorobenzv l,2,4-triazol-5(4H)-one
Figure imgf000068_0001
Figure imgf000068_0002
Figure imgf000068_0003
Step 1 : To a stirred solution of (2,5-difluorophenyl)methanamine (5.0 g, 34.9 mmol, 1 equiv) in pyridine (20 mL) was added phenyl carbonochloridate (4.9 mL, 38.4 mmol, 1.1 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. The solvents were completely evaporated and 1 M hydrazine solution in THF (20 mL) was added and the mixture was heated to 50°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature and solvents were completely evaporated to obtain crude product which was extracted in to ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain crude product Λ/-(2,5- difluorobenzyl)hydrazinecarboxamide as an oil (3.3 g, crude). LCMS (ES) m/z = 202.1 [M+H]+.
Step 2: To a stirred solution of A/-(2,5-difluorobenzyl)hydrazinecarboxamide (3.3 g, 16.41 mmol, 1 equiv) in THF (30 mL) was added ethyl formate (2.0 mL, 24.6 mmol, 1.5 equiv) at room temperature and heated to 50 °C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature and solvents were completely evaporated to obtain crude product. The product was extracted in to ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain crude product A/-(2,5-difluorobenzyl)-2- formylhydrazinecarboxamide as an oil (2.0 g, crude). LCMS (ES) m/z = 230.2 [M+H]+. Step 3: To a stirred solution of A/-(2,5-difluorobenzyl)-2-formylhydrazinecarboxamide (2.0 g, 8.73 mmol, 1 equiv) in 3N NaOH (20 ml_) was refluxed for 12 hours. The reaction mixture was allowed to cool to room temperature and neutralized with 6N HCI solution. The crude product was extracted in 5% MeOH : DCM solution. The organic layer was dried over sodium sulphate and evaporated to obtain 4-(2,5-difluorobenzyl)-1 /-/-1 ,2,4- triazol-5(4H)-one as an oil (1.0 g, 56 %). LCMS (ES) m/z = 212.2 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 4.78 (s, 2H), 7.08 - 7.12 (m, 1 H), 7.19 - 7.31 (m, 2H), 7.90 (s, 1 H), 1 1.69 (s, 1 H).
Step 4: To a stirred solution of 4-(2,5-difluorobenzyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (1.0 g, 4.73 mmol, 1.0 equiv), 5-bromo-2-iodopyridine (1.6 g, 5.68 mmol, 1.2 equiv), and CsF (2.2 g, 14.2 mmol, 3.0 equiv) in EtOAc (25 ml_) was added DM EDA (0.05 ml_, 0.47 mmol, 0.1 equiv) followed by Cul (0.05 g, 0.23 mmol, 0.05 equiv). The reaction mixture was stirred at room temperature for 24 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2S04 and evaporated to obtain crude product which was purified over silica gel flash column chromatography. The compound eluted out in 60 % EtOAc: Hexanes. The pure fractions were evaporated to obtain 1-(5- bromopyridin-2-yl)-4-(2,5-difluorobenzyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (0.5 g, 29 %) as yellow solid. LCMS (ES) m/z = 367.0, 369.0 [M+H. ]+. H NMR (400 MHz, DMSO-d6) δ ppm 4.90 (s, 2H), 7.27 - 7.33 (m, 3H), 7.90 - 7.92 (m, 1 H), 8.15 - 8.17 (m, 1 H), 8.32 (s, 1 H), 8.56 - 8.58 (m, 1 H).
Step 5: To a stirred solution of 1-(5-bromopyridin-2-yl)-4-(2,5-difluorobenzyl)-1 /-/-1 ,2,4- triazol-5(4/-/)-one (0.1 g, 0.27 mmol, 1 equiv) in 1 ,4-dioxane (6 ml_) was added bis(pinacolato)diboron (0.07 g, 0.27 mmol, 1 equiv), and potassium acetate (0.08 g, 8.1 mmol, 3 equiv). The reaction mixture was degassed with N2 for 15 minutes. PdCI2(dppf)- CH2CI2 adduct (0.022 g, 0.02 mmol, 0.1 equiv) was added and the mixture was degassed with N2 for an additional 5 minutes. The reaction mixture was stirred for 1 hour at 100 °C in a sealed vessel. The reaction mixture was cooled to room temperature. 5-bromo-7- methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.06 g, 0.27 mmol, 1.0 equiv), saturated aqueous NaHC03 (2 ml_) was added. PdCI2(dppf)-CH2Cl2 adduct (0.022 g, 0.02 mmol, 0.1 equiv) was added and the reaction mixture was degassed with N2 for 5 minutes. The vessel was sealed and the reaction mixture was stirred for further 1 hour at 100 °C. The crude was filtered through celite and the filtrate was evaporated to obtain crude product which was purified over silica gel flash column chromatography. The compound eluted out as a mixture in 2 % MeOH:DCM. The fractions were evaporated to obtain crude which was subjected to purification by manual preparative TLC. The band pertaining to the compound was collected and slurried in 10 % MeOH: DCM solution. The suspension was filtered and the filtrate was evaporated to obtain 1-(5-(4-amino-7-methyl-7/-/-pyrrolo[2,3- d]pyrimidin-5-yl)pyridin-2-yl)-4-(2,5-difluorobenzyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (0.015 g, 13 %) as an off white solid. LCMS (ES) m/z = 435.3 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3H), 4.95 (s, 2H), 6.23 (br. s., 2H), 7.24 - 7.32 (m, 3H), 7.43 (s, 1 H), 7.95 - 7.97 (m, 2H), 8.15 (s, 1 H), 8.32 (s, 1 H), 8.52 (s, 1 H). Example 6
1-(4-(4-Amino-6J-dimethyl-7H-pyrrolor2,3-dlpyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one
Figure imgf000070_0001
Z15 Z16 Z17 Z18
Figure imgf000070_0002
Z19 Z20 Z21 Z22
Figure imgf000070_0003
Step 1 : To a stirred solution of 4-chloro-7/-/-pyrrolo[2,3-c]pyrimidine (5.0 g, 32.56 mmol, 1 equiv) in DMF (50 mL) was added 60% sodium hydride (1.5 g, 39.07 mmol, 1.2 equiv) at 0°C and stirred for 15 min followed by addition of (2-(chloromethoxy)ethyl)trimethylsilane (5.7 mL, 32.56 mmol, 1.0 equiv) at same temperature. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice water. The crude product was extracted in to ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain 4-chloro-7-((2-(trimethylsilyl) ethoxy) methyl)-7/-/-pyrrolo [2,3-d]pyrimidine as brown liquid (8.0 g, 66.0 %). LCMS (ES) m/z = 284.10 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm -0.11 (s, 9H), 0.79-0.81 (m, 2H), 3.50 (t, J= 8.0 Hz, 2H), 5.62 (s, 1 H), 6.68-6.69 (m, 1 H), 7.85 (d, J=4.0 Hz, 1 H), 8.62 (s, 1 H).
Step 2: Run-1 : To a stirred solution of 4-chloro-7-((2-(trimethylsilyl) ethoxy) methyl)-7/-/- pyrrolo [2,3-d]pyrimidine (1.0 g, 3.52 mmol, 1.0 equiv), in THF (20 mL) was added LDA (1.9 mL, 3.82 mmol, 1.1 equiv) at -78°C under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 15 minutes. Methyl iodide (1.1 mL, 17.96 mmol, 5.1 equiv) was added at -78°C and the reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution. The crude reaction mixture was extracted in ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain 4-chloro-6-methyl-7-((2- (trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-c]pyrimidine as brown liquid (1.1 g, crude). LC-MS (ES) m/z = 298.1 [M+H]+.
Run-2: To a stirred solution of 4-chloro-7-((2-(trimethylsilyl) ethoxy) methyl)-7/-/-pyrrolo [2,3-c]pyrimidine (7.0 g, 25.06 mmol, 1.0 equiv), in THF (150 mL) was added LDA (14 mL, 27.56 mmol, 1.1 equiv) at -78°C under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 15 minutes. Methyl iodide (9.4 mL, 150.41 mmol, 5.1 equiv) was added at -78°C and the reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution andextracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain 4-chloro-6-methyl-7-((2- (trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-c]pyrimidine as brown liquid (7.0 g, crude). LC-MS (ES) m/z = 298.1 [M+H]+.
Step 3: Run-1 : To a stirred suspension of 4-chloro-6-methyl-7-((2- (trimethylsilyl)ethoxy)methyl)-7/-/-pyrrolo[2,3-c]pyrimidine (2.0 g , 6.71 mmol, 1 equiv) in DCM (20 mL) was added TFA (3.0 g, 26.84 mmol, 4.0 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 h at room temperature. The reaction mixture was quenched with sat. NaHC03 solution at 0°C and extracted in to ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain (4- chloro-6-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-7-yl)methanol as a pale brown solid (1.0 g, crude). LCMS (ES) m/z = 198.1 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 2.52 (s, 3H), 5.59 (d, J=7.2 Hz, 2H), 6.41 (s, 1 H), 6.57 (t, J=8.0 Hz, 1 H), 8.55 (s, 1 H).
Run-2: To a stirred suspension of 4-chloro-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)- 7/-/-pyrrolo[2,3-c]pyrimidine (5.0 g , 16.77 mmol, 1 equiv) in DCM (75 mL) was added TFA (7.6 g, 67.14 mmol, 4.0 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 h at room temperature. The reaction mixture was quenched with sat. NaHC03 solution at 0°C and extracted in to ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain (4-chloro-6-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-7-yl)methanol as a pale brown solid (3.0 g, crude). LCMS (ES) m/z = 198.1 [M+H]+.
Step 4: Run-1 : To a stirred solution of (4-chloro-6-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-7- yl)methanol (0.1 g, 0.50 mmol, 1.0 equiv) in THF (5 mL) was added borontrifluoride diethyl ether (0.25 mL, 2.52 mmol, 5.0 equiv. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was quenched with sat. NH4CI solution and extracted with ethyl acetate. The organic layer was dried over Na2S04 and evaporated to obtain crude 4-chloro-6-methyl-7/-/-pyrrolo[2,3-c]pyrimidine (0.09 g, crude) as an brown solid. LCMS (ES) m/z = 168.1 [M+H]+.
Run-2: To a stirred solution of (4-chloro-6-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-7-yl)methanol (4.0 g, 20.24 mmol, 1.0 equiv) in THF (50 mL) was added borontrifluoride diethyl etherate (10.7 mL, 101.2 mmol, 5.0 equiv. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was quenched with Sat. NH4CI solution and extracted with ethyl acetate. The organic layer was dried over Na2S04 and evaporated to obtain crude 4-chloro-6-methyl-7/-/-pyrrolo[2,3-c]pyrimidine (0.09 g, crude) as an brown solid. LCMS (ES) m/z = 168.1 [M+H]+.
Step 5: Run-1 : To a stirred solution of 4-chloro-6-methyl-7/-/-pyrrolo[2,3-c]pyrimidine (0.1 g, 0.59 mmol, 1.0 equiv), in DMF (5m L) was added 60% sodium hydride (0.035 g, 0.89 mmol, 1.5 equiv) at 0°C and stirred for 15 min at same temperature. Methyl iodide (0.101 g, 0.71 mmol, 1.2 equiv) was added to the reaction mixture at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain 4-chloro-6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrimidine (0.02 g, crude) as brown solid. LCMS (ES) m/z = 182.1 [M+H ]+.
Run-2: To a stirred solution of 4-chloro-6-methyl-7/-/-pyrrolo[2,3-c]pyrimidine (3.0 g, 17.64 mmol, 1.0 equiv), in DMF (50mL) was added 60% sodium hydride (1.0 g, 26.94 mmol, 1.5 equiv) at 0°C and stirred for 15 min at same temperature. Methyl iodide (3.06 g, 21.55 mmol, 1.2 equiv) was added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice waterand extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain 4-chloro-6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrimidine (0.6g, crude) as brown solid. LCMS (ES) m/z = 182.1 [M+H.]+.
Step 6: Run-1 : To a stirred solution of 4-chloro-6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrimidine (0.05 g, 0.27 mmol, 1 equiv) in DCM (5 mL) was added NBS (0.029 g, 0.16 mmol, 0.6 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain 5-bromo-4-chloro- 6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrimidine (0.02 g, crude) as pale yellow solid. LCMS (ES) m/z = 261.0, 263.0 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm - 2.44 (s, 3H), 3.76 (s, 3H), 8.56 (s, 1 H)
Run-2: To a stirred solution of 4-chloro-6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrimidine (0.6 g, 3.31 mmol, 1 equiv) in DCM (10 mL) was added NBS (0.38 g, 2.15 mmol, 0.6 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2h. The reaction mixture was quenched with water and extracted in to ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain 5-bromo-4-chloro-6,7- dimethyl-7/-/-pyrrolo[2,3-c]pyrimidine (0.65 g, crude) as pale yellow solid. LCMS (ES) m/z = 261.0, 263.0 [M+H. ]+. H NMR (400 MHz, DMSO-d6) δ ppm - 2.44 (s, 3H), 3.76 (s, 3H), 8.56 (s, 1 H)
Step 7: To a stirred solution of 5-bromo-4-chloro-6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrirTiidine ( 0.6 g, 2.5 mmol, 1 equiv) in 1 ,4-dioxane (5 ml_) was added NH4OH (10 ml_) at room temperature. The reaction mixture was heated to 100°C in an autoclave and stirred for 16h. The reaction mixture was cooled and the solids formed were filtered to obtain 5- bromo-6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.3 g, 50%) as pale yellow solid. LCMS (ES) m/z = 241.0, 243.0 [M+H. ]+. H NMR (400 MHz, DMSO-d6) δ ppm - 2.29 (s, 3H), 3.61 (s, 3H), 6.52 (br. s, 2H), 8.56 (s, 1 H).
Step 8: To a stirred solution of 1 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (0.4 g, 0.92 mmol, 1 equiv) in 1 ,4-dioxane (30 mL) was added 5-bromo-6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.2 g, 0.83 mmol, 0.9 equiv), tripotassium phosphate (0.39 g, 1.85 mmol, 2.0 equiv) and water (7mL). The reaction mixture was degassed with N2 for 15 minutes. Pd2(dba)3 (0.04 g, 0.046 mmol, 0.05 equiv) and (t-Bu)3HPBF4 (0.026 g, 0.098 mmol, 0.1 equiv) was added and degassed with N2 for 5 minutes. The reaction mixture was stirred for 10 h at 100 °C in a sealed vessel. The reaction mixture was cooled to room temperature and evaporated to obtain crude product. The crude product was purified over silica gel flash column chromatography. The compound eluted out in 3% MeOH:DCM along with some impurity and was purified by preparative HPLC. Preparative HPLC method - Column: CHIRALPAKIA (250 mm x 20 mm x 5μηι), Mobile Phase: (A)/(B)-0.1 % n-Hexane in Ethanol (50:50); Flow rate: 18 ml/min. Fractions obtained from prep HPLC were concentrated to give 1-(4-(4-amino-6,7-dimethyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-3- fluorophenyl)-4-(2,5-difluorobenzyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (0.04 g, 10 %) as off white solid. LCMS (ES) m/z = 466.1 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H), 3.66 (s, 3H), 4.95 (s, 2H), 5.72 (br. s, 2H), 7.21-7.33 (m, 3H), 7.41 (t, J=8.0 Hz, 1 H), 7.82- 7.85 (m, 2H), 8.07 (s, 1 H), 8.37 (s, 1 H).
Example 7
1-(4-(4-Amino-6-((dimethylamino)methyl)-7-methyl-7H-pyrrolor2,3-c/lpyrimidin-5-yl)-
3-fluorophenyl)-4-(2,5-difluorobenzyl)-1H-1 ,2,4-triazol-5(4H)-one
Figure imgf000074_0001
Figure imgf000074_0002
Step 1 : To a stirred solution of 5-bromo-4-chloro-67-dimethyl-7/-/-pyrrolo[2,3-c]pyrirTiidine (1.0 g, 3.83 mmol, 1 equiv) in DCM (10 ml_) was added NBS (0.81 g, 4.59 mmol, 1.2 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with water (20 ml_) and extracted in to ethyl acetate (2 χ 50 ml_). The organic layer was dried over sodium sulphate and evaporated to obtain 5-bromo-6-(bromomethyl)-4-chloro-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidine as pale yellow solid (1.0 g, 76%). LCMS (ES) m/z = 340.0, 341.9 [M+H]+. H NMR (400 MHz, CDCIs) δ ppm 3.94 (s, 3H), 4.70 (s, 2H), 8.64 (s, 1 H).
Step 2: To a stirred solution of 5-bromo-6-(bromomethyl)-4-chloro-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidine (1.0 g, 2.94 mmol, 1 equiv) in DCM (15 ml_) was added potassium carbonate (0.49 g, 3.53 mmol, 1.2 equiv) and dimethyl amine (2.94 ml_, 2.94 mmol, 1 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for overnight. The reaction mixture was quenched with cold water (30 ml_) and extracted in DCM (3 χ 20 ml_). The organic layer was dried over sodium sulphate and evaporated to obtain crude product, which was purified over silica gel flash column chromatography. The compound eluted out in 20 % EtOAc: Hexanes. The pure fractions were evaporated to obtain 1-(5-bromo-4-chloro-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-6-yl)-/\/,/\/- dimethylmethanamine as off white solid (0.65 g, 72%). LCMS (ES) m/z = 303.0,305.1 [M+H]+. H NMR (400 MHz, CDCI3) δ ppm 2.38 (s, 6H), 3.94 (s, 2H), 3.92 (s, 3H), 8.60 (s, 1 H).
Step 3: To a stirred solution of 1-(5-bromo-4-chloro-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin- 6-yl)-A/,A/-dimethylmethanamine ( 0.65 g, 2.14 mmol, 1 equiv) in 1 ,4-Dioxane (5 mL) was added NH4OH (5 mL) at RT. The reaction mixture was heated at 100°C in an autoclave for over night. The reaction mixture was cooled and the solids formed were filtered to obtain 5-bromo-6-((dimethylamino)methyl)-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.45 g, 75%) as an pale yellow solid. LCMS (ES) m/z = 284.0, 286.0 [M+H. ]+. H NMR (400 MHz, DMSO-d6) δ ppm - 2.19 (s, 6H), 3.53 (s, 2H), 3.68 (s, 3H), 6.65 (br. s, 2H), 8.07 (s, 1 H).
Step 4: To a stirred solution of 1 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one (0.5 g, 1.16 mmol, 1 equiv) in 1 ,4-dioxane (10 mL) was added 5-bromo-6-((dimethylamino)methyl)-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-4-amine (0.2 g, 0.83 mmol, 1.0 equiv), sodium bicarbonate (0.194 g, 2.32 mmol, 2.0 equiv) and water (4mL). The reaction mixture was degassed with N2 for 15 minutes. Pd(PPh3)4 (0.067 g, 0.058 mmol, 0.05 equiv) was added and degassed with N2 for further 5 minutes. The reaction mixture was stirred for 2 h at 100 °C under microwave. The reaction was cooled to room temperature and evaporated to obtain crude product which was purified over silica gel flash column chromatography. The compound eluted out in 2.8% MeOH:DCM. The pure fractions were evaporated and washed with n-Pentane and diethyl ether to give 1-(4-(4-amino-6- ((dimethylamino)methyl)-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-1H-1 ,2,4-triazol-5(4H)-one (0.025 g, 5 %) as white solid. LCMS (ES) m/z = 509.2 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm- 1.98 (s, 6H), 3.27 (s, 1 H), 3.40 - 3.44 (m, 1 H), 3.75(s, 3H), 4.96 (s, 2H), 5.74 (br. s, 2H), 7.24-7.31 (m, 3H), 7.42 (t, J=8.4 Hz, 1 H), 7.82 (s, 1 H), 7.85 (s, 1 H), 8.10 (s, 1 H), 8.38 (s, 1 H).
Example 9:
2-(4-(4-amino-7-methyl-7H-pyrrolor2,3-dlpyrimidin-5-yl)-3-fluorophenyl)-4-(3,5- dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one
Figure imgf000075_0001
Step 1 : To a stirred suspension of 2-(4-bromo-3-fluorophenyl)-2,4-dihydro-3H-1 ,2,4- triazol-3-one (0.74 g , 2.87 mmol, 1 equiv) in DMF (15 mL) at 0°C under N2 atmosphere, 60% NaH (0.138 g, 3.44 mmol, 1.2 equiv) was added portion wise, then stirred for 20 minutes. A solution of 1-(bromomethyl)-3,5-dimethylbenzene (0.628 g, 3.154 mmol, 1.1 equiv) in DMF was added and the reaction mixture was stirred for 1 h at room temperature. After completion of starting material, the reaction mixture was quenched with ice water, and the solids were filtered off and dried. Purification: Crude compound was washed with n-pentane and dried to get off white solid, 2-(4-bromo-3-fluorophenyl)-4-(3,5- dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one, (0.6 g , 55.6 % yield). LCMS (ES) m/z = 376.1 , 378.0 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 2.24 (s , 6 H), 4.78 (s , 2H), 6.95 (br.s, 3H), 7.73 (d , J = 8.8 Hz, 1 H), 7.79 (t , J = 8.0 Hz, 1 H), 7.90 - 7.87 (m , 1 H), 8.39 (s, 1 H).
Step 2: To a stirred solution of 2-(4-bromo-3-fluorophenyl)-4-(3,5-dimethylbenzyl)-2,4- dihydro-3H-1 ,2,4-triazol-3-one (0.6 g, 1.595 mmol, 1.0 equiv) in Dioxane, were added bis(pinacolato)diboron (0.410 g, 1.595 mmol, 1.0 equiv), and potassium acetate (0.470 g, 4.785 mmol, 3.0 equiv), and the mixture was degassed with argon for 15 minutes and then PdCl2(dppf)-CH2Cl2 adduct (0.065 g, 0.07975 mmol, 0.05 equiv) was added and again degassed with argon for 10 minutes. The reaction mixture was stirred for 5 hours at 100 °C in a sealed vessel. The reaction mixture was monitored by LCMS for completion, then the reaction was cooled down to room temperature and 5-bromo-7-methyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine (0.362 g, 1.595 mmol, 1.0 equiv) and saturated aqueous NaHC03 (6 mL) was added, and argon gas was bubbled through the reaction mixture for 15 minutes and PdCl2(dppf)-CH2Cl2 adduct (0.065 g, 0.07975 mmol, 0.05 equiv ) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The crude mixture was filtered through celite and the filtrate was dried over Na2S04 and concentrated. Purification: Flash column chromatography using silicagel column, the compound was eluted at 3.8 % MeOH in DCM, and the product was concentrated and triturated with acetonitrile and dried, 2-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)-3-fluorophenyl)-4-(3,5-dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one, Yield: (0.125 g, 17.68 %) as off white solid. LCMS (ES) m/z = 444.2 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 6H), 3.74 (s, 3H), 4.81 (s, 2H), 6.03 (br.s, 2H), 6.95 (s, 3H). 7.33 (s, 1 H), 7.48 (t, J = 9.2 Hz, 1 H), 7.84 (t, J = 6.8 Hz, 2H), 8.14 (s, 1 H), 8.39 (s, 1 H). 99.90% of purity by HPLC @280 nM.
Example 22:
2-(4-(4-amino-7-methyl-7H-pyrrolor2,3-dlpyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one
Figure imgf000077_0001
Q7
22
To a stirred solution 4-(2,5-dimethylbenzyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one (0.2 g, 0.47 mmol, 1 equiv) in 1 ,4-Dioxane (20 ml_) was added 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.085 g, 0.37 mmol, 0.8 equiv), tripotassium phosphate (0.2 g, 0.94 mmol, 2.0 equiv) and water (0.5ml_).The reaction mixture was degassed with argon for 10 minutes. Pd2(dba)3 (0.021 g, 0.023 mmol, 0.05 equiv) and (tBut)3PHBF4 (0.013 g, 0.047 mmol, 0.1 equiv) were added and degassed with argon for 10 minutes. The reaction mixture was stirred for O/N at 100 °C in a sealed vessel. The reaction was cooled to room temperature. The Reaction mixture was evaporated to obtain crude product, which was purified over silica gel flash column chromatography. The compound eluted out in 2% MeOH:DCM. Fractions obtained were concentrated to give 2-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)-3-fluorophenyl)-4-(2,5-dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one (0.07 g, 33 %) as off white solid. LCMS (ES) m/z = 444.2 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm: 2.23 (s, 3H), 2.28 (s, 3H), 3.73 (s, 3H), 4.84 (s, 2H), 6.03 (br.s, 2H), 6.97 (s, 1 H), 7.03 (d, J=7.2 Hz, 1 H), 7.10 (d, J=7.2 Hz, 1 H), 7.31 (s, 1 H), 7.47 (t, J=8.0 Hz, 1 H), 7.83- 7.86 (m, 2H), 8.13 (s, 1 H), 8.27 (s, 1 H)
Example 27:
2-(4-(4-amino-1-cvclopropyl-1 H-pyrazolor3,4-dlpyrimidin-3-yl)-3-fluorophenyl)-4-
(2,5-dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one
Figure imgf000078_0001
Figure imgf000078_0002
Step 1 : To a stirred solution of 2,5-dimethylbenzaldehyde (3.0 g, 22.3 mmol, 1 equiv) in MeOH (30 mL) was added sodium borohydride (1.0 g, 26.86 mmol, 1.2 equiv) in two lots at 0°C. The reaction mixture was stirred for 2h at 0°C. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was dried over Na2S04, concentrated under reduced vacuum to afford (2,5- dimethylphenyl)methanol (3.0 g, crude) as pale yellow liquid . H NMR (400 MHz, DMSO- d6) δ ppm 2.16 (s, 3H), 2.23 (s, 3H), 4.42 (d, J=8.0 Hz, 2H), 4.94 (t, J=8.0 Hz, 1 H), 6.91 (d, J=8.0 Hz, 1 H), 6.97 (d, J=8.0 Hz, 1 H), 7.13 (s, 1 H).
Step 2: To a stirred solution of (2,5-dimethylphenyl)methanol (3.0 g, 22.05 mmol, 1 equiv) in DCM (30 mL) was added Phosphorous tribromide (1.3 mL, 13.23 mmol, 0.6 equiv) at 0°C. The reaction mixture was stirred for 2h at 0°C. The reaction mixture was quenched with water and extracted with EtOAc . The combined organic layer was dried over Na2S04, concentrated under reduced vacuum to afford 2-(bromomethyl)-1 ,4- dimethylbenzene (4.5 g, crude) as pale yellow liquid. H NMR (400 MHz, CDCI3) δ ppm 2.30 (s, 3H), 2.36 (s, 3H), 4.49 (s, 2H), 7.01-7.07 (m, 2H), 7.12 (s, 1 H).
Step 3: To a stirred suspension of 2-(4-bromo-3-fluorophenyl)-2,4-dihydro-3H-1 ,2,4- triazol-3-one (3.0 g , 1 1.62 mmol, 1 equiv) in DMF (50 mL) was added 60% NaH (0.55 g, 13.95 mmol, 1.2 equiv) at 0°C and the mixture was stirred for 30 min at 0°C. 2- (bromomethyl)-1 ,4-dimethylbenzene (2.8 g, 13.95 mmol, 1.2 equiv) was added to the reaction mixture at 0°C. The reaction mixture was stirred for 2.5 h at room temperature. The reaction mixture was quenched with ice water and extracted with EtOAc. The combined organic layer was dried over Na2S04, concentrated under reduced vacuum to afford 2-(4-bromo-3-fluorophenyl)-4-(2,5-dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3- one (4.0 g, 90%) as pale yellow solid. LCMS (ES) m/z = 376.2, 378.2 [M+H]+. H NMR (400 MHz, DMSO-c/6) δ ppm : 2.22 (s, 3H), 2.27 (s, 3H), 4.81 (s, 2H), 6.98 (s, 1 H), 7.02 (d, J=8.0 Hz, 1 H), 7.09 (d, J=8.0 Hz, 1 H), 7.72-7.80 (m, 2H), 7.89 (d, J=10.0 Hz, 1 H), 8.28 (s, 1 H).
Step 4: To a stirred solution of 2-(4-bromo-3-fluorophenyl)-4-(2,5-dimethylbenzyl)-2,4- dihydro-3H-1 ,2,4-triazol-3-one (2.0 g, 5.31 mmol, 1.0 equiv) in Dioxane (100 ml_), was added bis(pinacolato)diboron (2.0 g, 7.97 mmol, 1.5 equiv) and potassium acetate (1.6 g, 15.95 mmol, 3.0 equiv) at room temperature. The mixture was degassed with Argon for 10 minutes. PdCI2(dppf).DCM adduct (0.43 g, 0.53 mmol, 0.1 equiv) was added and again degassed with Argon for 10 minutes. The reaction mixture was stirred for O/N at 100 °C in a round bottom flask. The reaction mixture was monitored by LCMS, the reaction was cooled to room temperature. The crude mixture was filtered through celite bed and washed with EtOAC. The filtrate was dried over Na2S04 and concentrated under reduced vacuum to afford black residue, which was purified by flash column chromatography using silica gel column, compound was eluted at 15% EtOAc in n-Hexane. Fractions obtained were concentrated to give 4-(2,5-dimethylbenzyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one (1.5 g, 65%) as off white solid. LCMS (ES) m/z = 424.2 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm: 1.28 (s, 12H), 2.22 (s, 3H), 2.27 (s, 3H), 4.81 (s, 2H), 6.99-7.03 (m, 2H), 7.09 (d, J=8.2 Hz, 1 H), 7.70-7.73 (m, 2H), 7.78 (d, J=8.0 Hz, 1 H), 8.28 (s, 1 H).
Step 5: To a stirred solution 4-(2,5-dimethylbenzyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one (0.18 g, 0.42 mmol, 1 equiv) in 1 ,4-Dioxane (30 ml_) was added 3-bromo-1-cyclopropyl-1 H-pyrazolo[3,4- d]pyrimidin-4-amine (0.08 g, 0.31 mmol, 0.75 equiv), tripotassium phosphate (0.18 g, 0.85 mmol, 2.0 equiv) and water (0.5ml_).The reaction mixture was degassed with argon for 10 minutes. Pd2(dba)3 (0.019 g, 0.021 mmol, 0.05 equiv) and (tBut)3PHBF4 (0.012 g, 0.042 mmol, 0.1 equiv) were added and degassed with argon for further 10 minutes. The reaction mixture was stirred for 5 h at 100 °C in a round bottom flask. The reaction mixture was cooled to room temperature and evaporated to obtain crude product, which was purified over silica gel flash column chromatography. The compound eluted out in 3% MeOH:DCM. Fractions obtained were concentrated to give 2-(4-(4-amino-1-cyclopropyl- 1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorophenyl)-4-(2,5-dimethylbenzyl)-2,4-dihydro-3H- 1 ,2,4-triazol-3-one (0.03 g, 20 %) as off white solid. LCMS (ES) m/z = 471.2 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm: 1.04-1.08 (m, 2H), 1.12-1.21 (m, 2H), 2.23 (s, 3H), 2.28 (s, 3H), 3.82-3.88 (m, 1 H), 4.82 (s, 2H), 6.51-6.90 (br.s, 2H), 6.98 (s, 1 H), 7.03 (d, J=8.0 Hz, 1 H), 7.10 (d, J=8.0 Hz, 1 H), 7.61 (t, J=8.0 Hz, 1 H), 7.88-7.91 (m, 2H), 8.22 (s, 1 H), 8.31 (s, 1 H). Example 28:
2-(4-(4-amino-7-cvclopropyl-7H-pyrrolor2,3-dlpyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one
28
To a stirred solution 4-(2,5-dimethylbenzyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one (0.18 g, 0.42 mmol, 1 equiv) in 1 ,4-Dioxane (30 ml_) was added 5-bromo-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4- amine (0.08 g, 0.31 mmol, 0.75 equiv), tripotassium phosphate (0.18 g, 0.85 mmol, 2.0 equiv) and water (0.5ml_).The reaction mixture was degassed with argon for 10 minutes. Pd2(dba)3 (0.019 g, 0.021 mmol, 0.05 equiv) and (tBut)3PHBF4 (0.012 g, 0.042 mmol, 0.1 equiv) was added and degassed with argon for further 10 minutes. The reaction mixture was stirred for 5 h at 100 °C in a RB flask. The reaction was cooled down to room temperature and evaporated to obtain the crude product which was purified over silica gel flash column chromatography. The compound eluted out in 3% MeOH:DCM. Fractions obtained were concentrated to give 2-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one (0.024 g, 20 %) as Off white solid. LCMS (ES) m/z = 470.2 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm: 1.00-1.02 (m, 4H), 2.23 (s, 3H), 2.28 (s, 3H), 3.53-3.58 (m, 1 H), 4.84 (s, 2H), 6.01 (br.s, 2H), 6.98 (s, 1 H), 7.03 (d, J=8.0 Hz, 1 H), 7.10 (d, J=8.0 Hz, 1 H), 7.24 (s, 1 H), 7.48 (t, J=8.0 Hz, 1 H), 7.82-7.86 (m, 2H), 8.13 (s, 1 H), 8.28 (s, 1 H)
Compounds 8, 10 to 21 , 23 to 26 and 29 were prepared generally according to the above Schemes and the procedures described for Examples 1 to 7, 9, 22, 27 and 28.
Table 1.
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Compound 30 is prepared generally according to the above Schemes and the procedures described for Examples 1 to 7, 9, 22, 27 and 28.
Table 2.
Figure imgf000086_0001
Example 31 : 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.
Enzyme assay protocol for PKR-Like Endoplasmic Reticulum Kinase (PERK) - HTRF - % Inhibition
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
Assay Plate Preparation:
1. Enzyme Preparation: 4X Enzyme Solution was prepared immediately prior to adding to compound plates.
3nM of GST-PERK in Assay buffer. Final [PERK] in 10 μΙ assay volume =
0.75nM
2. Substrate Preparation:
4X Substrate solution was prepared immediately prior to adding to compound plates.
4X Substrate solution in assay buffer 2000μΜ ATP and 160 nM Biotin-elF2a . Final [ATP] in 10 μΙ assay
Figure imgf000087_0001
Final [biotin-elF2a] in 10 μΙ assay volume =40 nM.
3. Quench/Detection Solution:
16 nM elF2 Phospho-Antibody
16 nM Eu anti-Rabbit IgG
160 nM Streptavidin-APC
60 mM EDTA
Final concentration in 10 μΙ_ assay volume:4 nM elF2 Phospho-Antibody, 4 nM Eu anti-Rabbit IgG 40 nM Streptavidin-APC
The activity of compounds in the PERK enzyme assay was determined at PERK Enzyme (500 μΜ ATP) IC50 (nM).
Example 32 - Capsule Composition
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.
Table 3
INGREDIENTS AMOUNTS
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- 7 mg
fluorophenyl)-4-(2,5-difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)
one (Compound of Example 1)
Lactose 53 mg
Talc 16 mg
Magnesium Stearate 4 mg Example 33 - Injectable Parenteral Composition
An injectable form for administering the present invention is produced by stirring 1.7% by weight of 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)- 4-benzyl-1 H-1 ,2,4-triazol-5(4H)-one (Compound of Example 2) in 10% by volume propylene glycol in water.
Example 34 Tablet Composition
The 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.
Table 4
INGREDIENTS AMOUNTS
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3 - 12 mg
fluorophenyl)-4-(2,5-difluorobenzyl)-3-methyl-1 H-1 ,2,4- triazol-5(4H)-one (Compound of Example 3)
calcium sulfate dihydrate 30 mg
sucrose 4 mg
starch 2 mg
talc 1 mg
stearic acid 0.5 mg
Biological Activity
Compounds of the invention are tested for activity against PERK in the above assay.
The compounds of Examples 1 to 29 were tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 μΜ ATP) IC50 (nM) value: < 5 μΜ against PERK. The compound of Example 2 was tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 μΜ ATP) IC50 (nM) value of 568 against PERK.
The compound of Example 9 was tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 μΜ ATP) IC50 (nM) value of 6.4 against PERK.
The compound of Example 22 was tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 μΜ ATP) IC50 (nM) value of 6.5 against PERK.
The compound of Example 1 1 was tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 μΜ ATP) IC50 (nM) value of 89.4 against PERK.
The compound of Example 15 was tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 μΜ ATP) IC50 (nM) value of 1435 against PERK.
The compound of Example 23 was tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 μΜ ATP) IC50 (nM) value of 51 against PERK.
The compound of Example 27 was tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 μΜ ATP) IC50 (nM) value of 54.8 against PERK.
The compound of Example 28 was tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 μΜ ATP) IC50 (nM) value of 36.9 against PERK.
The compound of Example 29 was tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 μΜ ATP) IC50 (nM) value of 269.1 against PERK. While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

What is claimed is:
1. A compound according to Formula (I):
Figure imgf000091_0001
wherein:
R is selected from:
bicycloheteroaryl,
substituted bicycloheteroaryl,
heteroaryl, and
substituted heteroaryl,
where said substituted bicycloheteroaryl and said substituted heteroaryl are substituted with from one to five substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
C-|-6alkyl,
C-|-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, cycloalkyl, -COOH, -CF3, -N02, and -CN,
-OH,
hydroxyC-|-6alkyl,
-COOH,
- 89 - tetrazole,
cycloalkyl,
oxo,
-OC-| -6alkyl,
-CF3,
-CF2H,
-CFH2,
-Ci-6alkylOCi-4alkyl,
-CONH2,
-CON(H)Ci-3alkyl,
-CH2CH2N(H)C(0)OCH2aryl,
diCi-4alkylaminoCi-4alkyl, aminoCi-6alkyl,
-CN,
heterocycloalkyi,
heterocycloalkyi substituted with from 1 to 4 substituents
independently selected from: C-|-4alkyl, C-|-4alkyloxy, -OH,
-COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02, -NH2 and -CN,
-N02,
-NH2,
-N(H)Ci-3alkyl, and -N(Ci-3alkyl)2;
2
R is selected from:
aryl,
aryl substituted with form one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, cycloalkyl,
C-|-4alkyloxy, -OH, -COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02, - 90 - -NH2, -OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, and -CN, heteroaryl,
heteroaryl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, cycloalkyl,
Ci-4alkyloxy, -OH, -COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02,
-NH2 ,-OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, and -CN, bicycloheteroaryl,
bicycloheteroaryl substituted with from one to five substituents
independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl,
Ci-4alkyloxy, -OH, -COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02,
-NH2, cycloalkyl ,-OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, and -CN, and
cycolalkyl;
3
R is selected from:
hydrogen,
-NH2,
-N(H)Ci.3alkyl,
-N(Ci.3alkyl)2,
-OH,
cycloalkyl,
Ci-6alkyl, and
C-|-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH, -CF3, -Ci-4alkylOC-|-4alkyl, -N02, -NH2 and -CN;
4
R is selected from: hydrogen, C-|-4alkyl, -CF3, -C(H)F2, -CH2F, fluoro, chloro, bromo and iodo;
5
R is selected from: hydrogen, C-|-4alkyl, -CF3, -C(H)F2, -CH2F, fluoro, chloro, bromo and iodo;
- 91 - X is CR1 00 or N,
where R1 00 is selected from: hydrogen, -CH3, fluoro, chloro, bromo and iodo;
Y and Y are independently selected from: hydrogn, -CF3 and C-|-4alkyl, or Y and
Y are taken together with the carbon to which they are attached to form a
C3-C6 cycloalkyl; and
Z is 0 or 1 ; or a salt thereof including a pharmaceutically acceptable salt thereof.
2. The compound of Claim 1 represented by the following Formula (II):
Figure imgf000094_0001
is selected from:
aryl,
aryl substituted with form one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-| -4alkyloxy, -OH,
-COOH, -CF3, -Ci-4alkylOC-|-4alkyl, -N02, -NH2, cycloalkyl,
-OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, and -CN, cycloalkyl,
heteroaryl, and
heteroaryl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy,
- 92 - -OH, -COOH, -CF3, -Ci -4alkylOC-|-4alkyl, -N02, -NH2, cycloalkyl, -OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, and -CN;
1 1
R is selected from:
hydrogen,
-NH2,
-N(H)Ci-3alkyl,
-N(Ci-3alkyl)2,
-OH,
cycloalkyl,
C-|-6alkyl, and
Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH, -CF3, -Ci -4alkylOC-|-4alkyl, -N02, -NH2 and -CN;
12
R is selected from: hydrogen, C-|-4alkyl, -CF3, -C(H)F2, -CH2F, fluoro and
chloro;
13
R is selected from:
hydrogen,
Ci-6alkyl, diCi -4alkylaminoC-|-4alkyl, and aminoC-| -6alkyl;
14
R is selected from:
hydrogen,
cycloalkyl,
heterocycloalkyi,
heterocycloalkyi substituted with from 1 to 4 substituents
independently selected from: Ci_4alkyl, Ci-4alkyloxy, -OH,
-COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02, -NH2 and -CN, - 93 - C-|-6alkyl, and
C-|-6alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, Ci-4alkyloxy, -OH, -CF3 -COOH, -NO2, -NH2 and -CN;
15
R is selected from: hydrogen and -CH3;
16
R is selected from: hydrogen, Ci_4alkyl, -CF3, -C(H)F2, -CH2F, fluoro and
chloro;
101
X is CR or N,
101
where R is selected from: hydrogen, fluoro and chloro; and 10 1 1
Y and Y are independently selected from: hydrogen, -CF3 and C-|-4alkyl, or
1
Y and Y are taken together with the carbon to which they are attached to form a C3-C6 cycloalkyl; or a salt thereof including a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 or claim 2 represented by the following Formula (III):
Figure imgf000096_0001
wherein:
R20 is selected from:
phenyl optionally substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl,
Ci-4alkyloxy, -OH, -COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02,
- 94 - cycloalkyl, -OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, -NH2 and -CN, and
cycloalkyl;
21
R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
22
R is is selected from:
hydrogen,
Ci-6alkyl, diCi -4alkylaminoC-|-4alkyl, and aminoC-| -6alkyl;
23
R is selected from:
hydrogen,
cycloalkyl,
heterocycloalkyi,
heterocycloalkyi substituted with from 1 to 4 substituents independently selected from: C-|-4alkyl, C-|-4alkyloxy, -OH,
-COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02, -NH2 and -CN, and
Ci-6alkyl;
24
R is selected from: hydrogen and -CH3;
25
R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
102
X is CR or N,
102
where R is selected from: hydrogen, fluoro and chloro; and
20 21
Y and Y are independently selected from: hydrogen, -CF3 and C-|-4alkyl,
1
or Y and Y are taken together with the carbon to which they are attached to form a C3-C6 cycloalkyl; or a salt thereof including a pharmaceutically acceptable salt thereof.
- 95 -
4. The compound of Claim 1 represented by the following Formula (IV):
Figure imgf000098_0001
R ,3' 1
(IV) wherein:
30
R is selected from:
phenyl optionally substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02, cycloalkyl, -OC(H)F2, -C(H)F2, -OCH2F, -CH2F, -OCF3, -NH2 and -CN, and
cycloalkyl;
31
R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
32
R is selected from:
hydrogen,
cycloalkyl,
heterocycloalkyl,
heterocycloalkyl substituted with from 1 to 4 substituents
independently selected from: C-|-4alkyl, C-|-4alkyloxy, -OH,
-COOH, -CF3, -Ci-4alkylOCi-4alkyl, -N02, -NH2 and -CN, and
Ci-6alkyl;
33
R is selected from: hydrogen and -CH3;
34
R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;
X is CR1 03 or N,
103
where R is selected from: hydrogen, fluoro and chloro;
- 96 - 30 31
Y and Y are independently selected from: hydrogen, CF3 and Ci_4alkyl, or Y and Y are taken together with the carbon to which they are attached to form a C3-C6 cycloalkyl; or a salt thereof including a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 selected from:
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-benzyl- 1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-3-methyl-1 H-1 ,2,4-triazol-5(4H)-one;
4-(4-amino-5-(4-(4-(2,5-difluorobenzyl)-5-oxo-4,5-dihydro-1 H-1 ,2,4-triazol-1-yl)-2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1 , 1-dimethylpiperidin-1-ium iodide;
1-(5-(4-Amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)pyridin-2-yl)-4-(2,5- difluorobenzyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one;
1-(4-(4-Amino-6,7-dimethyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one;
1-(4-(4-Amino-6-((dimethylamino)methyl)-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5- yl)-3-fluorophenyl)-4-(2,5-difluorobenzyl)-1 /-/-1 ,2,4-triazol-5(4/-/)-one;
1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(3,5- difluorobenzyl)-1/-/-1 ,2,4-triazol-5(4H)-one ;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(3,5- dimethylbenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
- 97 - 1-(4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidiri-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(3,5- dimethylbenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4- (cyclopentylmethyl)-l H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-4-(2,5- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-benzyl-1 H-1 ,2,4- triazol-5(4H)-one;
1-(4-(4-amino-1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-4-benzyl-1 H- 1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-4-(2,5- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(3- chloro-2-fluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,3- difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- fluorophenyl)-4-(2,5-difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-4-(2,5- dimethylbenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- dimethylbenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- dimethylbenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,3,6- trifluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
- 98 - 1-(4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(3- chloro-2-fluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one;
2-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrirnidin-5-yl)-3-fluorophenyl)-4-(5- chloro-2-fluorobenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one;
2-(4-(4-amino-1-cyclopropyl-1 H-pyrazolo[3,4-d]pyrirnidin-3-yl)-3-fluorophenyl)-4- (2,5-dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-onedihydro-3H-1 ,2,4-triazol-3-one;
2-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4- (2,5-dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one;
2-(4-(4-amino-1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorophenyl)-4-(2,5- dimethylbenzyl)-2,4-dihydro-3H-1 ,2,4-triazol-3-one; and
1-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4- (2,5-difluorobenzyl)-1 H-1 ,2,4-triazol-5(4H)-one; or a salt thereof including a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound of Formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
7. A method of treating a disease selected from: 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 disease, Neimann-Pick's disease, amyloidosis, cognitive
- 99 - impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula I, as described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
8. The method of claim 7 wherein the mammal is a human.
9. A method of treating a disease selected from: 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 disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 wherein the mammal is a human.
11. The method according to claim 7 wherein said cancer is selected from: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid.
- 100 -
12. The method according to claim 9 wherein: said cancer is selected from brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid.
13. Use of a compound of Formula (I), as described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating cancer.
14. The method of inhibiting PERK activity in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula I, as described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
15. The method of claim 14 wherein the mammal is a human.
16. A method of treating cancer in a mammal in need thereof, which comprises: administering to such mammal a therapeutically effective amount of
a) a compound of Formula (I), as described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof; and
b) at least one anti-neoplastic agent.
17. The method claim 16, wherein the at least one anti-neoplastic agent is 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,
- 101 - immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism.
18. A pharmaceutical combination as claimed in claim 16 for use in therapy.
19. The use of a pharmaceutical combination as claimed in claim 16 for the preparation of a medicament useful in the treatment of cancer.
20. The method according to claim 7 wherein said cancer is selected from: breast cancer, inflammatory breast cancer, ductal carcinoma, lobular carcinoma, colon cancer, pancreatic cancer, insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, skin cancer, melanoma, metastatic melanoma, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, 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, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia,
malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,
neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers and testicular cancer.
- 102 -
21. The method of claim 20 wherein the mammal is a human.
22. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound of Formula (I) as described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, which process comprises bringing the compound of Formula (I) or a pharmaceutically acceptable salt thereof into association with a pharmaceutically acceptable excipient.
23. The method according to claim 7 wherein said 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.
24. The method of claim 16, wherein the at least one anti-neoplastic agent is pazopanib.
25. A method of treating ocular diseases in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of Formula I, as described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
26. A method according to claim 25 wherein the ocular disease is selected from: rubeosis irides; neovascular glaucoma; pterygium; vascularized glaucoma filtering blebs; conjunctival papilloma; choroidal neovascularization associated with age-related macular degeneration (AMD), myopia, prior uveitis, trauma, or idiopathic; macular edema; retinal neovascularization due to diabetes; age-related macular degeneration (AMD); macular degeneration (AMD); ocular ischemic syndrome from carotid artery disease; ophthalmic or
- 103 - retinal artery occlusion; sickle cell retinopathy; retinopathy of prematurity; Eale's Disease; and VonHippel-Lindau syndrome.
27. A method according to claim 25 wherein the ocular disease is selected form: age-related macular degeneration (AMD) and macular degeneration.
28. A method of treating neurodegeneration in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of Formula I, as described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
29. A method of preventing organ damage during the transportation of organs for transplantation, which comprises adding a compound of Formula (I) as described in any one of claims 1 to 5 to the solution housing the organ during transportation.
30. A compound or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 5 for use in therapy.
31. A compound or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 5 for use in the treatment of disease selected from: cancer, precancerous 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 disease, Neimann-Pick's disease, amyloidosis, cognitive
- 104 - impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation.
32. A pharmaceutical composition comprising from 0.5 to 1 ,000 mg of a compound or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 5, and and from 0.5 to 1 ,000 mg of a pharmaceutically acceptable excipient.
- 105 -
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