TW201722958A - Chemical compounds - Google Patents

Abstract

The invention is directed to substituted triazolidinone derivatives. Specifically, the invention is directed to compounds according to Formula 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, 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. 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

Chemical compound

The present invention relates to a substituted triazolone derivative which is an inhibitor of protein kinase R (PKR)-like ER kinase PERK activity. The invention also relates to a pharmaceutical composition comprising such compounds, and the use of such compounds for the treatment of cancer, precancerous syndrome, and diseases/injuries associated with an activated unfolded protein reaction pathway, such as: Alzheimer's disease, spine Injury, traumatic brain injury, apoplexy stroke, stroke, Parkinson's disease, diabetes, metabolic syndrome, metabolic disease, Huntington's disease, Creutzfeldt-Jakob Disease, lethal familial Insomnia, Gerstmann-Sträussler-Scheinker syndrome, and related prion disease, amyotrophic lateral sclerosis, progressive Ocular nerve palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute liver disease, fatty liver disease, hepatic steatosis, liver fibrosis, chronic and acute lung disease, pulmonary fibrosis, chronic With acute kidney disease, renal fibrosis, chronic traumatic brain disease (CTE), neurodegeneration, dementia, frontotemporal dementia, Tau proteinopathy Pick's disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, eye disease, arrhythmia, organ transplantation, and Transport the transplanted organ.

Unfolded Protein Reaction (UPR) is a signal transduction pathway that allows cells to Survival under adverse stress caused by misfolded or unfolded proteins or protein aggregates (Walter and Ron, 2011), (Hetz, 2012). Environmental stress that interferes with protein folding and maturation in the endoplasmic reticulum (ER) also contributes to UPR activation (Feldman et al., 2005), (Koumenis and Wouters, 2006). UPR activation stress stimulation includes hypoxia, protein glycosylation breakdown (insufficient glucose supply), intraluminal ER calcium consumption, or ER redox status changes, etc. (Ma and Hendershot, 2004), (Feldman et al., 2005). ). These disturbances cause the ER redox state to collapse and accumulate unfolded or misfolded proteins in the ER. Cellular responses include transcriptional reprogramming to increase the content of the accompanying protein to enhance protein refolding, misfolded protein degradation, and deterrence translation to reduce the burden of the client protein into the ER (Ron, D. 2002) (Harding et al., 2002). These pathways also regulate cell survival by regulating apoptosis (Ma and Hendershot, 2004), (Feldman et al., 2005), and autophagy (Rouschop et al., 2010) and can be initiated under long-term ER stress conditions. Cell death (Woehlbier and Hetz, 2011).

Three ER membrane proteins have been identified as UPR one-effect effectors: protein kinase R (PKR)-like ER kinase [PERK, also known as eukaryotic initiation factor 2A kinase 3 (EIF2AK3), pancreatic ER kinase, or pancreas eIF2α kinase (PEK)], inositol-dependent gene 1 α/β (IRE1), and activated transcription factor 6 (ATF6) (Ma and Hendershot, 2004), (Hetz, 2012). Under normal conditions, these proteins remain inactive by binding to the ER-associated protein GRP78 (BiP) and its luminal sensing domain. The accumulation of unfolded proteins in the ER causes these perceptrons to release GRP78, causing activation of these UPR effectors (Ma et al., 2002), (Hetz, 2012).

PERK is a type I ER membrane protein that contains a pressure-sensing domain facing the ER lumen, a transmembrane segment, and a cytosolic kinase domain (Shi et al., 1998), (Harding et al., 1999), (S00d et al. , 2000). GRP78 is released by the stress sensing domain of PERK, resulting in oligomeric polymerization and autophosphorylation of multiple residues of serine, threonine and tyrosine (Ma et al, 2001), (Su et al, 2008). The phenotype of mice that exclude PERK includes diabetes (because it has been lost Islet cells), skeletal abnormalities, and growth retardation (Harding et al., 2001), (Zhang et al., 2006), (Iida et al., 2007). These features are similar to those found in patients with Wolcott-Rallison syndrome, which has germline mutations in the PERK gene (Julier and Nicolino, 2010). .

The main receptor for PERK is eukaryotic initiation factor 2α (eIF2α), which is treated with ER stress or pharmacological inducers (such as thapsigargin and tunicamycin) that are subject to ER stress. Phosphorylation in serine-51 (Marciniak et al., 2006). This site will also be phosphorylated by other EIF2AK family members [(Generally regulated non-anti-inhibitory 2 (GCN2), PKR, and blood matrix regulatory kinase (HRI)] in response to different stimuli.

Phosphorylation of eIF2α converts it into an inhibitor of guanine nucleotide exchange factor (GEF) eIF2B, which is required for efficient conversion of GDP into GTP in the eIF2 protein synthesis complex. Therefore, inhibition of eIF2B with P-eIF2a will reduce initial translation and full protein synthesis (Harding et al., 2002). Paradoxically, when UPR is activated and eIF2a is phosphorylated, translation of specific mRNAs is enhanced. For example, the transcription factor ATF4 has a 5'-upstream open reading frame (uORF) which normally inhibits ATF4 synthesis in normal whole protein synthesis. However, when PERK is activated under pressure and P-eIF2a inhibits eIF2B, a low amount of ternary complex selectively enhances ATF4 translation (Jackson et al., 2010). Therefore, when ER stress occurs, PERK activation enhances ATF4 translation, which up-regulates downstream target genes, such as CHOP (transcription factor C/EBP homologous protein). This transcriptional reprogramming regulates the cell survival pathway and induces a pro-apoptotic gene.

Activation of PERK and UPR are associated with human neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), progressive Upper eye nucleus pneumonia (PSP), dementia, and Preon protein disease (including Creutzfeldt-Jakob Disease) (CJD), (Doyle et al., 2011), (Paschen 2004), (Salminen Et al., 2009), (Stutzbach et al., 2013). All of this Common features of the disease are protein deposition with deformation/misfolding or agglutination (eg, tau tangles, Lewy bodies, alpha-synuclein, Aβ plaques, mutant prion proteins) ), Xianxin will cause physiological diseases of the primary disease, loss of neurons, and cognitive decline (Prusiner, 2012), (Doyle et al., 2011). The fate of cells (eg, neurons) that are subject to protein pressure without folding or folding deformation is under the control of PERK. Cells that are under ER stress may restore protein homeostasis and return to normal, or if stress cannot be overcome, sustained PERK activation may be transduced by ATF4/CHOP signaling plus inability to synthesize viable proteins, as cells are continuously inhibited by translation. death. Activated PERK and biomarkers associated with PERK activation can be detected in brain tissue and human prion protein disease after death in Alzheimer's disease patients (Ho et al., 2012), (Hoozemans et al., 2009) (Unterberger et al., 2006). Furthermore, P-eIF2α (the product of PERK activation) is associated with BACE1 levels in post-mortem brain tissue of patients with Alzheimer's disease (O’Connor et al., 2008). Recently, it has been shown in mice infected with prion protein that the small molecule PERK inhibitor GSK2606414 provides neuroprotective effects and prevents clinical signs (Moreno et al., 2013), which is in line with the past UPR/PERK/eIF2α pathway genes. The results obtained by the method of operation are consistent (Moreno et al., 2012). It has also been reported that this pathway involves ALS (Kanekura et al., 2009 and Nassif et al., 2010), spinal injury (Ohri et al., 2011) and traumatic brain injury (Tajiri et al., 2004). Taken together, these data show that UPR and PERK represent reliable drug interventions that prevent or reverse the clinical deterioration of many neurodegenerative diseases and the associated cognitive impairment.

Tumor cells undergo a period of hypoxia and undernutrition during their growth process based on improper blood supply and vascular dysfunction (Brown and Wilson, 2004), (Blais and Bell, 2006). Therefore, they may rely on active UPR signal transduction to promote their growth. Consistent with this, mouse fibroblasts derived from PERK-/-, XBP1-/-, and ATF4-/- mice and fibroblasts expressing mutant eIF2α showed reduced activity under hypoxic conditions in vitro. Clonal-derived growth and increased apoptosis, and when tumors were implanted in nude mice, the growth rate decreased significantly (Koumenis et al., 2002), (Romero-Ramirez et al., 2004), (Bi et al, 2005). Human tumor cell lines with a dominant dominant negative effect of PERK and lacking kinase activity also showed increased apoptosis in vitro under hypoxic conditions and disrupted tumor growth in vivo (Bi et al., 2005). In these studies, the area of UPR activation observed in tumors was consistent with the hypoxic zone. The apoptotic rate in these regions is higher than in tumors with intact UPR signal transduction. Other evidence supporting the role of PERK in promoting tumor growth is the number, size, and vascularity observed in insulinomas produced in insulin-producing beta cells of SV40-T antigen-transforming mice, at PERK- ^{/ - The} mice were significantly reduced compared to the wild type control group (Gupta et al., 2009). Activation of UPR was also observed in clinical samples. Human tumors (including those derived from cervical cancer, glioblastoma (Bi et al., 2005), lung cancer (Jorgensen et al., 2008) and breast cancer (Ameri et al., 2004), (Davies et al., 2008). The protein content of the UPR is shown to be higher than that of normal tissues. Therefore, the use of a compound that blocks the activity of other components of PERK and UPR inhibits the unfolded protein reaction and should have utility as an anticancer agent. Recently, this hypothesis has been supported by two small molecule inhibitors of PERK, which have been shown to inhibit the growth of human tumor xenografts in mice (Axten et al, 2012 and Atkins et al, 2013).

Loss of endoplasmic reticulum stability and misfolded protein accumulation may cause many disease states (Wek and Cavener 2007), (Zhang and Kaufman 2006). Inhibitors of PERK may be medically suitable for the treatment of various human diseases such as Alzheimer's disease and frontotemporal dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), progressive upper nucleus pneumonia (PSP), and other Tau protein lesions such as chronic traumatic brain lesions (CTE) (Nijholt, DA et al., 2012), (Lucke-Wold, BP et al. 2016), spinal injury, traumatic brain injury, stroke, CJD and related prion protein diseases such as: lethal familial insomnia (FFI), Jetsman-Stapleer-history Ink syndrome, and ablative white matter (VWM) disease. Inhibitors of PERK may also be suitable for the effective treatment of cancer (specifically, they are caused by secretory cell types such as pancreas and neuroendocrine-derived cancer), multiple myeloma, or Used in combination with chemotherapy sensitizers to enhance the killing of tumor cells. PERK inhibitors may also be suitable for myocardial infarction, cardiovascular disease, atherosclerosis (McAlpine et al, 2010; Civelek et al, 2009; Liu and Dudley 2016), arrhythmia, and kidney disease (Dickhout et al, 2011; Cybulsky , AV et al., 2005). PERK inhibitors may also be suitable for stem cell or organ transplantation to prevent organ damage and for transporting transplanted organs (Inagi et al., 2014), (Cunard, 2015), (Dickhout et al., 2011), (van Galen, P Et al. (2014). PERK inhibitors should have a variety of uses for the treatment of a wide variety of diseases in which primary lesions and symptoms are associated with disorders of unfolded protein responses.

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One of the objects of the present invention is to provide a novel compound which is a suppression of PERK. preparation.

It is also an object of the present invention to provide a pharmaceutical composition comprising a pharmaceutical carrier and a compound of formula (I).

It is also an object of the present invention to provide a disease/injury associated with the treatment of neurodegenerative diseases, cancer, and other pathways associated with activated unfolded proteins, such as: Alzheimer's disease, spinal injury, traumatic brain injury, and episodes of stroke , stroke, Parkinson's disease, diabetes, metabolic syndrome, metabolic disease, Huntington's disease, CJD, lethal familial insomnia, Jetsman-Stossler-Sykes syndrome, and related Preon protein disease, amyotrophic lateral sclerosis, progressive upper nucleus pneumonia, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute liver disease, fatty liver disease, liver fat Degeneration, liver fibrosis, chronic and acute lung disease, pulmonary fibrosis, chronic and acute kidney disease, renal fibrosis, chronic traumatic brain disease (CTE), neurodegeneration, dementia, frontotemporal dementia, Tau Proteinopathy, Pick's disease, Niemann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, eye disease, arrhythmia, for organ transplantation and for transport The method of the organ, which comprises administering a novel inhibitor of PERK activity.

This invention relates to a substituted triazolone derivative and its use. In particular, the invention relates to the use of a compound according to formula (I) and a compound of formula (I) for the treatment of a disease state.

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y, Y ¹ and Z are as defined below.

The invention also relates to the discovery that the compound of formula (I) has activity as an inhibitor of PERK.

The invention also relates to a method of treating cancer comprising administering to a subject in need thereof an effective amount of a PERK inhibiting compound of formula (I).

The invention also relates to a method of treating Alzheimer's disease comprising administering to a subject in need thereof an effective amount of a PERK inhibitory compound of formula (I).

The invention also relates to a method of treating Parkinson's disease comprising administering to a subject in need thereof an effective amount of a PERK inhibiting compound of formula (I).

The invention also relates to a method of treating amyotrophic lateral sclerosis comprising administering to a subject in need thereof an effective amount of a PERK inhibiting compound of formula (I).

The invention also relates to a method of treating Huntington's disease comprising administering to a subject in need thereof an effective amount of a PERK inhibiting compound of formula (I).

The invention also relates to a method of treating Creutzfeldt-Jakob Disease comprising administering to a subject in need thereof an effective amount of a PERK inhibitory compound of formula (I).

The invention also relates to a method of treating progressive upper nucleus pneumonia (PSP) comprising administering to a subject in need thereof an effective amount of a PERK inhibiting compound of formula (I).

The invention also relates to a method of treating dementia comprising administering to a subject in need thereof an effective amount of a PERK inhibiting compound of formula (I).

The invention also relates to a method of treating spinal injury comprising administering to a subject in need thereof an effective amount of a PERK inhibiting compound of formula (I).

The invention also relates to a method of treating traumatic brain injury comprising administering to a subject in need thereof an effective amount of a PERK inhibiting compound of formula (I).

The invention also relates to a method of treating a cardioversion stroke comprising administering to a subject in need thereof an effective amount of a PERK inhibiting compound of formula (I).

The invention also relates to a method of treating diabetes comprising administering to a subject in need thereof an effective amount of a PERK inhibiting compound of formula (I).

The invention also relates to a method of treating a disease state selected from the group consisting of myocardial infarction Plug, cardiovascular disease, atherosclerosis, eye disease, and arrhythmia, which include administering to a subject in need thereof an effective amount of a PERK inhibitory compound of formula (I).

The invention also relates to a method of using a compound of formula (I) for organ transplantation and for transporting a transplanted organ.

Another aspect of the invention provides a novel process and novel intermediate suitable for use in the preparation of the PERK inhibitory compounds of the invention.

The invention includes pharmaceutical compositions comprising a pharmaceutical carrier and a compound suitable for use in the methods of the invention.

The invention also encompasses co-administering other active ingredients of the PERK inhibitory compounds of the invention.

The invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medicine.

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 CJD.

The invention also relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of progressive upper nucleus pneumonia (PSP).

The invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, Used to treat dementia.

The invention also relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of spinal injuries.

The invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture 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 for the manufacture 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 for the manufacture of a medicament for the treatment of a disease state selected from the group consisting of myocardial infarction, cardiovascular disease, arteriosclerosis, eye disease, And the heart rhythm is not complete.

The invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of chronic traumatic brain lesions (CTE).

The invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for organ transplantation and for delivery of a transplanted organ.

The invention includes a pharmaceutical composition comprising 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 medical treatment.

The invention relates to the use of a novel compound of formula (I) and a compound of formula (I) in the process of the invention: Wherein: R ¹ is selected from the group consisting of: a bicyclic heteroaryl group, a substituted bicyclic heteroaryl group, a heteroaryl group, and a substituted heteroaryl group, wherein the substituted bicyclic heteroaryl group and the substituted heteroaryl group via line 1 to 5 are each independently selected from the following substituents: fluoro, chloro, bromo, iodo, C _1-6 alkyl, 1 to 5 substituents each independently selected from the substituents of C _1-6 Alkyl: fluorine, chlorine, bromine, iodine, C _1-4 alkyl oxygen, C _1-4 alkyl, -OH, -NH ₂ , cycloalkyl, -COOH, -CF ₃ , -NO ₂ and -CN , -OH, hydroxy C _1-6 alkyl, -COOH, tetrazole, cycloalkyl, pendant oxy, -OC _1-6 alkyl, -CF ₃ , -CF ₂ H, -CFH ₂ , -C _{1 -6} alkyl OC _1-4 alkyl, -CONH ₂ , -CON(H)C _1-3 alkyl, -CH ₂ CH ₂ N(H)C(O)OCH ₂ aryl, di C _1-4 Alkylamino C _1-4 alkyl, amino C _1-6 alkyl, -CN, heterocycloalkyl, heterocycloalkyl substituted with 1 to 4 substituents each independently selected from: C _{1 -4} alkyl, C _1-4 alkyloxy, -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ and -CN, -NO _{2, -NH 2, -N (H} ) C 1-3 alkyl, and -N (C _1-3 alkyl) ^_2; R ₂ is selected from: an aryl group, with 1 5 are each independently selected from the substituents of the aryl group: fluoro, chloro, bromo, iodo, C _1-4 alkyl, cycloalkyl, C _1-4 alkyloxy, -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ , -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF ₃ , with -CN, a heteroaryl group, a heteroaryl group substituted with 1 to 5 substituents each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, C _1-4 alkyl, cycloalkyl, C _1-4 alkyloxy, -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ , -OC(H)F ₂ , -C (H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF ₃ , and -CN, bicycloheteroaryl, biphenylheteroaryl substituted by 1 to 5 substituents each independently selected from the group consisting of fluorine , chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkyloxy, -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ , cycloalkyl, -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF ₃ , and -CN, and cycloalkyl; R ³ Selected from: hydrogen, -NH ₂ , -N(H)C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -OH, cycloalkyl, C _1-6 alkyl, and Up to 5 substituents independently selected from the following Instead C _1-6 alkyl group: fluoro, chloro, bromo, iodo, C _1-4 alkyl, C _{1-4 alkyloxy, -OH, -COOH, -CF 3,} -C 1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ and -CN; R ⁴ is selected from the group consisting of hydrogen, C _1-4 alkyl, -CF ₃ , -C(H)F ₂ , -CH ₂ F, fluorine , chlorine, bromine and iodine; R ⁵ is selected from the group consisting of hydrogen, C _1-4 alkyl, -CF ₃ , -C(H)F ₂ , -CH ₂ F, fluorine, chlorine, bromine and iodine; X is CR ¹⁰⁰ or N, wherein R ¹⁰⁰ is selected from the group consisting of hydrogen, -CH ₃ , fluorine, chlorine, bromine and iodine; and Y and Y ¹ are each independently selected from the group consisting of hydrogen, -CF ₃ and C _1-4 alkyl, or Y and Y ¹ is attached to carbon and the like thereto together form a C ₃ -C ₆ cycloalkyl; and Z is 0 or 1; and salts thereof.

The invention also relates to pharmaceutically acceptable salts of the compounds of formula (I).

In the compound of the formula (I), z is preferably 0.

In the compound of formula (I), R ^{3 is} preferably hydrogen.

In the compound of formula (I), X is preferably CH.

In the compound of the formula (I), R ^{4 is} preferably selected from the group consisting of hydrogen, methyl, -CF ₃ , fluorine, and chlorine.

In the compound of the formula (I), R ^{5 is} preferably selected from the group consisting of hydrogen, methyl, -CF ₃ , fluorine, and chlorine.

In the compound of the formula (I), R ^{2 is} preferably a phenyl group which may be optionally substituted with one to five substituents each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 Alkyloxy, -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , cycloalkyl, -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF ₃ , -NH ₂ and -CN.

In the compound of the formula (I), Y and Y ^{1 are} preferably hydrogen.

In the compound of formula (I), X is preferably CR ¹⁰⁰ wherein R ¹⁰⁰ is selected from the group consisting of hydrogen, -CH ₃ , fluorine, chlorine, bromine and iodine.

In the compound of formula (I), X is preferably N.

In the compound of the formula (I), R ^{1 is} preferably a substituted thieno[2,3-d]pyrimidinyl group.

In the compound of formula (I), R ^{1 is} preferably selected from the group consisting of substituted pyrrolo[2,3d]pyrimidin-5-yl and substituted pyrazolo[3,4d]pyrimidin-5-yl.

In the compound of formula (I), R ^{1 is} preferably selected from the group consisting of 4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl and 4-amino-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl.

The compound of the formula (I) of the present invention includes a compound of the formula (II): Wherein: R ¹⁰ is selected from the group consisting of: an aryl group substituted with 1 to 5 substituents each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkyl Oxygen, -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ , cycloalkyl, -OC(H)F ₂ , -C(H F ₂ , —OCH ₂ F, —CH ₂ F, —OCF ₃ , and —CN, cycloalkyl, heteroaryl, and heteroaryl substituted with 1 to 5 substituents each independently selected from the group consisting of: Fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkyloxy, -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ , cycloalkyl, -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF ₃ , and -CN; R ¹¹ is selected from the group consisting of: hydrogen , -NH ₂ , -N(H)C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -OH, cycloalkyl, C _1-6 alkyl, and 1 to 5 respectively C _1-6 alkyl optionally substituted with the following substituents: fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkyl oxygen, -OH, -COOH, -CF ₃ , - C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ and -CN; R ¹² is selected from the group consisting of: hydrogen, C _1-4 alkyl, -CF ₃ , -C(H)F ₂ , -CH ₂ F, fluorine and chlorine; R ¹³ is selected from: hydrogen, C _1-6 alkyl, di C _1-4 alkylamino C _1-4 alkyl, and amino C _1-6 alkyl; R ¹⁴ is selected from the group consisting of: hydrogen, cycloalkyl, heterocycloalkyl, a heterocycloalkyl group substituted with 1 to 4 substituents each independently selected from the group consisting of C _1-4 alkyl, C _1-4 alkyloxy, -OH, -COOH, -CF ₃ , -C ₁ - ₄ alkyl OC _1-4 alkyl, -NO _2, -NH ₂ and -CN, C _1-6 alkyl, and 1-4 through each independently selected from the substituents of C _1-6 alkyl: Fluorine, chlorine, bromine, iodine, C _1-4 alkyl oxygen, -OH, -CF ₃ , -COOH, -NO ₂ , -NH ₂ and -CN; R ¹⁵ is selected from the group consisting of: hydrogen and -CH ₃ ; ¹⁶ is selected from the group consisting of hydrogen, C _1-4 alkyl, -CF ₃ , -C(H)F ₂ , -CH ₂ F, fluorine and chlorine; X is CR ¹⁰¹ or N, wherein R ¹⁰¹ is selected from: hydrogen , fluorine and chlorine; and Y ¹⁰ and Y ¹¹ are each independently selected from: hydrogen, -CF ₃ and C _1-4 alkyl, or Y and Y ^{1 together} with the carbon attached thereto to form a C ₃ -C ₆ ring Alkyl; and salts thereof.

The invention also relates to pharmaceutically acceptable salts of the compounds of formula (II).

In the compound of formula (II), X is preferably CR ¹⁰¹ wherein R ¹⁰¹ is selected from the group consisting of hydrogen, fluorine and chlorine.

In the compound of the formula (II), X is preferably N.

The compound of the formula (I) of the present invention includes a compound of the formula (III): Wherein: R ²⁰ is selected from the group consisting of: phenyl, which may optionally be substituted with one to five substituents each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkyl oxygen. , -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , cycloalkyl, -OC(H)F ₂ , -C(H)F ₂ ,- OCH ₂ F, -CH ₂ F, -OCF ₃ , -NH ₂ and -CN, and a cycloalkyl group; R ²¹ is selected from the group consisting of hydrogen, methyl, -CF ₃ , fluorine and chlorine; and R ²² is selected from the group consisting of: Hydrogen, C _1-6 alkyl, di C _1-4 alkylamino C _1-4 alkyl, and amine C _1-6 alkyl; R ²³ is selected from: hydrogen, cycloalkyl, heterocycloalkane a heterocycloalkyl group substituted with 1 to 4 substituents each independently selected from the group consisting of C _1-4 alkyl, C _1-4 alkyloxy, -OH, -COOH, -CF ₃ , -C _{1 -4} alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ and -CN, and C _1-6 alkyl; R ²⁴ is selected from: hydrogen and -CH ₃ ; R ²⁵ is selected from: hydrogen, Methyl, -CF ₃ , fluorine and chlorine; X is CR ¹⁰² or N, wherein R ¹⁰² is selected from the group consisting of: hydrogen, fluorine and chlorine; and Y ²⁰ and Y ²¹ are independently selected from the group consisting of hydrogen, -CF ₃ and C _1-4 alkyl, or Y and Y ^{1 together} with the carbon to which it is attached form a C ₃ -C ₆ cycloalkyl group; and salts thereof.

The invention also relates to pharmaceutically acceptable salts of the compounds of formula (III).

In the compound of formula (III), X is preferably CH.

In the compound of the formula (III), R ^{21 is} preferably hydrogen.

In the compound of the formula (III), R ^{25 is} preferably hydrogen.

In the compound of the formula (III), R ^{20 is} preferably a phenyl group, which may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of fluorine and methyl, preferably methyl.

Among the compounds of the formula (III), Y ²⁰ and Y ^{21 are} preferably hydrogen.

In the compound of the formula (III), R ²² and R ^{24 are} preferably hydrogen.

In the compound of the formula (III), R ^{23 is} preferably selected from the group consisting of a methyl group and a cyclopropyl group, preferably a methyl group.

In the compound of formula (III), X is preferably CR ¹⁰² wherein R ¹⁰² is selected from the group consisting of hydrogen, fluorine, and chlorine.

In the compound of the formula (III), X is preferably N.

The compound of the formula (I) of the present invention includes a compound of the formula (IV): Wherein: R ³⁰ is selected from the group consisting of: phenyl, which may optionally be substituted with one to five substituents independently selected from the group consisting of fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkyl oxygen. , -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , cycloalkyl, -OC(H)F ₂ , -C(H)F ₂ ,- OCH ₂ F, -CH ₂ F, -OCF ₃ , -NH ₂ and -CN, and a cycloalkyl group; R ³¹ is selected from the group consisting of hydrogen, methyl, -CF ₃ , fluorine and chlorine; and R ³² is selected from the group consisting of: Hydrogen, cycloalkyl, heterocycloalkyl, heterocycloalkyl substituted with 1 to 4 substituents each independently selected from C _1-4 alkyl, C _1-4 alkyloxy, -OH, - COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ and -CN, and C _1-6 alkyl; R ³³ is selected from the group consisting of: hydrogen and -CH ₃ R ³⁴ is selected from the group consisting of hydrogen, methyl, -CF ₃ , fluorine and chlorine; X is CR ¹⁰³ or N, wherein R ¹⁰³ is selected from the group consisting of hydrogen, fluorine and chlorine; and Y ³⁰ and Y ³¹ are independently selected from the group consisting of Hydrogen, CF ₃ and C _1-4 alkyl, or Y and Y ^{1 together} with the carbon to which they are attached form a C ₃ -C ₆ cycloalkyl group; and salts thereof.

The invention also relates to pharmaceutically acceptable salts of the compounds of formula (IV).

In the compound of the formula (IV), X is preferably CH.

In the compound of the formula (IV), R ^{34 is} preferably hydrogen.

In the compound of the formula (IV), R ^{31 is} preferably hydrogen.

In the compound of the formula (IV), R ^{30 is} preferably a phenyl group, which may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of fluorine and methyl group, preferably a methyl group.

Among the compounds of the formula (IV), Y ³⁰ and Y ^{31 are} preferably hydrogen.

In the compound of the formula (IV), R ^{33 is} preferably hydrogen.

In the compound of the formula (IV), R ^{32 is} preferably selected from the group consisting of a methyl group and a cyclopropyl group, preferably a methyl group.

In the compound of formula (IV), X is preferably CR ¹⁰³ wherein R ¹⁰³ is selected from the group consisting of hydrogen, fluorine, and chlorine.

In the compound of the formula (IV), X is preferably N.

The compound of the formula (I) of the present invention includes: 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)- 4-(2,5-difluorobenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-methyl-7H- Pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-benzyl-1H-1,2,4-triazole-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-1H-1,2,4-triazole-5(4H)-one; 4-(4-amino-5-(4-(4-(2,5-difluorophenyl) -5-Sideoxy-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenyl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl) -1,1-dimethyl-piperidin-1-ium iodide; 1- (5- (4-amino-7-methyl -7 H - pyrrolo [2,3- d Pyrimidin-5-yl)pyridin-2-yl)-4-(2,5-difluorobenzyl)-1 H -1,2,4-triazole-5(4 H )-one; 1- (4- (4-amino-6,7-dimethyl -7 H - pyrrolo [2,3-d] pyrimidin-5-yl) -3-fluorophenyl) -4- (2,5- Difluorobenzyl)-1 H -1,2,4-triazole-5(4 H )-one; 1-(4-(4-amino-6-((dimethylamino)methyl) ) -7-methyl -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) -3-fluorophenyl) -4- (2,5-difluorobenzyl) -1 H - 1,2,4-triazole -5 (4 H) - one; l- (4- (4- amine 7-methyl -7 H - pyrrolo [2,3-d] pyrimidin-5-yl) -3-fluorophenyl) -4- (3,5-difluorobenzyl) -1 H -1 , 2,4-triazole-5( 4 H)-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)- 3-fluorophenyl)-4-(3,5-dimethylbenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino) -2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-difluorobenzyl)-1H- 1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl) 3-fluorophenyl)-4-(2,5-difluorobenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino) -2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(3,5-dimethylbenzyl)-1H -1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl) 3-fluorophenyl)-4-(cyclopentylmethyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-) -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-4-(2,5-difluorobenzyl)-1H-1,2,4- Triazol-5(4H)-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-benzene methyl-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-1-methyl-1H- Zoxao[3,4-d]pyrimidin-3-yl)phenyl)-4-benzyl-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4 -amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-4-(2,5-difluorobenzyl)-1H- 1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)- 3-fluorophenyl)-4-(3-chloro-2-fluorobenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino) -7-Methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,3-difluorobenzyl)-1H-1,2 , 4-triazole-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)-1H-1,2,4-triazole-5(4H)-one; 1-(5 -(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-4-(2,5-dimethylbenzyl) -1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5- 3-fluorophenyl)-4-(2,5-dimethylbenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4 -amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-dimethylbenzyl -1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3 -d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,3,6-trifluorobenzyl)-1H-1,2,4-triazole-5(4H)-one ; 1-(4-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(3-chloro- 2-fluorobenzyl)-1H-1,2,4-triazole-5(4H)-one; 2-(4-(4-amino-7-methyl-7H-pyrrolo[2,3 -d]pyrimidin-5-yl)-3-fluorophenyl)-4-(5-chloro-2-fluorobenzyl)-2,4-dihydro-3H-1,2,4-triazole- 3-keto; 2-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorophenyl)-4-( 2,5-Dimethylbenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one dihydro-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-1H-pyrazole) And [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)-1H-1,2,4-triazole-5(4H)-one; and salts thereof, including pharmaceutically acceptable salts thereof.

Those skilled in the art will appreciate that salts of the compounds of formula (I), including pharmaceutically acceptable salts, may be prepared. In fact, in certain embodiments of the invention, salts of the compounds according to formula (I), including pharmaceutically acceptable salts, may be preferred over individual individual free or non-salt compounds. Accordingly, the invention further relates to salts according to the compounds of formula (I), including pharmaceutically acceptable salts.

Salts of the compounds of the invention, including pharmaceutically acceptable salts, are readily prepared by those skilled in the art.

A compound according to formula (I) may contain one or more asymmetric centers (also known as a palm center) and thus may be individual enantiomers, diastereomers or other stereoisomeric forms, or mixture. A palmitic center (eg, a palmitic carbon atom) may be present in a substituent (eg, an alkyl group). Where the stereochemical chemistry of a compound of formula (I) or any of the chemical formulas shown herein is not explicitly indicated, it is intended to include all individual stereoisomers and all mixtures thereof. Thus a compound according to formula (I) comprising one or more pairs of palmar centers may be in the form of a racemic mixture, enriched A mixture of enantiomers or individual stereoisomers of pure enantiomeric nature.

The compounds according to formula (I) may also contain double bonds or other centers of geometric asymmetry. If the stereochemistry of the geometric asymmetry center contained therein is not specified in formula (I) or any of the chemical structures exemplified herein, the structural formula is intended to include trans (E) geometric isomers, cis (Z) geometric isomers. And all mixtures with it. Similarly, all tautomeric forms are also included in formula (I), whether or not such tautomers are in equilibrium or in one form.

The compounds or salts of formula (I), including pharmaceutically acceptable salts thereof, may be in solid or liquid form. When in solid form, the compounds of the invention may be crystalline or amorphous, or may be mixtures thereof. If the compound of the present invention is in a crystalline form, it is well understood by those skilled in the art that the pharmaceutically acceptable solvate is formed by the passage of solvent molecules into the crystal lattice during crystallization. Solvates in which water is the solvent entering the crystal lattice are often referred to as "hydrates". Hydrates include stoichiometric hydrates and compositions comprising various amounts of water.

It is also known to those skilled in the art that certain compounds of the formula (I) or salts (including pharmaceutically acceptable salts thereof) may be crystalline, including various solvates thereof, and may be polymorphic (also That is, the ability to have different crystal structures). These different crystal structures are often referred to as "polymorphs". Polymorphs have the same chemical composition, but differ in the stacking, geometric alignment, and other properties of the crystalline solid state. Therefore, polymorphs may have different physical properties such as shape, density, hardness, deformability, stability, and solubility. Polymorphs usually have different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for discrimination. Those skilled in the art will appreciate that different polytypes may be produced by, for example, changing or adjusting the reaction conditions or reagents used in the manufacture of the compound. For example, changing the temperature, pressure or solvent may result in a polytype. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

definition

"Alkyl" means a hydrocarbon chain having the specified number of "constituting atoms". For example, a C ₁ -C ₆ alkyl group means an alkyl group having 1 to 6 constituent atoms. The alkyl group can be a saturated, unsaturated, straight or branched chain. Representative branched alkyl groups have 1, 2, or 3 branches. Alkyl groups include methyl, ethyl, ethyl, propyl (n-propyl and isopropyl), butene, butyl (n-butyl, isobutyl, and tert-butyl), pentyl and hexyl .

"Alkoxy" means -O-alkyl, wherein "alkyl" is as defined herein. For example, C ₁ -C ₄ alkoxy means an alkoxy group having 1 to 4 constituent atoms. Representative branched alkoxy groups have 1, 2, or 3 branches. Examples of such groups include methoxy, ethoxy, propoxy, and butoxy.

"Aryl" means an aromatic hydrocarbon ring. An aryl group is a monocyclic ring system, a bicyclic ring system, and a tricyclic ring having a total of 5 to 14 ring constituent atoms, wherein at least one ring system is an aromatic system, and wherein each ring in the ring system contains 3 to 7 constituent atoms, Such as: phenyl, naphthalene, tetrahydronaphthalene and biphenyl. Suitable aryl groups are phenyl groups.

"Bicyclic heteroaryl" means two fused aromatic rings containing from 1 to 6 heteroatoms as constituent atoms. Bicyclic heteroaryl groups containing more than one hetero atom may contain different heteroatoms. The bicyclic heteroaryl ring has 6 to 11 constituent atoms. Bicyclic heteroaryl groups include: 1 H -pyrrolo[3,2- c ]pyridyl, 1 H -pyrazolo[4,3- c ]pyridyl, 1H-pyrazolo[3,4-d]pyrimidine 1,1H-pyrrolo[2,3-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, thieno[3,2-c]pyridyl, thieno[2,3-d Pyrimidinyl, furo[2,3-c]pyridyl, furo[2,3-d]pyrimidinyl, indolyl, isodecyl, anthracene Base, carbazolyl, fluorenyl, quinolyl, isoquinolinyl, quin Lolinyl, quinazolinyl, acridinyl, porphyrinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benzopyranyl, benzo Azyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5-c]pyridyl, imidazo[4.5-b]pyridyl, furopyridinyl and naphthalene Pyridyl.

Suitable "bicyclic heteroaryl" includes: 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrrolo[2,3-d]pyrimidinyl, 7H-pyrrolo[2,3-d] Pyrimidinyl, thieno[3,2-c]pyridyl, thieno[2,3-d]pyrimidinyl, furo[2,3-c]pyridinyl, indolyl, isodecyl, anthracene Base, carbazolyl, fluorenyl, quinolyl, isoquinolinyl, quin Lolinyl, quinazolinyl, acridinyl, porphyrinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benzopyranyl, benzo Azyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5-c]pyridyl, imidazo[4.5-b]pyridyl, furopyrimidinyl and naphthalene Pyridyl. Conveniently 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrrolo[2,3-d]pyrimidinyl, thieno[3,2-c]pyridyl, thieno[2,3 -d] pyrimidinyl, oxazolyl, quinolyl, quinazolinyl or benzothiazolyl. Conveniently, it is 1H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl or 1H-pyrrolo[2,3-d]pyrimidinyl. Conveniently, it is a 1H-pyrrolo[2,3-d]pyrimidinyl group.

"Cycloalkyl" means, unless otherwise stated, a saturated or unsaturated non-aromatic hydrocarbon ring containing from 3 to 7 carbon atoms. The cycloalkyl group is a monocyclic system. For example, a C ₃ -C ₇ cycloalkyl group means a cycloalkyl group having 3 to 7 constituent atoms. Examples of the cycloalkyl group used herein include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, and a cycloheptenyl group.

" Halo " means a halogen group of fluorine, chlorine, bromine, and iodine.

"Heteroaryl" means a monocyclic aromatic 4 to 8 membered ring containing from 1 to 7 carbon atoms and containing from 1 to 4 heteroatoms, with the proviso that when the number of carbon atoms is 3, the aromatic ring Contains at least 2 heteroatoms. Heteroaryl groups containing more than one hetero atom may contain different heteroatoms. Heteroaryl groups include: pyrrolyl, pyrazolyl, imidazolyl, Azolyl, different Azyl, thiazolyl, isothiazolyl, furyl, furyl, thienyl, triazolyl, pyridyl, pyrimidinyl, anthracene Base Base, three Base, four base. Conveniently. "Heteroaryl" includes: pyrazolyl, pyrrolyl, iso Azyl, pyridyl, pyrimidinyl, anthracene Base, and imidazolyl.

"Heterocycloalkyl" means a saturated or unsaturated non-aromatic ring containing 4 to 12 constituent atoms, wherein 1 to 11 are carbon atoms and 1 to 6 are heteroatoms. Heterocycloalkyl groups containing more than one hetero atom may contain different heteroatoms. The heterocycloalkyl group is a monocyclic ring system or a monocyclic ring fused to an aryl ring or to a heteroaryl ring containing 3 to 6 constituent atoms. Heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, piperidyl, tetrahydropyranyl, dihydropiperidyl, tetrahydrothiophenyl, pyrazolyl, Zyridinyl, oxetanyl, thiazolidinyl, piperidinyl, homocarbinyl, piperazine , morpholinyl, thiomorpholinyl, 1,3-dioxolyl, 1,3-dioxanyl, 1,3-oxathiolanyl, 1, 3-oxathiolanyl, 1,3-dithiane, 1,3- Azolidin-2-one, hexahydro-1H-azetidenyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, piperidinyl, 1,2,3,6- Tetrahydro-pyridyl and azacyclobutyl.

"Hetero atom" means a nitrogen, sulfur or oxygen atom.

The codes used in these processes, reaction flows, and examples are consistent with those used in contemporary scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry . Standard one-letter or three-letter abbreviations are often used to refer to amino acid residues and, unless otherwise indicated, refer to the L-configuration. All starting materials were obtained from commercial products and used without further purification unless otherwise stated. Specifically, the following abbreviations may be used throughout the examples and throughout the specification: Ac (acetamido); Ac ₂ O (acetic anhydride); ACN (acetonitrile); AIBN (azobis(isobutyronitrile)); BINAP ( 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); BMS (borane-dimethyl sulfide complex); Bn (benzyl); Boc (third) Oxycarbonyl); Boc ₂ O (di-tert-butyl dicarbonate); BOP (benzotriazol-1-yl-oxy-para-(dimethylamino)-phosphonium hexafluorophosphate); CAN (ammonium nitrate); Cbz (benzyloxycarbonyl); CSI (chlorosulfonyl isocyanate); CSF (fluorene fluoride); DABCO (1,4-diazabicyclo [2.2.2] octane); DAST (diethylamino)sulfur trifluoride); DBU (1,8-diazobicyclo[5.4.0]undec-7-ene); DCC (dicyclohexylcarbodiimide); DCE (1 ,2-dichloroethane); DCM (dichloromethane); DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone); ATP (adenosine triphosphate); Pinacol borate (4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked-1,3,2-dioxaborolan Alkane; BSA (fetal calf serum albumin); C18 (referred to as an 18-carbon alkyl group in the HPLC stationary phase) CH ₃ CN (acetonitrile) Cy (cyclohexyl); DCM (dichloromethane); DIPEA (Henny Alkaloids (Hüni G's base), N -ethyl- N- (1-methylethyl)-2-propylamine); Alkane (1,4-di Alkyl; DMAP (4-dimethylaminopyridine); DME (1,2-dimethoxyethane); DMEDA ( N , N' -dimethylethylenediamine); DMF ( N , N - II) Methylformamide); DMSO (dimethyl hydrazine); DPPA (diphenylphosphonium azide); EDC ( N- (3-dimethylaminopropyl) -N 'ethylcarbamate Imine); EDTA (ethylenediaminetetraacetic acid); EtOAc (ethyl acetate); EtOH (ethanol); Et ₂ O (diethyl ether); HEPES (4-(2-hydroxyethyl)-1-piperazine ethyl sulfonate Acid); HATU(O-(7-azabenzotriazol-1-yl) -N,N,N',N' -tetramethyluronium hexafluorophosphate); HOAt(1-hydroxy-7) -azabenzotriazole); HOBt (1-hydroxybenzotriazole); HOAc (acetic acid); HPLC (high performance liquid chromatography); HMDS (hexamethyldidecane aminide); Henn's base (Hunig's Base) ( N,N -diisopropylethylamine); IPA (isopropyl alcohol); porphyrin (2,3-dihydro-1 H -indole); KHMDS (hexamethyldiyl) Potassium decanohydride); LAH (lithium aluminum hydride); LDA (lithium diisopropylamide); LHMDS (lithium hexamethyldidecylamine) MeOH (methanol); MTBE (methyl tert-butyl ether) mCPBA (m-chloroperbenzoic acid); NaHMDS (sodium hexamethyldiazane); NBS ( N -bromosuccinimide); PE (petroleum ether) ; Pd ₂ (dba) ₃ (parade (diphenyleneacetone) dipalladium (0); Pd (dppf) Cl ₂ .DCM complex ([1,1 ' -bis(diphenylphosphino)) Ferric]dichloropalladium(II).dichloromethane complex);PyBOP (benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate); PyBrOP (bromotripyrrolidinylphosphonium hexafluorophosphate) Phosphate); RPHPLC (reverse phase high performance liquid chromatography); RT (room temperature); Sat. (saturated) SFC (supercritical liquid chromatography); SGC (silicone chromatography); SM (starting) 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 refer to diethyl ether and brine refers to a saturated aqueous solution of NaCl.

Compound method

The compounds according to formula I can be prepared by conventional organic synthesis. Suitable synthetic routes are shown in the following general reaction schemes. All starting materials are readily available from commercial products or are readily prepared by those skilled in the art using starting materials from commercial products.

Those skilled in the art will appreciate that if the substituents described herein are not compatible with the synthetic methods described herein, such substituents may be protected with suitable protecting groups which are stable to the reaction conditions. The protecting group can be removed at a suitable point in the reaction sequence to produce the desired intermediate or target compound. Suitable protecting groups and methods of protecting and removing the protection using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in T. Greene and P. Wuts "Protecting Groups in Chemical Synthesis (4th Edition), John Wiley and Sons, NY (2006)". In some cases, substituents that are reactive with the reaction conditions employed can be specifically selected. Under such circumstances, the reaction conditions are selected to convert the selected substituent into another substituent suitable for use as an intermediate compound or a desired substituent in the target compound.

The "x" and "r" groups used in the reaction scheme represent any corresponding position groups on the formulae I to IV. The compounds of formula G and M1 employed in the reaction scheme represent all corresponding R ¹ substituents of formula (I). All such substituents can be prepared according to the general instructions in the reaction scheme.

The compounds of the invention are generally prepared in accordance with Reaction Schemes 1 through 3. The substituted aryl hydrazine B is prepared by reacting the corresponding aniline A with concentrated HCl, sodium nitrite, and stannous chloride. Aryl hydrazine B is reacted with concentrated HCl and 2-sided oxyacetic acid to give the corresponding aryl thioglycolic acid C. The triazolone intermediate D is prepared by reacting intermediate C with TEA and DPPA and then treating with a suitable base such as sodium hydroxide. The triazolone intermediate D is alkylated using a substituted benzyl, cycloalkyl, or alkyl bromide to provide compound E. After conversion to the dihydroxyborate F , a palladium-catalyzed Suzuki-Miyaura reaction with the bicyclic heteroaryl bromide G yields the compound H which represents the structural formula of the compound of the present invention. In some embodiments of the invention, the formation of the dihydroxyborate and the Suzuki-Miyaura reaction are carried out in situ. In some instances, the dihydroxyborate is isolated and purified prior to the Suzuki-Miyaura reaction. The corresponding alkyl or aryl or cycloalkyl bromide employed is commercially available. The bicyclic heteroaryl bromide G is prepared according to the method described in the following literature: J. Med. Chem. , 2012, 55 (16), pp 7193-7207 and J. Med. Chem. , 2015, 58 (3) , pp 1426-1441. In general, the bicyclic heteroaryl halide G1 can be prepared in a similar manner and used to prepare a compound of the invention represented by H.

Reaction process 1

The 3-substituted triazolone of formula N is generally prepared according to Reaction Scheme 2. In the presence of: (DLPEA eg) of generating N - ethoxycarbonyl-acetyl J acid ethyl ester I-acetylamino acetimidate hydrochloride and ethyl chloroformate in a base. Ethoxycarbonyl acetimidate J is reacted with aryl hydrazine J1 in the presence of a base such as triethylamine to yield N -aryl-3-methyl-triazolone intermediate K. After alkylation of the triazolone K , a dihydroxyborate formation method and a Suzuki-Miyaura coupling method are carried out in a similar manner to the general method of Reaction Scheme 1 to produce a compound of the formula N.

The general linkage of the compound to the pyridyl group is prepared according to Reaction Scheme 3. The substituted carbamoylamine Z2 is prepared in two steps by reacting benzylamine Z with phenyl chloroformate Z1 and reacting with hydrazine hydrate. Z2 is formazylated by ethyl formate Z3 to give intermediate Z4 . Z4 is treated under basic conditions to give the triazolone. Z5 is arylated using bromoiodopyridine Z6 to give a disubstituted triazolone Z7 . After conversion to the dihydroxyborate Z8 , a palladium-catalyzed Suzuki-Miyaura reaction with bicyclic heteroaryl bromide G produces a compound of formula H1 which represents the structural formula of the compound of the invention.

Reaction process 3

Instructions

The compound according to formula (I) and its pharmaceutically acceptable salt are inhibitors of PERK. Such compounds have potential for the treatment of conditions caused by, but not limited to, activation of the UPR pathway as a starting cause, such as neurodegenerative diseases, cancer, cardiovascular and metabolic diseases. Thus, another aspect of the invention pertains to a method of treating such conditions.

The invention is preferably directed to a method of treating or reducing the severity of breast cancer, including inflammatory breast cancer, tubular carcinoma, and phyllodes carcinoma.

The invention is preferably directed to a method of treating or reducing the severity of colon cancer.

The invention is preferably directed to a method of treating or reducing the severity of pancreatic cancer, including insulinoma, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell tumor, and glucagonoma.

The invention is preferably directed to a method of treating or reducing the severity of skin cancer, including melanoma, including metastatic melanoma.

The invention is preferably related to a method for treating or reducing 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 is preferably directed to a method of treating or ameliorating the severity of a cancer selected from the group consisting of brain (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Barnnayan-Zonana's syndrome, Cowden's disease, Lhermitte-Duclos' disease, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medullary cells Tumor, head and neck, kidney, liver, melanoma, ovary, pancreas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell tumor, 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 myeloid leukemia, chronic Myeloid leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, Nuclear cell leukemia, multiple myeloma, acute megakaryoblastic leukemia, promyelocytic leukemia, erythrocytic leukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urinary epithelial cancer, vulvar cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, Salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal carcinoma, cheek cancer, oral cancer, GIST (gastrointestinal stromal tumor), neuroendocrine cancer and testicular cancer.

The present invention is preferably directed to a method of treating or ameliorating the severity of a precancerous syndrome in a mammal, including a human, wherein the precancerous syndrome is selected from the group consisting of: cervical intraepithelial neoplasia, unidentified individual gamma globulin (MGUS). , myelosynthesis syndrome, aplastic anemia, cervical damage, skin blemishes (pre-melanoma), prostatic intraepithelial (intra-tube) tumors (PIN), ductal carcinoma in situ (DCIS), colorectal polyps and severe hepatitis or hardening.

The present invention is preferably related to a method for treating or alleviating the severity of neurodegenerative diseases/injury, such as: Alzheimer's disease, spinal injury, traumatic brain injury, episodes of stroke, stroke, Parkinson's disease, metabolic syndrome, metabolic lesions, Huntington's disease, CJD, lethal familial insomnia, Jetsman-Stossler-Sykes syndrome, and related prion protein disease Progressive upper nucleus pneumonia, amyotrophic lateral sclerosis, and other diseases associated with UPR activation, including: diabetes, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute liver Disease, fatty liver disease, hepatic steatosis, chronic and acute lung disease of liver fibrosis, pulmonary fibrosis, chronic and acute kidney disease, renal fibrosis, chronic traumatic brain disease (CTE), neurodegeneration, dementia, amount Alfalfa dementia, Tau protein lesions, Pick's disease, Niemann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, eye disease, and arrhythmia.

The present invention is preferably directed to a method of preventing organ damage during and after organ transplantation and delivery of a transplanted organ. A method of preventing organ damage during and after organ transplantation involves administering a compound of formula (I) in vivo. The method of preventing organ damage during and after delivery of the transplanted organ comprises adding a compound of formula (I) to a solution of the preserved organ during transport.

The compounds of the invention inhibit angiogenesis, which is involved in the treatment of ocular diseases. Nature Reviews Drug Discovery 4 , 711-712 (September 2005). The invention is preferably directed to a method of treating or reducing the severity of ocular disease/angiogenesis. In a specific embodiment of the method according to the invention, the pathological condition of the eye disease including vascular leakage may be: edema or neovascularization of any occlusive or inflammatory retinal vascular disease, such as: iris redness, neovascular glaucoma, eye翳, vascularized glaucoma conjunctival blebs, conjunctival papilloma; choroidal neovascularization, such as: neovascular age-related macular degeneration (AMD), myopia, anterior uveitis, trauma, or idiopathic; Edema, such as: macular edema after surgery, macular edema followed by uveitis, including retinal and / or choroidal inflammation, macular edema followed by diabetes, and macular edema followed by retinal occlusive disease Branch and central retinal vein occlusion; retinal neovascularization due to diabetes, such as retinal vein occlusion, uveitis, ocular congestive syndrome caused by carotid artery disease, occlusion of the eye or retinal artery, sickle cell retina Lesions, other septic or occlusive neovascular retinopathy, retinopathy of prematurity, or Wales's disease (Eale's Disease); and genetic diseases, such as: Ping Xibai - Lindau's disease (VonHippel-Lindau syndrome) syndrome.

In some embodiments, the neovascular age-related macular degeneration is wet aging-related macular degeneration. In other embodiments, the neovascular age-related macular degeneration is dry aging-related macular degeneration, and the patient is characterized by a high risk of developing wet aging-related macular degeneration.

The method of treatment of the present invention comprises administering to a patient in need thereof an effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof.

The invention also provides a compound according to formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy, and in particular for the treatment of: cancer, precancerous syndrome, Alzheimer's disease, spinal injury, trauma Brain damage, blood-threatening stroke, stroke, diabetes, Parkinson's disease, metabolic syndrome, metabolic disease, Huntington's disease, Creutzfeldt-Jakob Disease, lethal familial insomnia, Gerstmann-Sträussler-Scheinker syndrome, related Prion protein disease, amyotrophic lateral sclerosis, progressive supranuclear nucleus, myocardial Infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute liver disease, fatty liver disease, hepatic steatosis, liver fibrosis, chronic and acute lung disease, pulmonary fibrosis, chronic and acute kidney disease, kidney Fibrosis, chronic traumatic brain lesions (CTE), neurodegeneration, dementia, frontotemporal dementia, Tau proteinopathy, Pick's disease, Niemann-Pick's disease (N eimann-Pick's disease), amyloidosis, cognitive impairment, atherosclerosis, eye disease, arrhythmia, use in organ transplantation and for the transport of transplanted organs. In another aspect, the invention relates to the use of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder characterized by UPR activation, such as cancer.

The term "treatment" and its derivatives used in reference to a disease herein means: (1) mitigating or preventing a condition or one or more biological symptoms of the condition, (2) interfering with (a) causing the condition or one or more points in the biological cascade responsible for the condition or (b) the condition One or more biological signs, (3) alleviating one or more symptoms or effects associated with the condition, or (4) slowing the progression of the condition or one or more of the symptoms of the condition.

Those familiar with this related skill know that "prevention" is not an absolute noun. In medicine, it is understood that "prevention" refers to prophylactic administration to substantially alleviate the likelihood or severity of a condition or its biological symptoms, or to delay the onset of such conditions or biological symptoms thereof.

Prophylactic Therapy is applicable to individuals who have, for example, a history of a strong family cancer or who are considered to have a high risk of developing cancer or who have been exposed to a carcinogen.

As used herein, the term "effective amount" and its derivatives mean a drug or agent that will elicit a biological or medical response in, for example, a tissue, system, animal or human being explored by a researcher or clinical person. In addition, the term "medicalally effective amount" and its derivative terms mean that when compared to a corresponding individual who does not receive such an amount, it may result in an improvement in treatment, cure, prevention or alleviation of a disease, a disease, or a side effect, or a reduction in the rate of progression of the disease or condition. Any amount used. The term also encompasses amounts effective to enhance normal physiological function.

The term "patient" or "individual" as used herein refers to a human or other animal. A suitable patient or individual is a human.

The compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration and parenteral administration. Parenteral administration refers to the administration of drugs other than enteral, transdermal or inhaled administration, and is mainly by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.

The compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered once or according to a dosing regimen wherein multiple doses can be administered separately at different time intervals for a specified period of time. For example: you can do it once, twice, three times or four times a day. The dose can be administered to reach Require medical effects or maintain the desired medical results indefinitely. Suitable administration regimens for the compounds of the invention will depend on the pharmacokinetic properties of the compound, such as absorbency, distribution, and half-life, as determined by those skilled in the art. In addition, the appropriate course of administration of the compounds of the present invention, including the duration of such treatment, depends on the condition being treated, the severity of the condition being treated, the age and condition of the patient being treated, the history of the patient being treated, and The nature of the therapy being performed, the nature of the medical treatment required, and the knowledge of those skilled in the art will be determined by similar factors known in the art. Those skilled in the art will also appreciate that suitable medication regimens may need to be adjusted as individual patients respond to the medication regimen or individual patient needs change over time.

Furthermore, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered as a prodrug. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, when administered to a patient, will ultimately release the compound of the invention in vivo. When a prodrug is administered to a compound of the invention, one or more of the following may be made by a person familiar with the art: (a) modifying the initial action of the compound in vivo; (b) modifying the duration of the compound in vivo (c) modifying the transport or distribution of the compound in vivo; (d) modifying the solubility of the compound in vivo; and (e) overcoming the side effects or other difficulties encountered with the compound. If -COOH or -OH groups are present, pharmaceutically acceptable esters may be used, for example: -COOH may be methyl, ethyl, and analog esters, and -OH may be acetate, Malay Esters, analogs, and related art are known to modify solubility esters.

The compound of formula (I) and its pharmaceutically acceptable salt can be co-administered with at least one other active agent known to be useful in the treatment of cancer or pre-cancerous syndrome.

The term "co-administered" as used herein means the simultaneous administration or in any separate order for administration of the PERK inhibitory compounds described herein, as well as other active agents (groups) known to be useful in the treatment of cancer, including chemotherapy and radiation therapy. Other active agent (group) terms as used herein include any compound or medical agent that is known or proven to have beneficial properties when administered to a patient in need of treatment for cancer. More If the system is not administered at the same time, the compounds are administered in a compact time between each other. In addition, it is not limited whether the compounds should be administered in the same dosage form, for example, one of the compounds may be administered by injection, and the other compound may be administered orally.

Generally, any tumor agent having activity against the therapeutic tumor being treated can be co-administered for use in the cancer treatment of the present invention. Examples of such formulations can be found in VT Devita and S. Hellman (eds.) "Cancer Principles and Practice of Oncology", 6th Edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. Those skilled in the art should be able to distinguish between combinations of agents that may be suitable depending on the nature of the drug and the cancer involved. Typical anti-tumor agents suitable for use in the present invention include, but are not limited to, anti-microtubule agents such as: diterpenes and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen hydrazine, Oxythiazepine benzene, alkyl sulfonate, nitrosourea, and three Antibiotic agents, such as: anthracyclines, actinomycin and bleomycin; topoisomerase II inhibitors, such as: epipodophyllotoxin; antimetabolites, such as: purines and pyrimidine analogs and anti-leaf Acid salt compounds; topoisomerase I inhibitors, such as: camptothecins; hormones and hormone analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunomedical agents; Apoptotic agents; cell cycle signal transduction inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.

Examples of other active ingredients (groups) (anti-tumor agents) which can be used in combination with or co-administered with the PERK inhibitory compounds of the invention are chemotherapeutic agents.

Conveniently, the pharmaceutically active compound of the present invention is used in combination with a VEGFR inhibitor, preferably 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2 -Pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, preferably in the form of a monohydrochloride salt thereof, which is in International Application No. PCT/US01/49367 (International The application date is December 19, 2001), the international publication number WO02/059110 (International Publication Date, August 1, 2002), which discloses and claims its patent rights, the complete disclosure of which is incorporated herein by reference. And is the compound of Example 69. 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide International Prepared by the description of application No. PCT/US01/49367.

Conveniently, 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonate The amine is monohydrochloride type. This salt type can be prepared by a person familiar with the relevant art in accordance with the description of International Application No. PCT/US01/49367 (International Application Date, December 19, 2001).

5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide The monohydrochloride type is sold as a commercial product known as pazopanib under the trade name Votrient ^® .

Pazopanib is involved in the treatment of cancer and eye diseases/angiogenesis. The invention is preferably directed to a method of treating cancer and eye disease/angiogenesis, preferably age-related macular degeneration, comprising administering a compound of formula (I), either alone or in combination with pazopanib.

In a specific embodiment, the cancer treatment method of the present invention comprises co-administering a compound of the formula (I) and/or a pharmaceutically acceptable salt thereof, and at least one antitumor agent, such as: one selected from the group consisting of the following: Formulations in the group: anti-microtubules, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormones Analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutics, pro-apoptotic agents, cell cycle signal transduction inhibitors, proteasome inhibitors, and inhibition of cancer metabolism Agent.

Conveniently, the compound of formula (I) and its pharmaceutically acceptable salt can be co-administered with at least one other active agent known to be useful in the treatment of neurodegenerative diseases/injuries. .

Conveniently, the compound of formula (I) and its pharmaceutically acceptable salt can be co-administered with at least one other active agent known to be useful in the treatment of diabetes.

Conveniently, the compound of formula (I) and its pharmaceutically acceptable salts can be co-administered with at least one other active agent known to be useful in the treatment of cardiovascular diseases.

Conveniently, the compound of formula (I) and its pharmaceutically acceptable salt may be at least another Other active agents known to be useful in the treatment of ocular diseases are co-administered.

Conveniently, the compound of formula (I) and its pharmaceutically acceptable salt can be co-administered with at least one other active agent known to be useful for preventing organ damage during and after organ transplantation and delivery of the transplanted organ.

Composition

The pharmaceutically active compounds within the scope of the invention are suitable for use in mammals in need, in particular human PERK inhibitors.

The invention therefore provides a method of treating cancer, neurodegeneration and other conditions in need of inhibiting PERK comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds of formula (I) also provide a means of treating the above indications as they have demonstrated competence as PERK inhibitors. The drug can be administered by any of the usual routes including, but not limited to, intravenous, intramuscular, oral, topical, subcutaneous, intradermal, intraocular, and parenteral. Conveniently, the PERK inhibitor can be delivered directly to the brain using an intrathecal or intraventricular route, or implanted in a suitable anatomical location in a device or pump for sustained release of the PERK inhibitor drug.

The pharmaceutically active compounds of the present invention are incorporated into conventional dosage forms such as capsules, troches, or injections. Use solid or liquid pharmaceutical carriers. Solid carrier materials include: starch, lactose, calcium sulfate dihydrate, gypsum, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, physiological saline, and water. Likewise, the carrier or diluent may include any extended release material such as glyceryl monostearate or glyceryl distearate, either alone or in combination with a wax. The amount of solid carrier used varies widely, but is preferably from about 25 mg to about 1 g per unit dose. When a liquid carrier is employed, the preparation will be in the form of syrups, elixirs, emulsions, soft gelatin capsules, sterile injections such as ampoules or aqueous or nonaqueous liquid suspensions.

Pharmaceutical compositions are manufactured according to commonly used medicinal chemistry techniques, which involve Mixing, granulating, and compressing to form a tablet, or suitably mixing, filling, and dissolving the ingredients to produce the desired oral or parenteral drug product.

The dose of the pharmaceutically active compound of the present invention in the above pharmaceutical dosage unit will be an effective non-toxic amount, preferably selected from the range of 0.001 to 500 mg/kg of the active compound, preferably 0.001 to 100 mg/kg. When treating a human patient in need of a PERK inhibitor, the selected dosage is preferably administered one to six times a day, either orally or parenterally. Preferred parenteral dosage forms include topical, rectal, transdermal, injection and continuous infusion. Dosage units for oral administration to humans preferably comprise from 0.05 to 3500 mg of active compound. Suitable oral unit dosages for oral administration to humans preferably comprise from 0.5 to 1,000 mg of active compound. It is preferred to use a lower dose for oral administration. However, when the patient is safe and convenient, a high dose can also be administered parenterally.

The optimal dosage will be readily determined by those skilled in the art and will vary with the particular PERK inhibitor used, the strength of the formulation, the mode of administration, and the condition of the disease. Other factors that require adjustment of the dosage with the particular patient being treated include the patient's age, weight, diet, and time of administration.

When administering a transplanted organ to administer a drug to prevent organ damage, it is preferred to add a buffer solution to the solution containing the formula (I) during transport to a solution containing the organ.

The method of the present invention for inducing a PERK inhibitory activity in a mammal, including a human, comprises administering to a subject in need of such activity an pharmaceutically effective compound of the present invention which inhibits a PERK effective amount.

The invention also provides a use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as a PERK inhibitor.

The invention also provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in medicine.

The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof Pharmacological uses for the treatment of cancer, precancerous syndrome, Alzheimer's disease, spinal injury, traumatic brain injury, acute stroke, stroke, Parkinson's disease, diabetes, metabolic syndrome, metabolic disease , Huntington's disease, Cui's disease, fatal familial insomnia, Jetsman-Stossler-Sykes syndrome, associated prion protein disease, amyotrophic lateral sclerosis, Progressive upper nucleus pneumonia, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute liver disease, fatty liver disease, hepatic steatosis, liver fibrosis, chronic and acute lung disease, lung fiber Renal, chronic and acute kidney disease, renal fibrosis, chronic traumatic brain disease (CTE), neurodegeneration, dementia, frontotemporal dementia, Tau proteinopathy, Pick's disease, Niemann-Pick's disease Amyloidosis, cognitive impairment, atherosclerosis, eye disease, and arrhythmia.

The invention also provides a pharmaceutical use for the manufacture of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention of organ damage during delivery of a transplanted organ.

The invention also provides a pharmaceutical composition for use as a PERK inhibitor comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The invention also provides a pharmaceutical composition for treating cancer comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Further, the pharmaceutically active compound of the present invention can be administered together with other active ingredients, such as other compounds known to treat cancer, or compounds known to be useful in combination with a PERK inhibitor.

The present invention also provides a pharmaceutical composition comprising 0.5 to 1,000 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof and 0.5 to 1,000 mg of a pharmaceutically acceptable excipient.

Without further elaboration, those skilled in the art will be able to utilize the present invention to the fullest extent. The following examples are therefore illustrative only and are not intended to limit the invention in any way.

Instance

The following examples illustrate the invention. The examples are not intended to limit the scope of the invention, but may be provided by those skilled in the art to prepare and use the compounds, compositions, and methods of the invention. Having described the specific embodiments of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.

Intermediate Examples 3 to 5 provide a synthesis method and corresponding experimental method for preparing bicyclic heteroaryl bromide intermediates C6 , C9 , and C13 for the examples.

Intermediate Example 1: 3-bromo-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine ( C6 )

Step 1: Add NBS (3.4 g, a stirred solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (2.5 g, 16.23 mmol, 1 equiv) in DCM (30 mL) 19.48 mmol, 1.2 equiv). The reaction mixture was allowed to warm 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 sulfate and evaporated to give a crude material. The compound was dissolved in 15% ethyl acetate in n-hexane to give 3-bromo-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.3 g, crude product ) a pale yellow solid. ^{1 H NMR (400MHz, DMSO-} d 6) δ ppm-8.02 (s, 1H), 12.18 (s, 1H), 14.00 (br.s, 1H)

Step 2: pyridine containing 3-bromo-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.3 g, 6.04 mmol, 1 equiv) at room temperature To a stirred solution was added cyclopropyldihydroxyboronic acid (1.03 g, 12.09 mmol, 2 equiv) and copper acetate (2.18 g, 12.09 mmol, 2 equiv). The reaction mixture was stirred at 90 ° C for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give a crude material. The compound was dissolved in 2% MeOH in DCM to give 3-bromo-1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.2 g , crude product) as a pale yellow solid. LCMS (ES) m / z = 255.0,257.0 [M + H.] +. ^{1 H NMR (400MHz, DMSO-} d 6) δ ppm-0.16 (m, 1H), 0.30 (m, 1H), 0.32 (m, 1H), 0.37-0.40 (m, 1H), 2.54 (s, 1H) , 7.21 (s, 1H), 7.65 (br.s, 1H)

Step 3: 3-bromo-1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.2 g, 4.70 mmol) at room temperature DMF (1.2 mL) and POCl ₃ (1.5 mL) were added to a stirred solution of dichloromethane (20 mL). The reaction mixture was stirred at 80 ° C for O/N. The reaction mixture was cooled Sat.NaHCO ₃ (0-5 deg.] C) to suspend the reaction, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to give a crude material. The compound was dissolved in 15% EtOAc in n-hexane to give 3-bromo-4-chloro-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine (0.4 g, 31%) solid. LCMS (ES) m / z = 273.1,275.1 [M + H.] +. ^{1 H NMR δ ppm-1.20-1.23 (} m, 2H) (400MHz, CDCl 3), 1.35 (s, 2H), 3.84-3.88 (m, 1H), 8.77 (s, 1H)

Step 4: At room temperature, in a mixture containing 3-bromo-4-chloro-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine (0.4 g, 1.46 mmol, 1 equiv) -two NH ₄ OH (10 mL) was added to a stirred solution of hexane (5 mL). The reaction mixture was heated to O/N in an autoclave at 100 °C. The reaction mixture was cooled and the solid formed was evaporated to crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LCMS (ES) m / z = 254.0,256.0 [M + H.] +. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm-1.02 (d, J = 5.6 Hz, 2H), 1.10 (s, 2H), 3.68-3.78 (m, 1H), 6.20-8.10 (br.s, 2H), 8.19 (s, 1H)

Intermediate Example 2: 5-Bromo-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( C9 )

Step 1: Operation 1: Add cyclopropyl at room temperature in a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 26.14 mmol, 1 equiv) in pyridine (40 mL) Diboronic acid (4.4 g, 52.28 mmol, 2 equiv) and copper acetate (9.4 g, 52.28 mmol, 2 equiv). The reaction mixture was stirred at 90 ° C for O/N. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give a crude material. The compound was dissolved in 20% EtOAc in n-hexane to yield 4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (0.7 g, 14%). LCMS (ES) m / z = 194.1 [M + H.] +. ^{1 H NMR (400MHz, CDCl3)} δ ppm-1.06-1.10 (m, 2H), 1.14-1.21 (m, 2H), 3.50-3.55 (m, 1H), 6.54 (d, J = 3.6Hz, 1H), 7.23 (d, J = 3.6 Hz, 1H), 8.67 (s, 1H)

Operation 2: 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 16.276 mmol, 1.0 eq), cyclopropyldihydroxyboronic acid (2.8 g, 32.55 mmol, 2 eq), sodium carbonate (3.45 g, 32.5 mmol, 2 eq) of a stirred suspension of dichloroethane (50 mL) containing Cu(OAc) ₂ (2.95 g, 16.3 mmol, 1.0 eq), and Bipy (2.54 g, 16.3 mmol, 1.0 eq) a suspension of hot dichloroethane (20 mL). The reaction mixture was heated to reflux and stirred overnight. The TLC was used to track whether the reaction was completed. The reaction mixture was cooled to room temperature and filtered over EtOAc. The strontium salt bed was thoroughly washed with dichloroethane. The filtrate was washed again with 1 N HCl and the layers were separated. The aqueous phase was extracted with DCM, combined organic layers were washed with brine, dried over Na ₂ SO ₄ dried, filtered, evaporated, and purified by flash column chromatography. The desired product was dissolved in 12% EtOAc in hexanes. The fractions containing the desired product were combined and concentrated to give the desired product, 4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine as a white solid (1.85 g, 53%).

Step 2: Add at 0 ° C in 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) NBS (0.61 g, 3.47 mmol, 1.0 equiv). The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated tolululululululululululululululululululululululu LCMS (ES) m / z = 272.5,274.5 [M + H.] +. ^{1 H NMR δ ppm-1.02-1.04 (} m, 4H) (400MHz, DMSO-d 6), 3.62-3.63 (m, 1H), 7.95 (s, 1H), 8.66 (s, 1H)

Step 3: 1,4-containing 5-bromo-4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (0.7 g, 2.57 mmol, 1 equiv) at room temperature two NH ₄ OH (10 mL) was added to a stirred solution of hexane (5 mL). The reaction mixture was heated in an autoclave at 100 ° C for 16 h. The reaction mixture was cooled and the solid formed was filtered to afford crystals of 5-bromo-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine (0.63 g, 96%). LCMS (ES) m / z = 253.0,255.0 [M + H.] +. ^{1 H NMR (400MHz, DMSO-} d 6) δ ppm-0.97 (s, 4H), 3.45-3.51 (m, 1H), 6.64 (br.s, 2H), 7.33 (s, 1H), 8.09 (s, 1H)

Intermediate Example 3: 3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine ( C13 )

Step 1: Add NBS (3.2 g, in a stirred solution of 44-chloro-1H-pyrazolo[3,4-d]pyrimidine (2.5 g, 16.17 mmol, 1 equiv) in DMF (50 mL). 17.78 mmol, 1.1 equiv). The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give crystallite crystallite LCMS (ES) m / z = 233.4,235.4 [M + H.] +. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm-8.82 (s, 1H), 14.80 (br.s, 1H)

Step 2: Add hydrogenation at 0 ° C in a stirred solution of 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (3.5 g, 15.02 mmol, 1 equiv) in DMF (60 mL) Sodium (0.72 g, 18.02 mmol, 1.2 equiv). The reaction mixture was stirred at 0 ° C for 15 min. 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 3 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give a crude material which was purified eluting The compound was dissolved in 30% EtOAc in n-hexanes. The resulting extract was concentrated to give 3-bromo-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (2.0 g, 57%). LCMS (ES) m / z = 247.4,249.4 [M + H.] +. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm-4.03 (s, 3H), 8.88 (s, 1H)

Step 3: 1,4-containing 3-bromo-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (2.0 g, 8.09 mmol, 1 equiv) at room temperature two NH ₄ OH (30 mL) was added to a stirred solution of hexane (10 mL). The reaction mixture was heated to O/N in an autoclave at 100 °C. The reaction mixture was cooled and the solid formed was filtered to afford crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal LCMS (ES) m / z = 228.0,230.0 [M + H.] +. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm-3.84 (s, 3H), 6.42-7.20 (br.s, 2H), 7.34-8.52 (br.s, 2H), 8.19 (s, 1H)

Example 1 1-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-difluoro Benzyl)-1H-1,2,4-triazole-5(4H)-one

Step 1: Add NaNO ₂ (56.3 g, 0.827 mol, 1.05 equiv) to a stirred solution of 4-bromo-3-fluoroaniline (150 g, 0.789 mol, 1 equiv) in concentrated HCl (756 mL). aqueous solution (390mL), the reaction mixture was stirred for 30min, containing added _{SnCl 2 .2H 2 O (343g,} 2.95mol, 3.7equiv) of concentrated HCl (582mL) was added. The resulting mixture was allowed to warm to room temperature and stirred for 1 h. The resulting opal suspension was filtered with EtOAc (EtOAc)EtOAc. ¹ H NMR (400 MHz, DMSO- d 6) δ ppm 6.76-6.78 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 11 Hz, 1H), 7.56 (t, J = 8.24 Hz, 1H), 8.73 (br.s, 1H), 10.46 (br.s, 3H).

Step 2: Concentrated HCl (121.66 mL) was added to a stirred suspension of (4-bromo-3-fluorophenyl)hydrazine hydrochloride (154 g, 0.641 mol, 1 EtOAc) (1. 50% 2-aqueous solution of acetoacetic acid (52 g, 0.705 mol, 1.1 equiv). The mixture turned orange and was 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 SO ₄ dried, filtered, and evaporated to dryness. Milled in diisopropyl ether to give the desired product ( E )-2-(2-(4-bromo-3-fluorophenyl)indenyl)acetic acid as a pale yellow powder (75 g, 45.18% yield ). LCMS (ES) m / z = 259,260.83 [M + H] +. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 6.85-6.87 (m, 1H), 7.07-7.10 (m, 1H), 7.15 (s, 1H), 7.53-7.57 (m, 1H), 11.37 (s , 1H), 12.54 (br.s, 1H).

Step 3: Add Et _{3 to a} stirred suspension of ( E )-2-(2-(4-bromo-3-fluorophenyl)indenyl)acetic acid (74 g, 0.284 mol, 1 equiv) in toluene (740 mL) N (39.91 mL, 0.284 mol, 1 equiv) and DPPA (61.65 mL, 0.284 mol, 1 equiv). The mixture was slowly heated under reflux for 5 hours. The reaction was cooled and 1N NaOH solution (1.0 L) and water (2. After the aqueous phase was washed with Et ₂ O, it was acidified to pH 2 using 1N HCl solution. The precipitate was filtered off, washed with water, dried EtOAc EtOAc EtOAc The organic phase was dried over Na ₂ SO ₄ dried, filtered, and evaporated to dryness. Milled with iPr ₂ O to give a pale yellow powder of 1-(4-bromo-3-fluorophenyl)-1 H -1,2,4-triazol-5( 4H )-one (33.0 g, 45.20 %Yield). LCMS (ES) m / z = 255.89,257.90 [M + H] +. ¹ H NMR (400 MHz, DMSO- d 6) δ ppm 7.71-7.80 (m, 2H), 7.89 (dd, J = 2.08, 10.8 Hz, 1H), 8.19 (s, 1H), 12.16 (s, 1H).

Step 4: Add 1-(4-bromo-3-fluorophenyl)-1 H -1 to a stirred suspension of 60% NaH (2 g, 50.387 mmol, 1.3 equiv) in DMF (50 mL). After 2,4-triazole-5( 4H )-one (10 g, 38.759 mmol, 1 equiv), stirred for 30 min, and added 2-(bromomethyl)-1,4-difluorobenzene (9.6 g) at 0 °C. , 46.511 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 2.5 h and quenched with ice water. The precipitate was filtered off, washed with water and dried to give 1-(4-bromo-3-fluorophenyl)-4-(2,5-difluorobenzyl)-1 H -1,2,4-triazole -5 ( 4H )-ketone as an off-white powder (13.2 g, 88% yield). LCMS (ES) m/z = 384.0, 386.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d 6) δ ppm 4.87 (s, 2H), 6.99-7.12 (m, 2H), 7.12-7.17 (m, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.59 (s, 1H), 7.73 (dd, J = 1.6, 8.8 Hz, 1H), 7.86 (dd, J = 2, 10.4 Hz, 1H).

Step 5: Dihydroxyborate isolation: Take 1-(4-bromo-3-fluorophenyl)-4-(2,5-difluorobenzyl)-1 H -1,2,4 Triazole-5( 4H )-one (11.2 g, 39.436 mmol, 1 equiv), bis-pinacol borate (15 g, 59.154 mmol, 1.5 equiv) and potassium acetate (11.59 g, 118.309 mmol, 3 equiv) 250mL 1,4-two The mixture of the alkane was degassed with nitrogen for 15 min, and a mixture of PdCl ₂ (dppf)-CH ₂ Cl ₂ (1.6 g, 1.971 mmol, 0.05 equiv) was added, and the reaction mixture was stirred at 100 ° C overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with EtOAc EtOAc The combined fractions containing the pure product were collected and concentrated in vacuo to give 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl) Grayish white of 1,3,3,2-dioxaborolan-2-yl)phenyl)-1 H -1,2,4-triazole-5(4 H )-one (8.1 g) solid. LC-MS (ES) m / z = 432.2 [M + H] +.

Step 6: Suzuki-Miyaura reaction:

Operation 1: Take 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa) Boronocyclic-2-yl)phenyl)-1 H -1,2,4-triazole-5(4 H )-one (2g, 4.640mmol, 1equiv), 5-bromo-7-methyl -7 H -pyrrolo[2,3- d ]pyrimidin-4-amine (1 g, 4.640 mmol, 1 equiv), K ₃ PO ₄ (1.96 g, 9.280 mmol, 2.0 equiv) and Pd ₂ (dba) ₃ (0.21 g, 0.232mmol, 0.05equiv) 60mL 1,4-two A mixture of alkane and 20 mL of water was bubbled through a sealed tube with nitrogen for 10 min, and tris-(t-butyl)phosphonium tetrafluoroborate (0.134 g, 0.464 mmol, 0.1 equiv) was added, and the reaction mixture was placed in a sealed container. Stir at 100 ° C overnight. After completion of the reaction mixture, the mixture was cooled to EtOAcqqqqm LC-MS (ES) m / z = 452.1 [M + H] +.

Operation 2: Take 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa) Boronocyclic-2-yl)phenyl)-1 H -1,2,4-triazole-5(4 H )-one (5g, 11.60mmol, 1equiv), 5-bromo-7-methyl -7 H -pyrrolo[2,3- d ]pyrimidin-4-amine (2.6 g, 11.60 mmol, 1 equiv), K ₃ PO ₄ (4.9 g, 23.201 mmol, 2.0 equiv) and Pd ₂ (dba) ₃ ( 0.53g, 0.58mmol, 0.05equiv) 100mL 1,4-two A mixture of alkane and 30 mL of water was placed in a 250 mL sealed tube, nitrogen was bubbled through for 15 min, tris-(t-butyl)phosphonium tetrafluoroborate (0.336 g, 1.160 mmol, 0.1 equiv) was added and the reaction mixture was placed in a sealed container. Stir at 100 ° C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered over EtOAc EtOAc. The crude product was purified by flash column chromatography eluting with EtOAc EtOAc EtOAc The combined fractions containing the pure product were combined and concentrated in vacuo. The solid product was milled with diethyl ether (3 x 30mL) and dried to give 1- (4- (4-amino-7-methyl -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) - 3-fluorophenyl)-4-(2,5-difluorobenzyl)-1 H -1,2,4-triazole-5(4 H )-one as an off-white solid (5.43 g, 74% yield Rate, combined yield of operation 1 and operation 2). LC-MS (ES) m / z = 452.1 [M + H] +. ¹ H NMR (400 MHz, DMSO- d 6) 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, 1H), 7.80-7.83 (m, 2H), 8.13 (s, 1H), 8.36 (s, 1H). The purity of the HPLC was determined to be 99.72% at 254 nM.

Example 2 1- (4- (4-amino-7-methyl -7 H - pyrrolo [2,3-d] pyrimidin-5-yl) -3-fluorophenyl) -4-benzyl -1 H -1,2,4-triazole-5(4 H )-one

Step 1: Containing 1-(4-bromo-3-fluorophenyl)-1 H -1,2,4-triazole-5(4 H )-one (0.5) at 0 ° C and N ₂ After adding 60% NaH (0.078 g, 1.94 mmol, 1 equiv) in portions to a stirred suspension of D.sub.1 (1. The reaction mixture was stirred at rt. Combined organic layers were washed with saline solution, dehydrated over Na ₂ SO _4, and concentrated. The crude product was purified by flash column chromatography eluting with EtOAc EtOAc EtOAc Phenyl)-1 H -1,2,4-triazole-5( 4H )-one as a pale yellow solid (0.52 g, 65.3% yield). LCMS (ES) m/z = 348.0, 350.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d 6) δ ppm 4.88 (s, 2 H), 7.29-7.39 (m, 5H), 7.72-7.74 (m, 1H), 7.79 (t, J = 7.6 Hz, 1 H ), 7.87-7.90 (m, 1 H), 8.42 (s, 1H).

Step 2: 4-Benzyl-1-(4-bromo-3-fluorophenyl)-1 H -1,2,4-triazole-5(4 H )-one (0.520 g, 1.494 mmol) , 1.0 equiv) Addition of bis-pinacol borate (0.130 g, 1.494 mmol, 1.0 equiv), potassium acetate (0.440 g, 1.494 mmol, 3.0 equiv), the mixture was degassed with argon for 10 min, and PdCl was added. ₂ (dppf)-CH ₂ Cl ₂ adduct (0.061 g, 0.075 mmol, 0.05 equiv) was again degassed with argon for 10 min. The reaction mixture was stirred in a sealed vessel at 100 ° C for 5 h. The reaction mixture was cooled to room temperature, 5-bromo-7-methyl -7 H - pyrrolo [2,3- d] pyrimidin-4-amine (0.340g, 1.494mmol, 1.0equiv) and saturated aqueous NaHCO ₃ ( 5 mL) was added to the reaction mixture, and argon was bubbled through the mixture for 10 min. PdCl ₂ (dppf)-CH ₂ Cl 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 at 100 ° C overnight. The reaction mixture was cooled to room temperature, filtered through celite and the filtrate was dehydrated over Na ₂ SO _4, and concentrated. The crude product was purified by flash column chromatography using a silica gel column using 4-5% MeOH in DCM as the eluent to give 1- (4- (4-amino-7-methyl -7 H - pyrrolo And [2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-phenylmethyl-1 H -1,2,4-triazole-5(4 H )-one as an off-white solid (0.044 g, 7.1%). LCMS (ES) m/z = 416.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d 6) 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, 1H), 7.84 (t, J = 6.0 Hz, 2H), 8.14 (s, 1H), 8.42 (s, 1H). HPLC obtained a purity of 99.79% at 254 nM.

Example 3 1- (4- (4-amino-7-methyl -7 H - -3- fluorophenyl-pyrrolo [2,3-d] pyrimidin-5-yl)) -4- (2,5- Fluorobenzyl)-3-methyl-1 H -1,2,4-triazole-5(4H)-one

Step 1: Add DIPEA to a stirred solution of ethyl acetimidate hydrochloride in DCM at 0 ° C and stir for 30 min, then add ethyl chloroformate to the reaction mixture and let the reaction mixture at room temperature Stir for 3 h. The reaction mixture was filtered and the filtrate through celite, and concentrated to yield N - ethoxycarbonyl-acetyl ethyl ester (3.8g crude) of a pale yellow oil. H NMR (CDCl ₃ , 400 MHz) 1.18-1.32 (m, 6H), 2.08 (s, 3H), 4.11-4.22 (m, 4H).

Step 2: Ethyl N -ethoxycarbonylacetamidate (0.8 g, 4.96 mmol, 1.2 equiv), (4-bromo-3-fluorophenyl)phosphonium hydrochloride (1.0 g, 4.14 mmol, 1.0 equiv) was dissolved in toluene with Et ₃ N (0.7 mL, 4.96 mmol, 1.2 equiv) and stirred at 45 ° C for 1 h, then warmed to 100 ° C and stirred overnight. The reaction mixture was concentrated under reduced pressure, the crude product was purified by flash chromatography on silica gel, eluting the compound in 50% EtOAc / hexanes to produce 1- (4-bromo-3-fluorophenyl) -3-methyl -1 H A pale solid of -1,2,4-triazole-5( 4H )-one (0.18 g, 16%). LC-MS (ES) m / z = 272.0,274.0 (M + H) +. ¹ H NMR (400 MHz, DMSO- d 6) δ </ RTI></RTI></RTI> 2.15 (s, 3H), 7.66-7.85 (m, 3H), 11.94 (s, 1H).

Step 3: at 0 ° C, containing 1-(4-bromo-3-fluorophenyl)-3-methyl-1 H -1,2,4-triazole-5(4 H )-one (0.16 g, 0.585 mmol, 1.0 equiv) of DMF (10.0 mL) was added NaH (60% in oil) (0.015 g, 0.647 mmol, 1.1 equiv) and stirred for 30 min. Add 2,5-difluorobenzyl bromide (0.08 mL, 0.647 mmol, 1.1 equiv) and continue stirring at 0 °C for 2 h. After the starting materials were used up, the reaction mixture was quenched with ice water. The resulting solid was filtered, washed and dried using pentane to give 1-(4-bromo-3-fluorophenyl)-4-(2,5-difluorobenzyl)-3-methyl- 1H -1. 2,4-Triazol-5( 4H )-one (0.14 g, 61%) as an off white solid. LC-MS (ES) m / z = 398.0,400.0 (M + H) +. _{^{1 H NMR (400MHz, CDCl 3}} ) δ ppm 2.27 (s, 3H), 4.88 (s, 2H), 6.97-7.25 (m, 3H), 7.55 (t, J = 7.6Hz, 1H), 7.26-7.53 ( m, 1H), 7.85-7.88 (m, 1H).

Step 4: In the presence of 1-(4-bromo-3-fluorophenyl)-4-(2,5-difluorobenzyl)-3-methyl-1 H -1,2,4-triazole- 5( 4H )-one (0.13g, 0.33mmol, 1.0equiv), bis-pinacol borate (0.099g, 0.39mmol, 1.2equiv), with potassium acetate (0.081g, 0.825mmol, 2.5equiv) Add 1,4-two to the mixture Dioxane (10mL), the mixture was degassed with N ₂ for 10 min. PdCl ₂ (dppf).CH ₂ Cl ₂ complex (0.027 g, 0.03 mmol, 0.1 equiv) was added and the mixture was again degassed with N _{2 for} 10 min. The reaction mixture was stirred in a sealed vessel at 100 ° C for 15 hours. The reaction mixture was cooled to room temperature and filtered thru a salt. The filtrate was concentrated to give a crude product. The crude product was purified by flash chromatography eluting with EtOAc EtOAc EtOAc EtOAc ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-1 H -1,2,4-triazole-5 ( 4H )-one (0.11 g, 69%) as an off white solid. LC-MS (ES) m/z = 446.2 [M+H] ⁺ .

Step 5: Take 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa) Boronocyclic-2-yl)phenyl)-3-methyl-1 H -1,2,4-triazole-5(4 H )-one (0.1g, 0.215mmol, 1.0equiv), 5 - bromo-7-methyl -7 H - pyrrolo [2,3- d] pyrimidin-4-amine (0.048g, 0.215mmol, 1.0equiv) and potassium phosphate (0.091g, 0.43mmol, 2equiv) of 1, 4-two Dioxane: water (4 mL: 1 mL) mixture was degassed with N ₂ for 15 min. Pd ₂ (dba) ₃ (0.009 g, 0.011 mmol, 0.05 equiv) and tributylphosphonium tetrafluoroborate (0.006 g, 0.0215 mmol, 0.1 equiv) were added and the reaction mixture was again degassed for 5 min. The vessel was sealed and the reaction mixture was heated to 100 ° C and stirred for 5 h. The reaction mixture was cooled to room temperature, filtered through celite and the filtrate was dehydrated over Na ₂ SO ₄ and concentrated to give the crude product compound. The crude product was purified by flash column chromatography using EtOAc EtOAc (EtOAc) A mixture of the product was eluted parts concentrated to give 1- (4- (4-amino-7-methyl -7 H - -3- fluorophenyl pyrrolo [2,3- d] pyrimidin-5-yl)) 4-(2,5-Difluorobenzyl)-3-methyl- 1H -1,2,4-triazole-5( 4H )-one (0.045 g, 43%) LCMS (ES) m/z = 466.2 [M+H] ⁺ . ^{1 H NMR (400MHz, 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, 1H), 7.80-7.83 (m, 2H), 8.13 (s, 1H).

Example 4 4-(4-Amino-5-(4-(4-(2,5-difluorobenzyl)-5-oxo-4,5-dihydro-1 H -1,2,4- Triazol-1-yl)-2-fluorophenyl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-1,1-dimethylpiperidine-1-indole iodide

In a sealed tube containing 1-(4-(4-amino-7-(1-methylpiperidin-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl )-3-fluorophenyl)-4-(2,5-difluorobenzyl)-1 H -1,2,4-triazole-5(4 H )-one (0.1 g, 0.187 mmol, 1.0) Methyl iodide (0.018 mL, 0.280 mmol, 1.5 equiv) was added to EtOAc (2 mL) EtOAc. The reaction mixture was cooled to room temperature. The solid was filtered off, washed with MeOH and dried to give 4-(4-amino-5-(4-(4-(2,5-difluorobenzyl)-5- </RTI> Dihydro-1 H -1,2,4-triazol-1-yl)-2-fluorophenyl)-7 H -pyrrolo[2,3-d]pyrimidin-7-yl)-1,1- Dimethylpiperidine-1-indole iodide (0.075 g, 60%) as an off-white solid. LCMS (ES) m / z- 549.3 (M + H) + -127. 1 H NMR (DMSO- d 6,400MHz) 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, 1H), 7.69 (s, 1H), 7.82-7.86 (m, 2H), 8.14 (s, 1H), 8.38 (s, 1H).

Example 5 1- (5- (4-amino-7-methyl -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) pyridin-2-yl) -4- (2,5-difluoro Benzyl)-1 H -1,2,4-triazole-5(4 H )-one

Step 1: Add phenyl chloroformate (4.9 mL, 38.4) to a stirred solution of (2,5-difluorophenyl)methylamine (5.0 g, 34.9 mmol, 1 equiv) in pyridine (20 mL). M, 1.1equiv). The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The solvent was completely evaporated, 1M THF solution (20 mL) was added and the mixture was warmed to 50 &lt;0&gt;C and stirred for 12 hours. The reaction mixture was cooled to rt. The organic layer was dried over sodium sulfate and evaporated to give crystals of crude crystals of crude product of N- (2,5-difluorobenzyl)carbohydrazide (3.3 g, crude product). LCMS (ES) m/z = 2021. [M+H] ⁺ .

Step 2: Ethyl formate (2.0) was added to a stirred solution of N- (2,5-difluorobenzyl)hydrazinamide (3.3 g, 16.41 mmol, 1 equiv) in THF (30 mL). mL, 24.6 mmol, 1.5 equiv), heated to 50 ° C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated to give a crude material. The product was extracted using ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give the crude product N - (2,5- difluorobenzyl) -2-acyl hydrazine 2carboxamide The oil (2.0 g of, crude product). LCMS (ES) m/z =21.21. [M+H] ⁺ .

Step 3: A solution of N- (2,5-difluorobenzyl)-2-carbamimidoximecarboxamide (2.0 g, 8.73 mmol, 1 EtOAc) (3 mL) The reaction mixture was allowed to cool to room temperature and then neutralized using 6N HCl solution. The crude product was extracted with 5% MeOH: DCM. The organic layer was dried over sodium sulfate and evaporated to give 4- (2,5-difluorobenzyl) -1 H -1,2,4- triazol -5 (4 H) - one of an oil (1.0g , 56%). LCMS (ES) m/z =21.21. [M+H] ⁺ . ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 4.78 (s, 2H), 7.08-7.12 (m, 1H), 7.19-7.31 (m, 2H), 7.90 (s, 1H), 11.69 (s, 1H ).

Step 4: Containing 4-(2,5-difluorobenzyl)-1 H -1,2,4-triazole-5(4 H )-one (1.0 g, 4.73 mmol, 1.0 equiv), 5 Add DMEDA (0.05 mL, 0.47 mmol, 0.1 equiv) to a stirred solution of CsF (2.2 g, 14.2 mmol, 3.0 equiv) in EtOAc (25 mL). Thereafter, CuI (0.05 g, 0.23 mmol, 0.05 equiv) was added. 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 Na ₂ SO ₄ and evaporated to give a crude material which was purified by EtOAc. The compound was dissolved in 60% EtOAc:hexanes. The pure fraction was evaporated to give 1-(5-bromopyridin-2-yl)-4-(2,5-difluorobenzyl)-1 H -1,2,4-triazole-5 (4 H )-ketone (0.5 g, 29%) as a yellow solid. LCMS (ES) m / z = 367.0,369.0 [M + H.] +. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 4.90 (s, 2H), 7.27-7.33 (m, 3H), 7.90-7.92 (m, 1H), 8.15-8.17 (m, 1H), 8.32 (s , 1H), 8.56-8.58 (m, 1H).

Step 5: In the presence of 1-(5-bromopyridin-2-yl)-4-(2,5-difluorobenzyl)-1 H -1,2,4-triazole-5( 4H )- Ketone (0.1g, 0.27mmol, 1equiv) of 1,4-two To the stirred solution of the alkane (6 mL) was added bis-pinacol borate (0.07 g, 0.27 mmol, 1 equiv), and potassium acetate (0.08 g, 8.1 mmol, 3 equiv). The reaction mixture was degassed using N _{2 for} 15 minutes. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.022 g, 0.02 mmol, 0.1 equiv) was added and the mixture was degassed with N ₂ for 5 min. The reaction mixture was stirred in a sealed container at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature. 5-bromo-7-methyl -7 H - pyrrolo [2,3- d] pyrimidin-4-amine (0.06g, 0.27mmol, 1.0equiv), saturated aqueous NaHCO ₃ (2mL). PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.022 g, 0.02 mmol, 0.1 equiv) was added and the reaction mixture was degassed with N _{2 for} 5 min. The vessel was sealed and the reaction mixture was stirred at 100 ° C for an additional 1 hour. The crude product was filtered through EtOAc (EtOAc) elute A mixture of the compounds was dissolved in 2% MeOH: DCM. The eluate was evaporated to give a crude material which was purified by preparative preparative TLC. A strip associated with the compound was collected and slurried in 10% MeOH: DCM. The suspension was filtered and the filtrate evaporated to give 1- (5- (4-amino-7-methyl -7 H - pyrrolo [2,3-d] pyrimidin-5-yl) pyridin-2-yl) -4 -(2,5-Difluorobenzyl)-1 H -1,2,4-triazole-5( 4H )-one (0.015 g, 13%) as an off white solid. LCMS (ES) m/z =435.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.73 (s, 3H), 4.95 (s, 2H), 6.23 (br.s., 2H), 7.24-7.32 (m, 3H), 7.43 (s, 1H), 7.95-7.97 (m, 2H), 8.15 (s, 1H), 8.32 (s, 1H), 8.52 (s, 1H).

Example 6 1- (4- (4-amino-6,7-dimethyl -7 H - pyrrolo [2,3-d] pyrimidin-5-yl) -3-fluorophenyl) -4- (2, 5-difluorobenzyl)-1 H -1,2,4-triazole-5(4 H )-one

Step 1: To a 0 ℃, containing 4-chloro -7 H - pyrrolo [2,3- d] pyrimidine (5.0g, 32.56mmol, 1equiv) of DMF (50mL) was stirred solution of 60% sodium hydride was added ( 1.5 g, 39.07 mmol, 1.2 equiv), and stirred for 15 min, then (2-(chloromethoxy)ethyl)trimethyldecane (5.7 mL, 32.56 mmol, 1.0 equiv). 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 with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give 4-chloro-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3-d] pyrimidine of brown Liquid (8.0 g, 66.0%). LCMS (ES) m/z = 284.10 [M+H] ⁺ . ^{1 H NMR (400MHz, DMSO-} d 6) δ ppm-0.11 (s, 9H), 0.79-0.81 (m, 2H), 3.50 (t, J = 8.0Hz, 2H), 5.62 (s, 1H), 6.68 -6.69 (m, 1H), 7.85 (d, J = 4.0 Hz, 1H), 8.62 (s, 1H).

Step 2: Operation-1: 4-chloro-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[ LDA (1.9 mL, 3.82 mmol, 1.1 equiv) was added to a stirred solution of 2,3- d ]pyrimidine (1.0 g, 3.52 mmol, 1.0 equiv) in THF (20 mL). 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 mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with a saturated ammonium chloride solution. The crude reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give 4-chloro-6-methyl-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d ] A brown liquid of pyrimidine (1.1 g, crude product). LC-MS (ES) m / z = 298.1 [M + H] +. Operation-2: 4-chloro-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3] at -78 ° C under nitrogen atmosphere - d ] Pyrimidine (7.0 g, 25.06 mmol, 1.0 equiv) in THF (150 mL) EtOAc. 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 mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with a saturated ammonium chloride solution. Extract with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give 4-chloro-6-methyl-7 - ((2- (trimethyl silicon alkyl) ethoxy) methyl) -7 H - pyrrolo [2,3- d ] A brown liquid of pyrimidine (7.0 g, crude product). LC-MS (ES) m / z = 298.1 [M + H] +.

Step 3: Operation-1: at 0 ° C in the presence of 4-chloro-6-methyl-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[ TCA (3.0 g, 26.84 mmol, 4.0 equiv) was added to a stirred suspension of 2,3- d ]pyrimidine (2.0 g, 6.71 mmol, 1 EtOAc). The reaction mixture was warmed to room temperature and stirred at room temperature for 16 h. The reaction mixture was quenched with a sat. NaHCO ₃ solution at 0 ° C and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give (4-chloro-6-methyl -7 H - pyrrolo [2,3- d] pyrimidin-7-yl) methanol, as a light brown solid (1.0 g of, crude product) . LCMS (ES) m/z = 198.1 [M+H] ⁺ . ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 2.52 (s, 3H), 5.59 (d, J = 7.2Hz, 2H), 6.41 (s, 1H), 6.57 (t, J = 8.0Hz, 1H) , 8.55 (s, 1H).

Operation-2: at 0 ° C in the presence of 4-chloro-6-methyl-7-((2-(trimethyldecyl)ethoxy)methyl)-7 H -pyrrolo[2,3 - d] pyrimidin (5.0g, 16.77mmol, 1equiv) of DCM (75mL) was stirred suspension was added TFA (7.6g, 67.14mmol, 4.0equiv) . The reaction mixture was warmed to room temperature and stirred at room temperature for 16 h. The reaction mixture was quenched with a sat. NaHCO ₃ solution at 0 ° C and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give (4-chloro-6-methyl -7 H - pyrrolo [2,3- d] pyrimidin-7-yl) methanol, as a light brown solid (3.0 g of, crude product) . LCMS (ES) m/z = 198.1 [M+H] ⁺ .

Step 4: Operation -1: containing - THF (4- chloro-6-methyl -7 H pyrrolo [2,3- d] pyrimidin-7-yl) methanol (0.1g, 0.50mmol, 1.0equiv) of (5 mL) A boron trifluoride etherate (0.25 mL, 2.52 mmol, 5.0 equiv) was added to the stirred solution. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with a sat. NH ₄ Cl solution and extracted with ethyl acetate. The organic layer was dehydrated with Na ₂ SO ₄ and evaporated to give crude product 4-chloro-6-methyl -7 H - pyrrolo [2,3- d] pyrimidine (0.09 g of, crude product) of a brown solid. LCMS (ES) m/z = 168.1 [M+H] ⁺ .

Operation -2: containing - THF (4- chloro-6-methyl -7 H pyrrolo [2,3- d] pyrimidin-7-yl) methanol (4.0g, 20.24mmol, 1.0equiv) of (50mL) Boron trifluoride etherate (10.7 mL, 101.2 mmol, 5.0 equiv) was added to the stirred solution. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with a sat. NH ₄ Cl solution and extracted with ethyl acetate. The organic layer was dehydrated with Na ₂ SO ₄ and evaporated to give crude product 4-chloro-6-methyl -7 H - pyrrolo [2,3- d] pyrimidine (0.09 g of, crude product) of a brown solid. LCMS (ES) m/z = 168.1 [M+H] ⁺ .

Step 5: Operation -1: at 0 ℃, containing 4-chloro-6-methyl -7 H - pyrrolo [2,3- d] pyrimidine (0.1g, 0.59mmol, 1.0equiv), the DMF ( 5 mL of a stirred solution was added 60% sodium hydride (0.035 g, 0.89 mmol, 1.5 equiv) and stirred at the same temperature for 15 min. 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 sulfate and evaporated to give 4-chloro-6,7-dimethyl -7 H - pyrrolo [2,3- d] pyrimidine (0.02 g of, crude product) of a brown solid. LCMS (ES) m/z = 1821. [M+H] ⁺ .

Operation -2: at 0 ℃, containing 4-chloro-6-methyl -7 H - pyrrolo [2,3- d] pyrimidine (3.0g, 17.64mmol, 1.0equiv) of DMF (50mL) was stirred solution of 60% sodium hydride (1.0 g, 26.94 mmol, 1.5 equiv) was added and stirred at the same temperature for 15 min. 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 water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give 4-chloro-6,7-dimethyl -7 H - pyrrolo [2,3- d] pyrimidine (0.6 g of, crude product) of a brown solid. LCMS (ES) m / z = 182.1 [M + H.] +.

Step 6: Operation -1: at 0 ℃, containing 4-chloro-6,7-dimethyl -7 H - pyrrolo [2,3- d] pyrimidine (0.05g, 0.27mmol, 1equiv) of DCM (5 mL) NBS (0.029 g, 0.16 mmol, 0.6 equiv) was added to the stirred solution. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give 5-bromo-4-chloro-6,7-dimethyl -7 H - pyrrolo [2,3- d] pyrimidine (0.02 g of, crude product) as a pale yellow solid of . LCMS (ES) m / z = 261.0,263.0 [M + H] +. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm - 2.44 (s, 3H), 3.76 (s, 3H), 8.56 (s, 1H)

Operation -2: at 0 ℃, containing 4-chloro-6,7-dimethyl -7 H - pyrrolo [2,3- d] pyrimidine (0.6g, 3.31mmol, 1equiv) of DCM (10mL) NBS (0.38 g, 2.15 mmol, 0.6 equiv) was added to the stirred solution. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give 5-bromo-4-chloro-6,7-dimethyl -7 H - pyrrolo [2,3- d] pyrimidine (0.65 g, crude product) as a pale yellow solid of . LCMS (ES) m / z = 261.0,263.0 [M + H.] +. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm - 2.44 (s, 3H), 3.76 (s, 3H), 8.56 (s, 1H)

Step 7: To a solution containing 5-bromo-4-chloro-6,7-dimethyl -7 H - pyrrolo [2,3- d] pyrimidine (0.6g, 2.5mmol, 1equiv) of 1 , 4-two NH ₄ OH (10 mL) was added to a stirred solution of hexane (5 mL). The reaction mixture was heated to 100 ° C in the microwave and stirred for 16 h. The reaction mixture was cooled, the formed solid was filtered off to give 5-bromo-6,7-dimethyl -7 H - pyrrolo [2,3- d] pyrimidin-4-amine (0.3g, 50%) of a pale yellow solid. LCMS (ES) m / z = 241.0,243.0 [M + H] +. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt;

Step 8: containing 14-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa) Borane-heterocyclopentan-2-yl)phenyl)-1 H -1,2,4-triazole-5( 4H )-one (0.4g, 0.92mmol, 1equiv) 1,4-di Add 5-bromo-6,7-dimethyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine (0.2 g, 0.83 mmol, 0.9 equiv), phosphoric acid to a stirred solution of alkane (30 mL) Potassium (0.39 g, 1.85 mmol, 2.0 equiv) and water (7 mL). The reaction mixture was degassed using 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) were added and degassed with N _{2 for} 5 min. The reaction mixture was stirred in a sealed vessel at 100 ° C for 10 h. The reaction mixture was cooled to room temperature and evaporated to give a crude material. The crude product was purified by silica gel flash column chromatography. The compound was isolated in 3% MeOH: DCM eluted with EtOAc (EtOAc). Preparative HPLC method - column: CHIRALPAKIA (250 mm x 20 mm x 5 μm), mobile phase: (A) / (B) - 0.1% n-hexane in ethanol (50:50); flow rate: 18 ml/min. Made from the parts by preparative HPLC elution was concentrated to give 1- (4- (4-amino-6,7-dimethyl -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) -3 -Fluorophenyl)-4-(2,5-difluorobenzyl)-1 H -1,2,4-triazole-5( 4H )-one (0.04 g, 10%) as an off white solid. LCMS (ES) m/z = 466.1 [M+H] ⁺ . ^{1 H NMR (400MHz, DMSO-} d 6) 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, 1H), 7.82-7.85 (m, 2H), 8.07 (s, 1H), 8.37 (s, 1H).

Example 7 1- (4- (4-amino-6 - ((dimethylamino) methyl) -7-methyl -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) -3 -fluorophenyl)-4-(2,5-difluorobenzyl)-1 H -1,2,4-triazole-5(4 H )-one

Step 1: To a 0 ℃, the 4-chloro-6,7-dimethyl-5-bromo-containing -7 H - pyrrolo [2,3- d] pyrimidine (1.0g, 3.83mmol, 1equiv) of DCM (10 mL) NBS (0.81 g, 4.59 mmol, 1.2 equiv) was added to the stirred solution. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with water (20 mL)EtOAc. The organic layer was dried over sodium sulfate and evaporated to give 5-bromo-6- (bromomethyl) -4-chloro-7-methyl -7 H - pyrrolo [2,3- d] pyrimidin of a pale yellow solid (1.0 g, 76%). LCMS (ES) m/z = 340.0, 341.9 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ δ 3.94 (s, 3H), 4.70 (s, 2H), 8.64 (s, 1H).

Step 2: at 0 ℃, containing 5-bromo-6- (bromomethyl) -4-chloro-7-methyl -7 H - pyrrolo [2,3- d] pyrimidine (1.0g, 2.94mmol Potassium carbonate (0.49 g, 3.53 mmol, 1.2 equiv) and dimethylamine (2.94 mL, 2.94 mmol, 1 equiv) were added to a stirred solution of EtOAc (1 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with cold water (30 mL)EtOAc. The organic layer was dried over sodium sulfate and evaporated to give a crude material which was purified eluting The compound was dissolved in 20% EtOAc:hexanes. Pure eluted parts taken and evaporated to give 1- (5-bromo-4-chloro-7-methyl -7 H - pyrrolo [2,3- d] pyrimidin-6-yl) - N, N - dimethylformamide Amine gray solid (0.65 g, 72%). LCMS (ES) m/z = 303.0, 305.1 [M+H] ⁺ . ¹ H NMR (40 O MHz, CDCl 3 ) δ δ 2.38 (s, 6H), 3.94 (s, 2H), 3.92 (s, 3H), 8.60 (s, 1H).

Step 3: to RT, the solution of 1- (4-chloro-7-methyl -7 H - pyrrolo [2,3- d] pyrimidin-6-yl) - N, N - dimethyl Methylamine (0.65g, 2.14mmol, 1equiv) 1,4-two NH ₄ OH (5 mL) was added to a stirred solution of hexane (5 mL). The reaction mixture was heated in an autoclave at 100 ° C overnight. The reaction mixture was cooled, the formed solid was filtered off to give 5-bromo-6 - ((dimethylamino) methyl) -7-methyl -7 H - pyrrolo [2,3- d] pyrimidin-4 A light yellow solid of the amine (0.45 g, 75%). LCMS (ES) m / z = 284.0,286.0 [M + H.] +. ^{1 H NMR δ ppm-2.19 (} s, 6H) (400MHz, DMSO-d 6), 3.53 (s, 2H), 3.68 (s, 3H), 6.65 (br.s, 2H), 8.07 (s, 1H) .

Step 4: Containing 1 4-(2,5-difluorobenzyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxo) Heteroborolane-2-yl)phenyl)-1 H -1,2,4-triazole-5( 4H )-one (0.5g, 1.16mmol, 1equiv) 1,4-di Add 5-bromo-6-((dimethylamino)methyl)-7-methyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine (0.2) to a stirred solution of alkane (10 mL) g, 0.83 mmol, 1.0 equiv), sodium bicarbonate (0.194 g, 2.32 mmol, 2.0 equiv) and water (4 mL). The reaction mixture was degassed using N _{2 for} 15 minutes. Pd(PPh ₃ ) ₄ (0.067 g, 0.058 mmol, 0.05 equiv) was added and degassed using N _{2 for} 5 min. The reaction mixture was stirred under microwave at 100 °C for 2 h. The reaction was cooled to room temperature and evaporated to give a crude material which was purified elute The compound was dissolved in 2.8% MeOH: DCM. Pure eluted parts taken evaporated, washed with diethyl ether and n-pentane, to produce l- (4- (4-amino-6 - ((dimethylamino) methyl) -7-methyl -7 H - pyrrolo [2,3- d ]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-difluorobenzyl)-1 H -1,2,4-triazole-5 (4 H )-ketone (0.025 g, 5%) as a white solid. LCMS (ES) m/z = 509.2 [M+H] ⁺ . ^{1 H NMR δ ppm-1.98 (} s, 6H) (400MHz, DMSO-d 6), 3.27 (s, 1H), 3.40-3.44 (m, 1H), 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, 1H), 7.82 (s, 1H), 7.85 (s, 1H), 8.10 (s, 1H) ), 8.38 (s, 1H).

Example 9: 2-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(3,5-dimethyl Benzomethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Step 1: Containing 2-(4-bromo-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one at 0 ° C and N ₂ After stirring 60% NaH (0.138 g, 3.44 mmol, 1.2 equiv) in a stirred suspension of (0.74 g, 2.87 mmol, 1 equiv) in DMF (15 mL), stirred for 20 min. A solution of 1-(bromomethyl)-3,5-dimethylbenzene (0.628 g, 3.154 mmol, 1.1 EtOAc) was then evaporated. After the starting material was used up, the reaction mixture was quenched with ice water, filtered, and dried. Purification: the crude compound was washed with n-pentane and dried to give an 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] ⁺ . ¹ H NMR (400 MHz, DMSO- d 6) 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, 1H).

Step 2: Containing 2-(4-bromo-3-fluorophenyl)-4-(3,5-dimethylbenzyl)-2,4-dihydro-3H-1,2,4-tri Izol-3-one (0.6g, 1.595mmol, 1.0equiv) To the stirred solution of the alkane, bis-pinacol borate (0.410 g, 1.595 mmol, 1.0 equiv) was added, and potassium acetate (0.470 g, 4.785 mmol, 3.0 equiv) was added. After the mixture was degassed for 15 minutes using argon gas, PdCl was added. ₂ (dppf)-CH ₂ Cl ₂ adduct (0.065 g, 0.07975 mmol, 0.05 equiv) was again degassed with argon for 10 min. The reaction mixture was stirred in a sealed container at 100 ° C for 5 hours. After LCMS was used to track whether the reaction mixture was completed, the reaction was cooled 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) was added. With saturated aqueous NaHCO ₃ (6 mL), argon was bubbled through the reaction mixture for 15 min, and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.065 g, 0.07975 mmol, 0.05 equiv) was added, and the vessel was sealed and reacted. The mixture was stirred at 100 ° C overnight. The crude mixture was filtered through celite and the filtrate was dehydrated over Na ₂ SO _4, and concentrated. Purification: Rapid column chromatography using a ruthenium tube column, the compound was dissolved in 3.8% MeOH in DCM, the product was concentrated, and EtOAc was then evaporated and dried to give 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 an off-white solid. LCMS (ES) m/z = 444.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d 6) 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, 1H), 7.48 (t, J = 9.2 Hz, 1H), 7.84 (t, J = 6.8 Hz, 2H), 8.14 (s, 1H), 8.39 (s, 1H). The purity was 99.90% as determined by HPLC @280 nM.

Example 22: 2-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-dimethyl Benzomethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

In the presence of 4-(2,5-dimethylbenzyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Cyclopentane-2-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (0.2 g, 0.47 mmol, 1 equiv) 1,4-di Add 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.085 g, 0.37 mmol, 0.8 equiv) and tripotassium phosphate (0.2 g) to a stirred solution of alkane (20 mL). , 0.94 mmol, 2.0 equiv) with water (0.5 mL). The reaction mixture was degassed using argon for 10 minutes. Pd ₂ (dba) ₃ (0.021 g, 0.023 mmol, 0.05 equiv) and (tBut) ₃ PHBF ₄ (0.013 g, 0.047 mmol, 0.1 equiv) were added, and degassed using argon for 10 minutes. The reaction mixture was placed in a sealed vessel and the O/N was stirred at 100 °C. The reaction was cooled to room temperature. The reaction mixture was evaporated to give a crude material which was purified eluting eluting The compound was dissolved in 2% MeOH: DCM. The resulting extract was 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 an off white solid. LCMS (ES) m/z = 444.2 [M+H] ⁺ . ^{1 H NMR (400MHz, DMSO- d} 6) 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, 1H), 7.03 (d, J = 7.2 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 7.31 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H) ,7.83-7.86(m,2H),8.13(s,1H),8.27(s,1H)

Example 27: 2-(4-(4-Amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorophenyl)-4-(2,5- Dimethylbenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Step 1: Sodium borohydride (1.0 g, 26.86 mmol, 1.2) in a stirred solution of 2,5-dimethylbenzaldehyde (3.0 g, 22.3 mmol, 1 equiv) in MeOH (30 mL). Equiv) is added in two parts. The reaction mixture was stirred at 0 ° C for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. Combined organic layers were dehydrated over Na ₂ SO _4, concentrated in vacuo under reduced pressure to give (2,5-dimethylphenyl) methanol (3.0 g of, crude product) of a pale yellow liquid. ^{1 H NMR (400MHz, DMSO-} d 6) δ ppm 2.16 (s, 3H), 2.23 (s, 3H), 4.42 (d, J = 8.0Hz, 2H), 4.94 (t, J = 8.0Hz, 1H) , 6.91 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H).

Step 2: Add phosphorus tribromide (1.3 mL, 13.23 mmol) to a stirred solution of (2,5-dimethylphenyl)methanol (3.0 g, 22.05 mmol, 1 equiv) in DCM (30 mL). , 0.6equiv). The reaction mixture was stirred at 0 ° C for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. Combined organic layers were dehydrated over Na ₂ SO _4, concentrated in vacuo under reduced pressure, to produce 2- (bromomethyl) -1,4-dimethylbenzene (4.5 g of, crude product) of a pale yellow liquid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.30 (s, 3H), 2.36 (s, 3H), 4.49 (s, 2H), 7.01 - 7.07 (m, 2H), 7.12 (s, 1H).

Step 3: 2-(4-bromo-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (3.0 g, 11.62) at 0 °C 60% NaH (0.55 g, 13.95 mmol, 1.2 equiv) was added to a stirred suspension of EtOAc (1 mL). 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 at room temperature for 2.5 h. The reaction mixture was quenched with ice water and extracted with EtOAc. Combined organic layers were dehydrated over Na ₂ SO _4, concentrated in vacuo under reduced pressure to give 2 (4-bromo-3-fluorophenyl) -4- (2,5-dimethylphenoxy) -2,4- Dihydro-3H-1,2,4-triazol-3-one (4.0 g, 90%) as a pale yellow solid. LCMS (ES) m/z = 376.2, 378.2 [M+H] ⁺ . ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm: 2.22 (s, 3H), 2.27 (s, 3H), 4.81 (s, 2H), 6.98 (s, 1H), 7.02 (d, J = 8.0Hz , 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.72-7.80 (m, 2H), 7.89 (d, J = 10.0 Hz, 1H), 8.28 (s, 1H).

Step 4: at room temperature in 2-(4-bromo-3-fluorophenyl)-4-(2,5-dimethylbenzyl)-2,4-dihydro-3H-1,2 , 4-triazol-3-one (2.0g, 5.31mmol, 1.0equiv) To the stirred solution of alkane (100 mL) was added bis-pinacol borate (2.0 g, 7.97 mmol, 1.5 equiv) and potassium acetate (1.6 g, 15.95 mmol, 3.0 equiv). The mixture was degassed using argon for 10 minutes. PdCl ₂ (dppf).DCM adduct (0.43 g, 0.53 mmol, 0.1 equiv) was added and degassed again using argon for 10 min. The reaction mixture was stirred in a round bottom flask at 100 ° C. The reaction mixture was followed by LCMS and the reaction was cooled to room temperature. The crude mixture was filtered through a bed of celite and washed using EtOAC. The filtrate was dehydrated over Na ₂ SO _4, and concentrated under reduced vacuum, to produce a black residue, which was purified by flash column chromatography, purified using silica gel column, 15% hexane in EtOAc compound of the eluting solution. The resulting extract was 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 an off white solid. LCMS (ES) m/z =424.2 [M+H] ⁺ . ^{1 H NMR (400MHz, 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, 1H), 7.70 - 7.73 (m, 2H), 7.78 (d, J = 8.0 Hz, 1H), 8.28 (s, 1H).

Step 5: Containing 4-(2,5-dimethylbenzyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxo) 1,4-Bisorocyclopentan-2-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (0.18 g, 0.42 mmol, 1 equiv) 1,4- two To a stirred solution of alkane (30 mL) was added 3-bromo-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.08 g, 0.31 mmol, 0.75 equiv), 0.18 g, 0.85 mmol, 2.0 equiv) and water (0.5 mL). The reaction mixture was degassed using argon for 10 minutes. Pd ₂ (dba) ₃ (0.019 g, 0.021 mmol, 0.05 equiv) and (tBut) ₃ PHBF4 (0.012 g, 0.042 mmol, 0.1 equiv) were added, and degassed again using argon for 10 minutes. The reaction mixture was stirred in a round bottom flask at 100 ° C for 5 h. The reaction mixture was cooled to room temperature and evaporated to give a crude material. The compound was dissolved in 3% MeOH: DCM. The resulting extract was concentrated to give 2-(4-(4-amino-1-cyclopropyl-1H-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%). LCMS (ES) m/z = 4721. [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d 6) 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, 1H), 4.82 (s, 2H), 6.51-6.90 (br.s, 2H), 6.98 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz) , 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.88-7.91 (m, 2H), 8.22 (s, 1H), 8.31 (s, 1H).

Example 28: 2-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-di Methylbenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

In the presence of 4-(2,5-dimethylbenzyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Cyclopentan-2-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (0.18g, 0.42mmol, 1equiv) 1,4-di Add 5-bromo-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.08 g, 0.31 mmol, 0.75 equiv) and tripotassium phosphate (0.18) to a stirred solution of alkane (30 mL). g, 0.85 mmol, 2.0 equiv) and water (0.5 mL). The reaction mixture was degassed using argon for 10 minutes. Pd ₂ (dba) ₃ (0.019 g, 0.021 mmol, 0.05 equiv) and (tBut) ₃ PHBF ₄ (0.012 g, 0.042 mmol, 0.1 equiv) were added, and degassed again using argon for 10 minutes. The reaction mixture was stirred in an RB flask at 100 ° C for 5 h. The reaction was cooled to room temperature and evaporated to give a crude material. The compound was dissolved in 3% MeOH: DCM. The resulting extract was 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 an off white solid. LCMS (ES) m/z = 470.2 [M+H] ⁺ . ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm: 1.00-1.02 (m, 4H), 2.23 (s, 3H), 2.28 (s, 3H), 3.53-3.58 (m, 1H), 4.84 (s, 2H), 6.01 (br.s, 2H), 6.98 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.48(t, J=8.0Hz, 1H), 7.82-7.86(m, 2H), 8.13(s,1H), 8.28(s,1H)

Compounds 8, 10 to 21, 23 to 26 and 29 are generally prepared according to the procedures described above and the procedures illustrated in Examples 1 to 7, 9, 22, 27 and 28.

Compound 30 was prepared generally according to the procedures described above and the procedures illustrated in Examples 1 through 7, 9, 22, 27 and 28.

Table 2

Example 31: PERK Enzyme Analysis

The conditions previously proposed (Axten et al., J. Med. Chem., 2012, 55, 7193-7207) were modified to analyze the PERK enzyme inhibitory activity of the compounds of the present invention. Briefly, various concentrations of compounds (up to 1% DMSO) were dispensed into a 384-well plate containing GST-PERK enzyme. After pre-incubation of the compound for 30-60 minutes, ATP and biotin-eIF2α were added, and the reaction was stopped after 60 minutes. After 2 hours, the inhibition was measured using a disc fluorescence analyzer, and the IC50 was calculated.

PKR-like endoplasmic reticulum kinase (PERK) enzyme assay - HTRF-inhibition %

The assay buffer contains HEPES (pH 7.5) 10 mM, CHAPS 2 mM, MgCl ₂ 5 mM and DTT 1 mM aqueous solution.

The assay buffer contains HEPES (pH 7.5) 10 mM and CHAPS 2 mM aqueous solution.

Analytical tray preparation:

1. Enzyme preparation:

Immediately after preparation of the 4X enzyme solution, it was added to the compound analysis plate.

3nM GST-PERK contained in assay buffer. Final [PERK]=0.75nM in 10μl analytical volume

2. Preparation of the substrate:

Immediately after preparation of the 4X receptor solution, it was added to the compound assay disk.

4X substrate in assay buffer: 2000 μM ATP and 160 nM biotin-eIF2a.

Final [ATP]=500μM in 10μl analytical volume

Final [biotin-eIF2a]=40nM in 10μl analytical volume

3. Suspend reaction / test solution:

16nM eIF2 Phospho-antibody

16nM Eu anti-rabbit IgG

160nM Streptavidin-APC

60mM EDTA

Final concentration in 10 μL assay volume: 4 nM eIF2 phospho-antibody, 4nM Eu Anti-rabbit, IgG 40nM Streptavidin-APC

The activity IC50 (nM) of the compound was determined by PERK enzyme (500 μM ATP) in the PERK enzyme assay.

Example 32 - Capsule Composition

The dosage form for oral administration of the present invention is a standard two-stage hard gelatin capsule filled with a component of the ratio shown in Table 3 below.

Example 33 - Injectable parenteral composition

The injection molding method for administration of the present invention is 1.7% by weight of 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- Fluorophenyl)-4-benzyl-1H-1,2,4-triazole-5(4H)-one (Compound 2) was stirred in an aqueous solution of 10% by volume of propylene glycol.

Example 34 Lozenge Composition

The sucrose, calcium sulfate dihydrate and PERK inhibitors shown in Table 4 below were mixed according to the ratios shown in the table, and granulated using a 10% gelatin solution. The wet granules are sieved, dried, mixed with starch, talc and stearic acid, sieved and pressed into ingots.

Biological activity

The activity of the compounds of the invention against PERK was determined in the above assays.

Generally based on the above PERK enzyme assay and at least one experimental operation test The compounds of Examples 1 to 29 have IC50 (nM) values against PERK at PERK enzyme (500 μM ATP): <5 μM.

The compound of Example 2 was generally tested according to the above PERK enzyme assay and at least one experimental procedure with an IC50 (nM) value of 568 against PERK under PERK enzyme (500 μM ATP).

The compound of Example 9 was generally tested according to the above PERK enzyme assay and at least one experimental procedure with an IC50 (nM) value of 6.4 against PERK at PERK enzyme (500 μM ATP).

The compound of Example 22 was generally tested according to the above PERK enzyme assay and at least one experimental procedure with an IC50 (nM) value of 6.5 against PERK at PERK enzyme (500 μM ATP).

The compound of Example 11 was generally tested according to the above PERK enzyme assay and at least one experimental procedure with an IC50 (nM) value of 89.4 against PERK at PERK enzyme (500 μM ATP).

The compound of Example 15 was generally tested according to the above PERK enzyme assay and at least one experimental procedure with an IC50 (nM) value of 1435 against PERK under PERK enzyme (500 μM ATP).

The compound of Example 23 was generally tested according to the above PERK enzyme assay and at least one experimental procedure with an IC50 (nM) value of 51 against PERK under PERK enzyme (500 μM ATP).

The compound of Example 27 was generally tested according to the above PERK enzyme assay and at least one experimental procedure with an IC50 (nM) value of 54.8 against PERK at PERK enzyme (500 μM ATP).

The compound of Example 28 is generally tested according to the above PERK enzyme assay and at least one experimental procedure against IC50 (nM) of PERK under PERK enzyme (500 μM ATP). The value is 36.9.

The compound of Example 29 was generally tested according to the above PERK enzyme assay and at least one experimental procedure with an IC50 (nM) value of 269.1 against PERK under PERK enzyme (500 μM ATP).

While the preferred embodiment of the invention has been described above, it is understood that the invention is not to

Claims (32)

a compound according to formula (I), Wherein: R ¹ is selected from the group consisting of: a bicyclic heteroaryl group, a substituted bicyclic heteroaryl group, a heteroaryl group, and a substituted heteroaryl group, wherein the substituted bicyclic heteroaryl group and the substituted heteroaryl group via line 1 to 5 are each independently selected from the following substituents: fluoro, chloro, bromo, iodo, C _1-6 alkyl, 1 to 5 substituents each independently selected from the substituents of C _1-6 Alkyl: fluorine, chlorine, bromine, iodine, C _1-4 alkyl, cycloalkyl, -COOH, -CF ₃ , -NO ₂ and -CN, -OH, hydroxy C _1-6 alkyl, -COOH, Tetrazole, cycloalkyl, pendant oxy, -OC _1-6 alkyl, -CF ₃ , -CF ₂ H, -CFH ₂ , -C _1-6 alkyl OC _1-4 alkyl, -CONH ₂ , -CON(H)C _1-3 alkyl, -CH ₂ CH ₂ N(H)C(O)OCH ₂ aryl, di C _1-4 alkylamino C _1-4 alkyl, amine C _{1 -6} alkyl, -CN, heterocycloalkyl, heterocycloalkyl substituted with 1 to 4 substituents each independently selected from C _1-4 alkyl, C _1-4 alkyloxy, -OH , -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ and -CN, -NO ₂ , -NH ₂ , -N(H)C _1-3 alkyl, and -N (C _1-3 alkyl) ^_2; R ₂ is selected from: aryl, 1-5 are each independently selected from The substituted aryl group: fluoro, chloro, bromo, iodo, C _1-4 alkyl, cycloalkyl, C _{1-4 alkyloxy, -OH, -COOH, -CF 3,} -C 1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ , -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF ₃ , and -CN, a heteroaryl group, which is substituted with 1 to 5 heteroaryl groups each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, C _1-4 alkyl, cycloalkyl, C _1-4 alkyloxy, -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ , -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF ₃ , and -CN, bicycloheteroaryl, biphenylheteroaryl substituted by 1 to 5 substituents each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, C ₁ - ₄ alkyl, C _1-4 alkyloxy, -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ , cycloalkyl, -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF ₃ , and -CN, and a cycloalkyl group; R ³ is selected from the group consisting of hydrogen, -NH ₂ , -N(H)C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -OH, cycloalkyl, C _1-6 alkyl, and 1 to 5 are each independently selected from the following the substituents of the C _1-6 alkyl group: fluoro, , Bromo, iodo, C _1-4 alkyl, C _{1-4 alkyloxy, -OH, -COOH, -CF 3,} -C 1-4 alkyl OC _1-4 alkyl, -NO _2, -NH ₂ and -CN; R ⁴ is selected from: hydrogen, C _{1-4 alkyl, -CF 3, -C (H)} F 2, -CH 2 F, fluoro, chloro, bromo and iodo; R ⁵ is selected from Hydrogen, C _1-4 alkyl, -CF ₃ , -C(H)F ₂ , -CH ₂ F, fluorine, chlorine, bromine and iodine; X is CR ¹⁰⁰ or N, wherein R ¹⁰⁰ is selected from: hydrogen , -CH ₃ , fluorine, chlorine, bromine and iodine; Y and Y ¹ are each independently selected from: hydrogen, -CF ₃ and C _1-4 alkyl, or Y and Y ^{1 together} with the carbon attached thereto C ₃ -C ₆ cycloalkyl; and Z is 0 or 1; or a salt thereof, including a pharmaceutically acceptable salt thereof. According to the compound of claim 1, which is represented by the following formula (II): Wherein: R ¹⁰ is selected from the group consisting of: an aryl group substituted with 1 to 5 substituents each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkyl Oxygen, -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ , cycloalkyl, -OC(H)F ₂ , -C(H F ₂ , —OCH ₂ F, —CH ₂ F, —OCF ₃ , and —CN, cycloalkyl, heteroaryl, and heteroaryl substituted with 1 to 5 substituents each independently selected from the group consisting of: Fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkyloxy, -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ , cycloalkyl, -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF ₃ , and -CN; R ¹¹ is selected from the group consisting of: hydrogen , -NH ₂ , -N(H)C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -OH, cycloalkyl, C _1-6 alkyl, and 1 to 5 respectively C _1-6 alkyl optionally substituted with the following substituents: fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkyl oxygen, -OH, -COOH, -CF ₃ , - C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ and -CN; R ¹² is selected from the group consisting of: hydrogen, C _1-4 alkyl, -CF ₃ , -C(H)F ₂ , -CH ₂ F, fluorine and chlorine; R ¹³ is selected from: hydrogen, C _1-6 alkyl, di C _1-4 alkylamino C _1-4 alkyl, and amino C _1-6 alkyl; R ¹⁴ is selected from the group consisting of: hydrogen, cycloalkyl, heterocycloalkyl, a heterocycloalkyl group substituted with 1 to 4 substituents each independently selected from the group consisting of C _1-4 alkyl, C _1-4 alkyloxy, -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO _2, -NH ₂ and -CN, C _1-6 alkyl, and 1-4 through each independently selected from the substituents of C _1-6 alkyl: Fluorine, chlorine, bromine, iodine, C _1-4 alkyloxy, -OH, -CF ₃ , -COOH, -NO ₂ , -NH ₂ and -CN; R ¹⁵ is selected from the group consisting of: hydrogen and -CH ₃ ; ¹⁶ is selected from the group consisting of hydrogen, C _1-4 alkyl, -CF ₃ , -C(H)F ₂ , -CH ₂ F, fluorine and chlorine; X is CR ¹⁰¹ or N, wherein R ¹⁰¹ is selected from: hydrogen , fluorine and chlorine; and Y ¹⁰ and Y ¹¹ are each independently selected from: hydrogen, -CF ₃ and C _1-4 alkyl, or Y and Y ^{1 together} with the carbon attached thereto to form a C ₃ -C ₆ ring An alkyl group; or a salt thereof, including a pharmaceutically acceptable salt thereof. A compound according to claim 1 or 2, which is represented by the following formula (III): Wherein: R ²⁰ is selected from the group consisting of: phenyl, which may optionally be independently selected from the following substituents: fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkyl oxygen. , -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , cycloalkyl, -OC(H)F ₂ , -C(H)F ₂ , - OCH ₂ F, -CH ₂ F, -OCF ₃ , -NH ₂ and -CN, and a cycloalkyl group; R ²¹ is selected from the group consisting of hydrogen, methyl, -CF ₃ , fluorine and chlorine; and R ²² is selected from the group consisting of: Hydrogen, C _1-6 alkyl, di C _1-4 alkylamino C _1-4 alkyl, and amine C _1-6 alkyl; R ²³ is selected from: hydrogen, cycloalkyl, heterocycloalkane a heterocycloalkyl group substituted with 1 to 4 substituents each independently selected from the group consisting of C _1-4 alkyl, C _1-4 alkyloxy, -OH, -COOH, -CF ₃ , -C _{1 -4} alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ and -CN, and C _1-6 alkyl; R ²⁴ is selected from: hydrogen and -CH ₃ ; R ²⁵ is selected from: hydrogen, Methyl, -CF ₃ , fluorine and chlorine; X is CR ¹⁰² or N, wherein R ¹⁰² is selected from the group consisting of: hydrogen, fluorine and chlorine; and Y ²⁰ and Y ²¹ are independently selected from the group consisting of hydrogen, -CF ₃ and C _1-4 alkyl, or Y and Y ¹ is attached to carbon and the like thereto together form a C ₃ -C ₆ cycloalkyl; or a salt thereof, which comprises Pharmacologically acceptable salt thereof. According to the compound of claim 1, which is represented by the following formula (IV): Wherein: R ³⁰ is selected from the group consisting of: phenyl, which may optionally be substituted with one to five substituents independently selected from the group consisting of fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkyl oxygen. , -OH, -COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , cycloalkyl, -OC(H)F ₂ , -C(H)F ₂ ,- OCH ₂ F, -CH ₂ F, -OCF ₃ , -NH ₂ and -CN, and a cycloalkyl group; R ³¹ is selected from the group consisting of hydrogen, methyl, -CF ₃ , fluorine and chlorine; and R ³² is selected from the group consisting of: Hydrogen, cycloalkyl, heterocycloalkyl, heterocycloalkyl substituted with 1 to 4 substituents each independently selected from C _1-4 alkyl, C _1-4 alkyloxy, -OH, - COOH, -CF ₃ , -C _1-4 alkyl OC _1-4 alkyl, -NO ₂ , -NH ₂ and -CN, and C _1-6 alkyl; R ³³ is selected from the group consisting of: hydrogen and -CH ₃ R ³⁴ is selected from the group consisting of hydrogen, methyl, -CF ₃ , fluorine and chlorine; X is CR ¹⁰³ or N, wherein R ¹⁰³ is selected from the group consisting of hydrogen, fluorine and chlorine; and Y ³⁰ and Y ³¹ are independently selected from the group consisting of Hydrogen, CF ₃ and C _1-4 alkyl, or Y and Y ^{1 together} with the carbon to which it is attached form a C ₃ -C ₆ cycloalkyl group; or a salt thereof, including a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is selected from the group consisting of: 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorobenzene 4-(2,5-difluorobenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-methyl) -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-benzyl-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-difluoro Benzyl)-3-methyl-1H-1,2,4-triazole-5(4H)-one; 4-(4-amino-5-(4-(4-(2,5-di) Fluorobenzyl)-5-sideoxy-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenyl)-7H-pyrrolo[2,3 -d] pyrimidin-7-yl) -1,1-dimethyl-piperidin-1-ium iodide; 1- (5- (4-amino-7-methyl -7 H - pyrrolo [2, 3- d ]pyrimidin-5-yl)pyridin-2-yl)-4-(2,5-difluorobenzyl)-1 H -1,2,4-triazole-5(4 H )-one ; 1-(4-(4-Amino-6,7-dimethyl-7 H -pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2 ,5-difluorobenzyl)-1 H -1,2,4-triazole-5(4 H )-one; 1-(4-(4-amino-6-((dimethylamino)) ) methyl) -7-methyl -7 H - pyrrolo [2,3- d] pyrimidin-5-yl) -3-fluorophenyl) -4- (2,5-difluorobenzyl) - 1 H -1,2,4- triazol -5 (4 H) - one 1- (4- (4-amino-7-methyl -7 H - -3- fluorophenyl-pyrrolo [2,3-d] pyrimidin-5-yl)) 4- (3,5- Fluorobenzyl)-1 H -1,2,4-triazole-5( 4 H)-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3 -d]pyrimidin-5-yl)-3-fluorophenyl)-4-(3,5-dimethylbenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-Amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5 -difluorobenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-isopropyl-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-difluorobenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-Amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(3,5 - dimethylbenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(cyclopentylmethyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4 -(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl)-4-(2,5-difluorobenzyl -1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5 -yl)phenyl)-4-benzyl-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-1) -methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-4-benzyl-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-chlorophenyl)-4-(2,5-difluoro Benzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d] Pyrimidin-5-yl)-3-fluorophenyl)-4-(3-chloro-2-fluorobenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-( 4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,3-difluorobenzyl -1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-(1-methylpiperidin-4-yl)-7H-pyrrole [2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-difluorobenzyl)-1H-1,2,4-triazole-5(4H) -ketone; 1-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-4-(2,5- Dimethylbenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3 -d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-dimethylbenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-Amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5 - dimethylbenzyl)-1H-1,2,4-triazole-5(4H)-one; 1-(4-(4-amino-7-methyl-7H -pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,3,6-trifluorobenzyl)-1H-1,2,4-triazole -5(4H)-one; 1-(4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)- 4-(3-chloro-2-fluorobenzyl)-1H-1,2,4-triazole-5(4H)-one; 2-(4-(4-amino-7-methyl-7H) -pyrrolo[2,3-d]pyrimidin-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-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro Phenyl)-4-(2,5-dimethylbenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 2-(4-(4-amine) -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-1H-pyrazolo[3,4-d]pyrimidine- 3-yl)-3-fluorophenyl)-4-(2,5-dimethylbenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 1-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-di Fluorobenzyl)-1H-1,2,4-triazole-5(4H)-one; or a salt thereof, including a pharmaceutically acceptable salt thereof. 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. A method for treating a disease in a mammal in need thereof, which is selected from the group consisting of cancer, precancerous syndrome, spinal injury, traumatic brain injury, severe stroke, stroke, diabetes, metabolic syndrome, metabolic disease, and Huntington's disease ( Huntington's disease), Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Sträussler-Scheinker syndrome, and related prion protein Disease, amyotrophic lateral sclerosis, progressive upper nucleus pneumonia, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute liver disease, fatty liver disease, hepatic steatosis, liver fibrosis Chemotherapy, chronic and acute lung disease, pulmonary fibrosis, chronic and acute Kidney disease, renal fibrosis, chronic traumatic brain disease (CTE), neurodegeneration, dementia, frontotemporal dementia, cognitive impairment, atherosclerosis, eye disease, arrhythmia, use in organ transplantation and The delivery of a transplant organ comprising administering to the mammal a therapeutically effective amount of a compound of formula I as claimed in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. The method of claim 7, wherein the mammal is a human. A method for treating a disease in a mammal in need thereof, which is selected from the group consisting of cancer, precancerous syndrome, spinal injury, traumatic brain injury, severe stroke, stroke, diabetes, metabolic syndrome, metabolic disease, and Huntington's disease ( Huntington's disease), Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Sträussler-Scheinker syndrome, and related prion protein Disease, amyotrophic lateral sclerosis, progressive upper nucleus pneumonia, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute liver disease, fatty liver disease, hepatic steatosis, liver fibrosis Chemotherapy, chronic and acute lung disease, pulmonary fibrosis, chronic and acute kidney disease, renal fibrosis, chronic traumatic brain disease (CTE), neurodegeneration, dementia, frontotemporal dementia, cognitive impairment, Atherosclerosis, eye disease, arrhythmia, use in organ transplantation, and in the delivery of transplanted organs, including the administration of a therapeutically effective amount to such mammals A compound according to claim 5, or a pharmaceutically acceptable salt thereof. The method of claim 9, wherein the mammal is a human. The method according to claim 7, wherein the cancer is selected from the group consisting of: brain (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Bannayan-Zonana syndrome, Gaudden's disease ( Cowden disease), Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovary, pancreas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell tumor , glucagonoma, insulinoma, prostate, sarcoma and thyroid. According to the method of claim 9, wherein the cancer is selected from the group consisting of: brain (glioma), colloidal mother Tumor, astrocytoma, glioblastoma multiforme, Bannayan-Zonana's syndrome, Cowden's disease, Lhermitte-Duclos' disease, breast, colon, head and neck, kidney, lung, liver , melanoma, ovary, pancreas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell tumor, glucagonoma, insulinoma, prostate, sarcoma and thyroid. A use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, for the manufacture of a medicament for the treatment of cancer. A method of inhibiting PERK activity in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable compound thereof salt. The method of claim 14, wherein the mammal is a human. A method of treating cancer in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount: a) a compound of formula (I) according to any one of claims 1 to 5 or a pharmaceutical thereof An acceptable salt; and b) at least one anti-tumor agent. The method of claim 16, wherein the at least one anti-tumor agent is selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerases II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunomedical agents, pro-apoptosis Agents, cell cycle signal transduction inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. A pharmaceutical combination according to claim 16 which is for medical use. A use of a pharmaceutical combination according to claim 16 for the preparation of a medicament suitable for the treatment of cancer. The method according to claim 7, wherein the cancer is selected from the group consisting of breast cancer, inflammatory breast cancer, and tubular cancer Tumor, phyllodes carcinoma, colon cancer, pancreatic cancer, insulinoma, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell tumor, glucagonoma, skin cancer, melanoma, metastasis Melanoma, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, brain (glioma), glioblastoma, stellate cell tumor, polymorphic colloid Blastoma, Bannayan-Zonana's syndrome, Cowden's disease, Lhermitte-Duclos' disease, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma , medulloblastoma, head and neck, kidney, liver, melanoma, ovary, pancreas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell tumor, 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 white blood Disease, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryocytic leukemia, multiple bone marrow Tumor, acute megakaryoblastic leukemia, promyelocytic leukemia, erythrocytic leukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Bob's lymphoma (Burkitt's) Lymphoma), follicular lymphoma, neuroblastoma, bladder cancer, urinary epithelial cancer, vaginal cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, Gastric cancer, nasopharyngeal carcinoma, cheek cancer, oral cancer, GIST (gastrointestinal stromal tumor), neuroendocrine cancer and testicular cancer. The method of claim 20, wherein the mammal is a human. A process for the preparation of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, which is prepared. This includes combining a compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient. According to the method of claim 7, wherein the pre-cancerous syndrome is selected from the group consisting of: cervical intraepithelial neoplasia, unidentified individual gamma globulin (MGUS), myelodysplastic syndrome, aplastic anemia, cervical damage, Skin blemishes (pre-melanoma), prostatic intraepithelial (intraductal) tumors (PIN), ductal carcinoma in situ (DCIS), colorectal polyps and severe hepatitis or sclerosis. The method of claim 16, wherein the at least one anti-tumor agent is pazopanib. A method of treating an ocular condition in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. The method of claim 25, wherein the eye disease is selected from the group consisting of: iris redness; neovascular glaucoma; eyelid; vascularized glaucoma conjunctival effusion blisters; conjunctival papilloma; age-related macular degeneration (AMD) , myopia, anterior uveitis, traumatic, or idiopathic related choroidal neovascularization; macular edema; retinal neovascularization due to diabetes; aging-related macular degeneration (AMD); macular degeneration (AMD) Eye damage syndrome caused by carotid artery disease; occlusion of the eye or retinal artery; sickle cell retinopathy; retinopathy of prematurity; Eale's Disease; and Von Hippel syndrome -Lindau syndrome). The method of claim 25, wherein the eye disease is selected from the group consisting of: age-related macular degeneration (AMD) and macular degeneration. A method of treating neurodegeneration in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. A method of preventing organ damage during delivery of a transplanted organ, comprising adding a compound of formula (I) according to any one of claims 1 to 5 to a solution containing the organ during transport. A compound as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use in medical treatment. A compound as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease selected from the group consisting of cancer, pre-cancerous syndrome, Alzheimer's disease, spinal injury, trauma Brain damage, blood-threatening stroke, stroke, Parkinson's disease, diabetes, metabolic syndrome, metabolic disease, Huntington's disease, Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Sträussler-Scheinkersyndrome, related prion protein disease, amyotrophic lateral sclerosis, progressive supraventricular nucleus paralysis, myocardial infarction , cardiovascular disease, inflammation, organ fibrosis, chronic and acute liver disease, fatty liver disease, hepatic steatosis, liver fibrosis, chronic and acute lung disease, pulmonary fibrosis, chronic and acute kidney disease, kidney fiber Chronic traumatic brain lesions (CTE), neurodegeneration, dementia, frontotemporal dementia, Tau proteinopathy, Pick's disease, Niemann-Pick's disease (Neiman) n-Pick's disease), amyloidosis, cognitive impairment, atherosclerosis, eye disease, arrhythmia, use in organ transplantation and in the delivery of transplanted organs. A pharmaceutical composition comprising 0.5 to 1,000 mg of a compound as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and 0.5 to 1,000 mg of a pharmaceutically acceptable excipient.