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Definitions

• the present invention relates to substituted pyrrolidinone 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 associated with activated unfolded protein response pathways, such as Alzheimer's disease, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt- Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, neurodegeneration, atherosclerosis, ocular diseases, and arrhythmias.
• 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 (Ma and Hendershot, 2004), (Feldman et al., 2005).
• Cellualr 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, 2011).
• 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).
• 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, and by pharmacological inducers of ER stress such as thapsigargin and tunicamycin.
• GCN2 general control non-derepressed 2
• PKR PKR
• HRI 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 decrease in translation initiation and 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 which is regulated by PERK, has 5'-upstream open reading frames (uORFs) that normally represses ATF4 synthesis.
• PERK is activated under stress and P-elF2a inhibits elF2B
• low levels of ternary complex allows for selective enhanced translation of ATF4 (Jackson et al. 2010). Therefore, when ER stress ensues due to the presence of misfolded proteins, PERK activation causes an increase in ATF4 translation, which transcriptionally upregulates downstream target genes such as CHOP (transcription factor C/EBP homologous protein), which modulates cellular survival pathways and induces 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) and prion diseases including Creutzfeldt-Jakob Disease (CJD), (Doyle et al. 2011), (Paschen 2004), (Salminen et al. 2009).
• human neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) and prion diseases including Creutzfeldt-Jakob Disease (CJD), (Doyle et al. 2011), (Paschen 2004), (Salminen et al. 2009).
• malformed/misfolded or aggregated protein deposits e.g tau tangles, Lewy bodies, a-synuclein, ⁇ plaques, mutant prion proteins
• malformed/misfolded or aggregated protein deposits e.g tau tangles, Lewy bodies, a-synuclein, ⁇ plaques, mutant prion proteins
• the fate of a cell (e.g a neuron) enduring unfolded or malfolded 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 signaling 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. 2008).
• 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.
• 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), 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.
• ALS amyotrophic lateral sclerosis
• CJD Creutzfeldt-Jakob Disease
• CJD Creutzfeldt-Jakob Disease
• 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), and arrhythmias.
• 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 regulates the proliferation and development of insulin-secreting beta-cell tumors in the endocrine pancreas of mice, PLoS One 4, e8008.
• PERK and GCN2 contribute to elF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway, Mol Biol Cell 16, 5493-501.
• Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells, BMC Cancer 8, 229. Julier, C; Nicolino, M. (2010) Wolcott-Rallison syndrome Orphanet J. Rare Diseases 5 (29) 1-13. http://www.ojrd.eom/content/5/1/29
• XBP1 is essential for survival under hypoxic conditions and is required for tumor growth, Cancer Res 64, 5943-7. Ron, D. (2002) Translational control in the endoplasmic reticulum stress response. J. Clin. Invest. 1 10, 1383-1388.
• compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention.
• the invention is directed to substituted pyrrolidinone derivatives. Specifically, the invention is directed to compounds according to Formula X:
• R 4 , R 42 , R 43 , R 44 , R 45 , R 46 , and R 47 are defined below.
• the present invention also relates to the discovery that the compounds of Formula (X) 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 (X).
• 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 (X).
• 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 (X).
• 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 (X).
• 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 (X).
• 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 (X).
• 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 (X).
• 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 (X).
• This invention also relates to a method of treating stroke, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (X).
• 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 (X).
• 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 (X).
• a disease state selected from:, myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias
• novel processes and novel intermediates useful in preparing the presently invented PERK inhibiting compounds include pharmaceutical compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention.
• This invention relates to novel compounds of Formula (X):
• substituted bicycloheteroaryl and said substituted heteroaryl are substituted with from one to five substituents independently selected from:
• R 43 is selected from:
• Ci-6alkoxy Ci-6alkyl
• -6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-
• R is selected from:
• -6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF 3 , -Ci-4alkylOC-
• R is selected from:
• -6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-
• R is selected from: H, fluoro, chloro, bromo and iodo; or R5 and are optionally taken together to form a 5 to 6 member saturated or unsaturated ring containing up to one other heteroatom selected from oxygen and nitrogen; and
• R is selected from: H, C-
• This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (X).
• R 50 is selected from:
• R is selected from: H and CH3 ;
• R is selected from: -NH 2 ,
• Ci-6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-
• R is selected from: H, C-
• R is selected from:
• -6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF 3 , -Ci-4alkylOC-
• This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (XI).
• R is selected from: H and CH3;
• R is phenyl optionally substituted with form one to five substituents independently selected from:
• R is selected from: H, methyl, -CF3, fluoro and chloro; and salts thereof.
• This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (XII).
• R is selected from: H and CH3;
• R is phenyl optionally substituted with form one to five substituents independently selected from:
• R is selected from: H, methyl, -CF3, fluoro and chloro; and salts thereof.
• This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (XIII).
• R is selected from:
• substituted bicycloheteroaryl and said substituted heteroaryl are substituted with from one to five substituents independently selected from:
• 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 substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-
• R is selected from:
• -6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-
• R is selected from: C-
• -6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-
• R is selected from: H, fluoro, chloro, bromo and iodo;
• R5 and R6 are optionally taken together to form a 5 to 6 member saturated or unsaturated ring containing up to one other heteroatom selected from oxygen and nitrogen;
• R 7 is selected from: H, fluoro, chloro, bromo and iodo; and salts thereof.
• This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (I). Included in the presently invented compounds of Formula (I) are compounds of Formula (II):
• R 10 is selected from:
• R is selected from: H and CH3 ;
• R is selected from:
• -6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF 3 , -Ci-4alkylOC-
• R is selected from: H, fluoro and chloro
• R is selected from: C-
• -6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF 3 , -Ci-4alkylOC-
• This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (II).
• R is selected from: H and CH3; a nd
• R is phenyl optionally substituted with form one to five substituents independently selected from:
• This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (III). Included in the presently invented compounds of Formula (I) are compounds of Formula (IV):
• R is selected from: H and CH3; a nd
• R is phenyl optionally substituted with form one to five substituents independently selected from:
• This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (IV).
• salts, including pharmaceutically acceptable salts, of the compounds according to Formula X may be prepared. Indeed, in certain embodiments of the invention, salts including pharmaceutically-acceptable salts of the compounds according to Formula X may be preferred over the respective free or unsatled compound. Accordingly, the invention is further directed to salts, including pharmaceutically-acceptable salts, of the compounds according to Formula X.
• 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 X 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 X, 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 X 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 X may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula X, 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 X whether such tautomers exist in equilibrium or predominately in one form.
• the compounds of Formula X 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. The invention includes all such solvates.
• 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.
• the invention includes all such polymorphs.
• Alkyl refers to a hydrocarbon chain having the specified number of "member atoms".
• C-1-C4 alkyl refers to an alkyl group having from 1 to 4 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, and butyl (n-butyl, isobutyl, and t-butyl).
• 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 11 member atoms.
• Bicycloheteroaryl includes: 1 /-/-pyrrolo[3,2-c]pyridine, 1 /-/-pyrazolo[4,3- c]pyridine, 1 H-pyrazolo[3,4-d]pyrimidine, 1 H-pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3- d]pyrimidine, thieno[3,2-c]pyridine, thieno[2,3-d]pyrimidine, furo[2,3-c]pyridine, furo[2,3- d]pyrimidine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl,
• 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 11 member atoms.
• Bicycloheteroaryl includes: 1 H-pyrazolo[3,4-d]pyrimidine, 1 H-pyrrolo[2,3- d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, thieno[3,2-c]pyridine, thieno[2,3-d]pyrimidine, furo[2,3-c]pyridine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5-c]
• Bicycloheteroaryl includes: 1 H-pyrazolo[3,4-d]pyrimidine, 1 H-pyrrolo[2,3- d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, thieno[3,2-c]pyridine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5- c] pyridine, imidazo[4.5-b]pyridine, furopyri
• Cycloalkyi refers to a saturated or unsaturated non aromatic hydrocarbon ring having from three to seven carbon atoms. Cycloalkyi groups are monocyclic ring systems. For example, C3-C7 cycloalkyi refers to a cycloalkyi group having from 3 to 7 member atoms.
• cycloalkyi examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.
• 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.
• heteroaryl includes: pyrazole, pyrrole, isoxazole, pyridine, pyrimidine, pyridazine, and imidazole.
• Heterocycloalkyl refers to a saturated or unsaturated non-aromatic ring containing 4 to 12 member atoms, of which 1 to 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-one, hexahydro-1 H-azepin, 4,5,6,7,tetrahydro-1 H-benzimidazol,
• Heteroatom refers to a nitrogen, sulphur or oxygen atom.
• “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• ACN acetonitrile
• AIBN azobis(isobutyronitrile)
• BINAP (2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthyl
• BOP Benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate
• CSF cesium fluoride
• ATP adenosine triphosphate
• BSA bovine serum albumin
• C18 refers to 18-carbon alkyl groups on silicon in HPLC stationary phase
• DIPEA Hinig's base, A/-ethyl-A/-(1-methylethyl)-2-propanamine
• 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,/ ⁇ /,/ ⁇ /',/ ⁇ /-tetramethyluronium hexafluorophosphate); HOAt (1-hydroxy-7-azabenzotriazole);
• HMDS hexamethyldisilazide
• Hunig's Base (A/,A/-Diisopropylethylamine);
• LAH lithium aluminum hydride
• mCPBA m-chloroperbezoic acid
• NaHMDS sodium hexamethyldisilazide
• NBS (/V-bromosuccinimide
• PE petroleum ether
• TFA trifluoroacetic acid
• 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 Wley & 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.
• 2-aryl-4- pentenoic acids B were prepared by alkylation of an arylacetic acid A dianion with allyl bromide according to a reported procedure (Organic Letters, 2009, 17, 3858, supplementary material p26). Reaction of the 2-aryl-petenoic acid B with substituted 4- bromoaniline and a coupling reagent to form an amide bond, such as HATU, afforded the pentenamide C. The pentenamide C was then cyclized to the pyrrolidinone ring using a two step process.
• X3 S, NMe
• Lactone V was reacted with PBr3, Br2 followed by thionylchloride at ambient to elevated temperature followed by addition of base such as triethylamine and substituted aniline V1 to give compound W, which was further treated with base such as NaH to give 3-bromopyrrolidinone X.
• reaction was performed in situ to give compound X using potassium phosphate and sodium hydroxide instead of NaH and without isolating W.
• the compounds according to Formula X 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, such as Alzheimer's disease, stroke, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, and other diseases associated with UPR activation including: diabetes, myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias.
• neurodegenerative diseases such as Alzheimer's disease, stroke, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, and other diseases associated with UPR activation including: diabetes, myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias.
• 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 X or a pharmaceutically acceptable salt, thereof to a patient in need thereof.
• the invention also provides a compound according to Formula X or a pharmaceutically-acceptable salt thereof for use in medical therapy, and particularly in cancer therapy.
• the invention is directed to the use of a compound according to Formula X 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.
• treating is meant prophylactic and therapeutic therapy.
• Prophylactic therapy is appropriate, for example, when a subject has 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.
• patient or subject is a human.
• the compounds of Formula X 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 X 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 X 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 & Wlkins 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/U S01/49367, 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 (X) 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 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 (X) or a pharmaceutically acceptable salt thereof.
• the compounds of Formula (X) 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, subcutaneous, intradermal, 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.
• 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.
• 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.
• 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.
• 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 (X) 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 (X) 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 (X) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating neurodegenerative diseases.
• the invention also provides for the use of a compound of Formula (X) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating cancer.
• the invention also provides for a pharmaceutical composition for use as a PERK inhibitor which comprises a compound of Formula (X) 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 (X) 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 mixture was filtered, and the solid was taken up into a mixture of 20% CH 3 OH/CH2CI2, and injected into a 40 g Si0 2 column, and purified via flash chromatography (gradient: 100% Hexanes to 100% EtOAc to 20% CH 3 OH/EtOAc). The fractions containing the desired product were combined and concentrated to afford a yellow solid.
• This material was dissolved into 2 ml_ of DMSO and purified via HPLC (gradient (0.1 % TFA): 15%CH 3 CN/H 2 0 to 40%CH 3 CN/H 2 O). The fractions containing the desired product were combined and concentrated under vacuum to remove most of the CH 3 CN.
• the filtrate was diluted with DCM (up to 150 mL) and washed with 1 N HCI (2 x 30 mL). The organic was dried over MgS0 4 , filtered, and concentrated in vacuo. The residue was taken up in DCM and hexane as a bilayer mixture. The top solvent layer was decanted. The bottom layer was triturated in MTBE to give a suspension, which was filtered. The solids were not product by LCMS and discarded. The filtrate, which contained the desired product by LCMS, was concentrated in vacuo and then dissolved in 10 mL of DCM, and stored in a refigerator for 18 hours.
• the glass-like foamy residue was pumped under vacuum for 1 hour to give 5.68 g of a foam.
• LCMS showed it was a mixture of of hydroxypyrrolidinone diastereomers in 28:44 ratio by UV.
• the foam was taken up in 20 mL of DCM and 10 mL of TFA, and then treated with triethylsilane (9.22 mL, 57.9 mmol, 4 equiv). The mixture (pale yellow clear solution) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo.
• the residue was dissolved in CHCI 3 and absorbed onto 4 x 90 g dryload silica gel cartridges (equal portions).
• the solidified product was taken up in DCM (5 mL) and hexane (15mL) to give a suspension, which was filtered. The solids were collected and dried under vacuum to give A/-(4-bromophenyl)-2-[3-(trifluoromethyl)phenyl]-4- pentenamide (3.16 g, 57% recovery) as white solids. A second crop was obtained (1.41 g, 25% recovery) as white solids.
• LCMS showed it was a mixture of diastereomers in 23:52 ratio by UV. This material was taken up in 20 mL of DCM and 10 mL of TFA (11.5equiv), and then triethylsilane (7.20 mL, 45.2 mmol, 4 equiv) was added. The mixture (dark brownish) was stirred for 2 hours (LCMS showed conversion complete). The mixture was concentrated in vacuo, and stored at -20 °C freezer for 3 days. The residue was dissolved in CHCI 3 and absorbed onto 4 dryload cartridges (equal portions).
• the reaction mixture was stirred for 3h at 100 °C in a sealed vessel.
• the reaction was cooled down to room temperature.
• 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (102 mg, 0.449 mmol, 1 equiv) and saturated aqueous NaHC0 3 (3 ml_) was added, and N 2 gas was bubbled through the mixture for 10 minutes.
• PdCl 2 (dppf)-CH 2 Cl 2 adduct (18.32 mg, 0.022 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C.
• the reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel.
• the reaction was cooled to room temperature.
• 5-bromo-7- methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (1.01 g, 4.49 mmol, 1 equiv) and saturated aqueous NaHC0 3 (30 mL) was added, and N 2 gas was bubbled through the reaction mixture for 10 minutes.
• PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.183 g, 0.22 mmol, 0.05 eq) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C.
• the reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel.
• the reaction was cooled to room temperature.
• 5-bromo-7- methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (1.79 g, 7.911 mmol, 1 equiv) and saturated aqueous NaHC0 3 (30 mL) was added, and N 2 gas was bubbled through the mixture for 10 minutes.
• PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.32 g, 0.395 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C.
• the reaction mixture was forwarded to next step without any workup.
• the reaction mixture was cooled to room temperature, 5-bromo-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-4-amine (0.145 g, 0.639 mmol, 1.1 equiv) and saturated aqueous NaHC0 3 (10 ml_) were added to that, degassed thoroughly and added with Pd(dppf)CI 2 .DCM complex (0.048 g, 0.06 mmol, 0.1 equiv) the vessel was sealed, and the reaction mixture was heated to 100°C for overnight. After completion of the starting material, the reaction mixture was partitioned between EtOAc and water. The two layers were separated.
• reaction mixture was cooled to room temperature, 5-bromo-7- methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.282 g, 1.2 mmol, 1.25 equiv) and saturated aqueous NaHC0 3 (13 mL) were added to that, degassed thoroughly and added with Pd(dppf)CI 2 .DCM complex (0.081 g, 0.1 mmol, 0.1 equiv) the vessel was sealed, and the reaction mixture was heated to 100°C for overnight. After completion of the starting material (by TLC monitoring), the reaction mixture was partitioned between EtOAc and water.
• reaction mixture was quenched with 10 mL of 1 N HCI and extracted with ethyl acetate and the organic layers were combined and washed with brine and dried over Na 2 S0 4 , filtered and concentrated in vacuo to give 2-(m-tolyl)pent-4-enoic acid as yellow color oil (0.41 g).
• LC-MS (ES) m/z 190.1 [M+H] + .
• reaction mixture was quenched with 30 mL of 1 N HCI and extracted with ethyl acetate and the organics were combined and washed with brine and dried over Na 2 S0 4 , filtered and concentrated in vacuo to give 2-(m-tolyl)pent-4-enoic acid as yellow color oil (3.21 g).
• LC-MS (ES) m/z 190.1 [M+H] + .
• reaction mixture was quenched with 30 mL of aqueous solution of sodium thiosulfate, and the resulting mixture was stirred for 10 minutes.
• the mixture was extracted with EtOAc (2 x 50 mL), and sat. aqueous NaHC0 3 (35 mL).
• the organic layer was separated, washed with brine solution (50 mL), dried over Na 2 S0 4 , and concentrated to afford the crude product as 1-(4-bromo-3-fluorophenyl)-5- hydroxy-3-(m-tolyl) pyrrolidin-2-one (5.98 g) as black color semi solid.
• LC-MS (ES) m/z 364.0, 366.0 [M+H] + .
• the reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel.
• the reaction was cooled to room temperature.
• 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.326 g, 1.436 mmol, 1.0 equiv) and saturated aqueous NaHC0 3 (6 mL) was added, and Argon gas was bubbled through the reaction mixture for 10 minutes and PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.05 g, 0.072 mmol, 0.05 equiv) was added.
• the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C.
• reaction mixture was quenched with 30 mL of aqueous solution of sodium thiosulfate, and the resulting mixture was stirred for 10 minutes.
• the mixture was extracted into EtOAc (2 x 50 mL), and saturated aqueous NaHC0 3 .
• the organic layer was separated, washed with brine solution (50 mL), dried over Na 2 S0 4 , and concentrated to afford the crude product as 1-(4-bromo- 3-fluorophenyl)-3-(3-fluorophenyl)-5-hydroxypyrrolidin-2-one (1.60 g, crude) as black color semi solid.
• LC-MS (ES) m/z 368.0, 370.0 [M+H] + .
• the reaction mixture was stirred for 4 hours at 100 °C in a sealed vessel.
• the reaction was cooled to room temperature.
• 5-bromo-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-4-amine (0.322 g, 1.4 mmol, 1.0 equiv) and saturated aqueous NaHC0 3 (5 ml_) was added, and Argon gas was bubbled through the mixture for 10 minutes.
• PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.071 g, 0.09 mmol.O. 05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C.
• reaction mixture was quenched with 1 N HCI and extracted with ethyl acetate, dried over Na 2 S0 4 , and evaporated under vacuum to get 2-(3,5-difluorophenyl)pent-4-enoic acid as brown liquid .(3.6 g, crude) as crude product, and was forwarded for next stage.
• reaction mixture was diluted with DCM (100 mL), Organic layer was washed with 1 N HCI (2 x 50 mL) and saturated NaHC0 3 (2 X 50mL), dried over Na 2 S04, filtered, and concentrated and the crude product was purified by flash chromatography. The product was eluted in DCM. The collected fractions with pure product were concentrated and washed with n-pentane (3 x 10 mL) and dried to afford the desired product A/-(4-bromophenyl)-2-(3,5-difluorophenyl)pent-4-enamide as white solid (1.08 g, 42%).
• reaction mixture was quenched with aqueous solution of sodium thiosulfate, and stirred for 10 minutes.
• the mixture was extracted into EtOAc (2 x 50 mL), and saturated aqueous NaHC0 3 .
• the organic layer was separated, washed with brine solution (50 mL), dried over Na 2 S0 4 ), and concentrated to afford the crude product 1-(4-bromophenyl)-3-(3,5- difluorophenyl)-5-hydroxypyrrolidin-2-one (1.32 g, crude) as off white color oil.
• the reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel.
• the reaction was cooled to room temperature.
• 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (195 mg, 0.8 mmol, 1 equiv) and saturated aqueous NaHC0 3 (5 mL) was added, and N 2 gas was bubbled through the mixture for 10 minutes.
• PdCl 2 (dppf)-CH 2 Cl 2 adduct 33 mg, 0.040 mmol, 0.05 equiv was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C.
• reaction mixture After consumption of the starting material, the reaction mixture was cooled to room temperature and was combined with the reaction mixture from run 1 to afford a total 18 ml_. The combined reaction mixture waspartitioned between water and EtOAc. The two layers were separated and the combined organic layers were washed with brine, dried over Na 2 S0 4 , evaporated and the crude product was purified via silica gel flash chromatography. The desired product was eluted over a solvent gradient of 19 - 20% EtOAC: Hexanes.
• reaction mixture was stirred at room temperature for 30 min, after consumption of the starting material, the reaction mixture was washed with 1 N HCI (30 mL), saturated aqueous NaHC0 3 (30 mL), water and brine successively. The mixed organic layer was dried over Na 2 S0 4 , filtered and evaporated. The crude material was washed in n-pentane to afford the desired product as brown oil (2.897 g, crude), crude product was preceded to next step without purification.
• reaction mixture was cooled to room temperature (combined with the reaction mixture from run1), 5-bromo-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-4-amine (0.224 g, 1.0 mmol, 1.3 equiv) and sat. NaHC0 3 (11 mL) were added and degassed thoroughly.
• Pd(dppf)CI 2 .DCM complex (0.062 g, 0.076 mmol, 0.1 equiv) was added and the vessel was sealed, and the reaction mixture was heated to 100°C and stirred overnight. After consumption of the starting material, the reaction mixture was partitioned between water (35 mL) and EtOAc (200 mL).
• reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. After completion of the reaction, the reaction was cooled to room temperature. 5-bromo-7-methyl-7H-pyrrolo[2,3- d]pyrimidin-4-amine (140 mg, 0.769 mmol, 1.0 equiv) and saturated aqueous NaHC0 3 (5 mL) was added, and argon gas was bubbled through the mixture for 10 minutes. PdCl 2 (dppf)-CH 2 Cl 2 adduct (31.0 mg, 0.038 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100°C.
• reaction mixture was degassed with N 2 for 15 minutes, PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.033 g, 0.04 mmol, 0.05 equiv) was added and the reaction mixture was stirred for 3 hours at 100 °C in a sealed tube.
• the reaction was cooled to room temperature, 5-bromo-7- methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.27 g, 1.2 mmol, 1.5 equiv) and saturated aqueous NaHC0 3 (10 mL) were added, and N 2 gas was bubbled through the mixture for 10 minutes.
• the reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel.
• the reaction was cooled to room temperature.
• 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (306 mg, 1.35 mmol, 1.0 equiv) and saturated aqueous NaHC0 3 (7 mL) was added, and N 2 gas was bubbled through the mixture for 10 minutes.
• PdCl 2 (dppf)-CH 2 Cl 2 adduct 55 mg, 0.067 mmol, 0.05 equiv was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C.
• reaction mixture was washed with 1 N HCI followed by saturated aqueous NaHC0 3 and brine solution successively and dried over Na 2 S0 4 , filtered, & evaporated to get desired product A/-(4-bromo-3-fluorophenyl)-2-(3-(trifluoromethyl) phenyl)pent-4-enamide as yellow oil (8.012 g, crude) which has a purity of 79% as evidenced by LCMS and proceeded to next step without purification.
• reaction mixture was quenched with saturated Sodium thiosulphate solution and the two layers were separated. The combined organic layers were washed with saturated aqueous NaHC0 3 followed by brine, dried over Na 2 S0 4 , filtered and evaporated to afford the desired product 1-(4-bromo-3-fluorophenyl)- 5-hydroxy-3-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one as dark brown semi solid (6.864 g, crude [M+H] + .
• reaction mixture was proceeded for Suzuki coupling without any work-up.
• the reaction mixture was cooled to room temperature, 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4- amine (0.257 g, 1.131 mmol, 1.3 equiv) and sat. NaHC0 3 (6 ml_) were added, degassed under Argon and added Pd(dppf)CI 2 .DCM complex (0.070 g, 0.087 mmol, 0.1 equiv).
• the vessel was sealed and the reaction mixture was heated to 100°C for overnight.
• the reaction mixture was cooled to room temperature and partitioned between EtOAc and water.
• reaction mixture was quenched with aqueous solution of sodium thiosulfate and saturated aqueous NaHC0 3 , and extracted with EtOAc. Combined organic layer was dried over Na 2 S0 4 , and concentrated. The crude product was used for next reaction with
• Run-1 and Run-2 were mixed and purified using 100 - 200 silica gel, 24g column in Rf-cobiflash, eluted with 5% MeOH in DCM as mobile phase.
• reaction mixture was quenched with 25 mL of 1 N HCI and extracted with ethyl acetate and the organics were combined and washed with brine and dried over Na 2 S0 4 , filtered and concentrated in vacuo to give 2-(2-cyclopropylphenyl)pent-4-enoic acid as pale yellow liquid (2.5 g, crude).
• LC-MS (ES) m/z 193.0 [M-H] + .
• reaction mixture was quenched with 35 mL of H 2 0, and extracted with EtOAc, organics were washed with 1 N HCI (1 x 50 mL), and sat NaHC0 3 (2 x 50mL), dried over Na 2 S0 4 , filtered, and concentrated to get A/-(4-bromophenyl)-2-(2- cyclopropylphenyl)pent-4-enamide as pale yellow solid (1.320 g, crude).
• LC-MS (ES) m/z 370.1 , 372.0 [M+H] + .
• reaction mixture was quenched with 30 mL of aqueous solution of sodium thiosulfate and the resulting mixture was stirred for 10 minutes.
• the reaction mixture was extracted with EtOAc (2 x 50 mL), organic layer was washed with saturated aqueous NaHC0 3 , brine solution (50 mL), and dried over Na 2 S0 4 ), and concentrated to afford the crude product 1-(4-bromophenyl)-3-(2-cyclopropylphenyl)-5-hydroxypyrrolidin-2- one (1.530 g, crude) as pale yellow semi solid.
• LC-MS (ES) m/z 372.0, 374.0 [M+H] + .

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