FIELD OF THE INVENTION

The present invention relates to substituted imidazolidinone derivatives that are inhibitors of the activity of the protein kinase R (PKR)-like ER kinase, PERK. The present invention also relates to pharmaceutical compositions comprising such compounds and methods of using such compounds in the treatment of cancer, pre-cancerous syndromes and diseases/injuries associated with activated unfolded protein response pathways, such as Alzheimer's disease, neuropathic pain, spinal cord injury, traumatic brain injury,. ischemic stroke, stroke, Parkinson's disease, diabetes, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute diseases of the liver, fatty liver disease, liver steatosis, liver fibrosis, chronic and acute diseases of the lung, lung fibrosis, chronic and acute diseases of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, frontotemporal dementias, tauopathies, Pick's disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation.

BACKGROUND OF THE INVENTION

The unfolded protein response (UPR) is a signal transduction pathway that allows cells to survive stress caused by the presence of misfolded or unfolded proteins or protein aggregates (Walter and Ron, 2011), (Hetz, 2012). Environmental stresses that perturb protein folding and maturation in the endoplasmic reticulum (ER) also can lead to activation of the UPR (Feldman et al., 2005), (Koumenis and Wouters, 2006). UPR activating stress stimuli include hypoxia, disruption of protein glycosylation (glucose deprivation), depletion of luminal ER calcium, or changes in ER redox status, among others (Ma and Hendershot, 2004), (Feldman et al., 2005). These perturbations result in disruption of ER redox homeostasis and the accumulation of unfolded or mis-folded proteins in the ER. Cellular responses include transcriptional reprogramming to increase the level of chaperone proteins to enhance protein re-folding, degradation of the mis- folded proteins, and translational arrest to decrease the burden of client proteins entering the ER (Ron, D. 2002), (Harding et al., 2002). These pathways also regulate cell survival by modulating apoptosis (Ma and Hendershot, 2004), (Feldman et al., 2005), and autophagy (Rouschop et al. 2010), and can trigger cell death under conditions of prolonged ER stress (Woehlbier and Hetz, 201 1).

Three ER membrane proteins have been identified as primary effectors of the UPR: protein kinase R (PKR)-like ER kinase [PERK, also known as eukaryotic initiation factor 2A kinase 3 (EIF2AK3), pancreatic ER kinase, or pancreatic elF2a kinase (PEK)], inositol-requiring gene 1 α/β (IRE1), and activating transcription factor 6 (ATF6) (Ma and Hendershot, 2004), (Hetz, 2012). Under normal conditions these proteins are held in the inactive state through binding of the ER chaperone GRP78 (BiP) to their luminal sensor domain. Accumulation of unfolded proteins in the ER leads to release of GRP78 from these sensors resulting in activation of these UPR effectors (Ma et al., 2002), (Hetz, 2012).

PERK is a type I ER membrane protein containing a stress-sensing domain facing the ER lumen, a transmembrane segment, and a cytosolic kinase domain (Shi et al., 1998), (Harding et al., 1999), (Sood et al., 2000). Release of GRP78 from the stress- sensing domain of PERK results in oligomerization and autophosphorylation at multiple serine, threonine and tyrosine residues (Ma et al., 2001), (Su et al., 2008). Phenotypes of PERK knockout mice include diabetes, due to loss of pancreatic islet cells, skeletal abnormalities, and growth retardation (Harding et al., 2001), (Zhang et al., 2006), (lida et al., 2007). These features are similar to those seen in patients with Wolcott-Rallison syndrome, who carry germline mutations in the PERK gene (Julier and Nicolino, 2010). The major substrate for PERK is the eukaryotic initiation factor 2a (elF2a), which PERK phosphorylates at serine-51 (Marciniak et al., 2006) in response to ER stress or treatment with pharmacological inducers of ER stress such as thapsigargin and tunicamycin. This site is also phosphorylated by other EIF2AK family members [(general control non- derepressed 2 (GCN2), PKR, and heme-regulated kinase (HRI)] in response to different stimuli.

Phosphorylation of elF2a converts it to an inhibitor of the guanine nucleotide exchange factor (GEF) elF2B which is required for efficient turnover of GDP for GTP in the elF2 protein synthesis complex. As a result, the inhibition of elF2B by P-elF2a causes a general decrease in translation initiation and thus a reduction in global protein synthesis (Harding et al. 2002). Paradoxically, translation of specific mRNAs is enhanced when the UPR is activated and elF2a is phosphorylated. For example, the transcription factor ATF4 has 5'-upstream open reading frames (uORFs) that normally represses ATF4 synthesis during normal global protein synthesis. However, when PERK is activated under stress and P-elF2a inhibits elF2B, the lower levels of ternary translation complex allows for selective enhanced translation of ATF4 (Jackson et al. 2010). Therefore, when ER stress ensues, PERK activation causes an increase in ATF4 translation, which transcriptionally upregulates downstream target genes such as CHOP (transcription factor C/EBP homologous protein). This transcriptional reprogramming modulates cell survival pathways and can lead to the induction of pro-apoptotic genes.

The activation of PERK and the UPR is associated with human neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), dementias, and prion diseases including Creutzfeldt-Jakob Disease (CJD), (Doyle et al. 201 1), (Paschen 2004), (Salminen et al. 2009), (Stutzbach et al. 2013). The common hallmark of all these diseases is the presence of malformed/misfolded or aggregated protein deposits (e.g tau tangles, Lewy bodies, a-synuclein, Αβ plaques, mutant prion proteins) believed to contribute to the underlying disease pathophysiology, neuron loss, and cognitive decline (Prusiner, 2012), (Doyle et al. 2011). The fate of a cell (e.g a neuron) enduring unfolded or misfolded protein stress is under control of PERK. A cell enduring ER stress may restore proteostasis and return to normal, or if the stress is insurmountable, sustained PERK activation may lead to cell death through ATF4/CHOP driven autophagy coupled with the inability to synthesize vital proteins because of the persistent translational repression. Activated PERK and associated biological markers of PERK activation are detected in post-mortem brain tissue of Alzheimer's disease patients and in human prion disease (Ho et al. 2012), (Hoozemans et al, 2009) (Unterberger et al. 2006). Furthermore, P-elF2a (the product of PERK activation) correlates with levels of BACE1 in post-mortem brain tissue of Alzheimer's disease patients (O'Connor et al. 2008). Recently, the small molecule PERK inhibitor GSK2606414 was shown to provide a neuroprotective effect and prevent clinical signs of disease in prion infected mice (Moreno et al. 2013), consistent with previous results derived from genetic manipulation of the UPR/PERK/elF2a pathway (Moreno et al. 2012). Involvement of the pathway in ALS (Kanekura et. al., 2009 and Nassif et. al. 2010), spinal cord injury (Ohri et al. 201 1) and traumatic brain injury (Tajiri et al. 2004) is also reported. Taken together these data suggest that the UPR and PERK represent a promising node of drug intervention as a means to halt or reverse the clinical progression and associated cognitive impairments of a wide range of neurodegenerative diseases.

Tumor cells experience episodes of hypoxia and nutrient deprivation during their growth due to inadequate blood supply and aberrant blood vessel function (Brown and Wilson, 2004), (Blais and Bell, 2006). Thus, they are likely to be dependent on active UPR signaling to facilitate their growth. Consistent with this, mouse fibroblasts derived from PERK-/-, XBP1-/-, and ATF4-/- mice, and fibroblasts expressing mutant elF2a show reduced clonogenic growth and increased apoptosis under hypoxic conditions in vitro and grow at substantially reduced rates when implanted as tumors in nude mice (Koumenis et al., 2002), (Romero-Ramirez et al., 2004), (Bi et al., 2005). Human tumor cell lines carrying a dominant negative PERK that lacks kinase activity also showed increased apoptosis in vitro under hypoxia and impaired tumor growth in vivo (Bi et al., 2005). In these studies, activation of the UPR was observed in regions within the tumor that coincided with hypoxic areas. These areas exhibited higher rates of apoptosis compared to tumors with intact UPR signaling. Further evidence supporting the role of PERK in promoting tumor growth is the observation that the number, size, and vascularity of insulinomas arising in transgenic mice expressing the SV40- T antigen in the insulin- secreting beta cells, was profoundly reduced in PERK mice compared to wild-type control (Gupta et al., 2009). Activation of the UPR has also been observed in clinical specimens. Human tumors, including those derived from cervical carcinomas, glioblastomas (Bi et al., 2005), lung cancers (Jorgensen et al., 2008) and breast cancers (Ameri et al., 2004), (Davies et al., 2008) show elevated levels of proteins involved in UPR, compared to normal tissues. Therefore, inhibiting the unfolded protein response with compounds that block the activity of PERK and other components of the UPR is expected to have utility as anticancer agents. Recently, this hypothesis was supported by two small molecule inhibitors of PERK that were shown to inhibit the growth of human tumor xenografts in mice (Axten et al. 2012 and Atkins et al. 2013).

Loss of endoplasmic reticulum homeostasis and accumulation of misfolded proteins can contribute to a number of disease states (Wek and Cavener 2007), (Zhang and Kaufman 2006). Inhibitors of PERK may be therapeutically useful for the treatment of a variety of human diseases such as Alzheimer's disease and frontotemporal dementias, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and other tauopathies such chronic traumatic encephalopathy (CTE) (Nijholt, D. A., et al. 2012), (Lucke-Wold, B. P., et al. 2016), spinal cord injury, traumatic brain injury, stroke, Creutzfeldt-Jakob Disease (CJD) and related prion diseases, such as fatal familial insomnia (FFI), Gerstmann-Straussler-Scheinker Syndrome, and vanishing white matter (VWM) disease. Inhibitors of PERK may also be useful for effective treatment of cancers, particularly those derived from secretory cell types, such as pancreatic and neuroendocrine cancers, multiple myeloma, or for use in combination as a chemosensitizer to enhance tumor cell killing. A PERK inhibitor may also be useful for myocardial infarction, cardiovascular disease, atherosclerosis (McAlpine et al., 2010, Civeiek et al. 2009, Liu and Dudley 2016), arrhythmias, and kidney disease (Dickhout et al., 2011 , Cybulsky, A. V., et al. 2005). A PERK inhibitor may also be useful in stem cell or organ transplantation to prevent damage to the organ and in the transportation of organs for transplantation (Inagi et al., 2014), (Cunard, 2015), (Dickhout et al., 2011), (van Galen, P., et al. (2014). A PERK inhibitor is expected to have diverse utility in the treatment of numerous diseases in which the underlying pathology and symptoms are associated with dysregulaton of the unfolded protein response. References

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Zhang, K. and R. J. Kaufman (2006). The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology 66(2 Suppl 1): S102-109 It is an object of the instant invention to provide novel compounds that are inhibitors of PERK.

It is also an object of the present invention to provide pharmaceutical compositions that comprise a pharmaceutical carrier and compounds of Formula (I).

It is also an object of the present invention to provide a method for treating neurodegenerative diseases, cancer, and other diseases/injuries associated with activated unfolded protein response pathways such as: Alzheimer's disease, neuropathic pain, spinal cord injury, traumatic brain injury,, ischemic stroke, stroke, Parkinson disease, diabetes, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt- Jakob Disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute diseases of the liver, fatty liver disease, liver steatosis, liver fibrosis, chronic and acute diseases of the lung, lung fibrosis, chronic and acute diseases of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, frontotemporal dementias, tauopathies, Pick's disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation that comprises administering novel inhibitors of PERK activity.

SUM MARY OF THE INVENTION

The invention is directed to substituted imidazolidinone derivatives and uses thereof. Specifically, the invention is directed to compounds according to Formula (I) and the use of compounds of Formula (I) in treating disease states.

The present invention also relates to the discovery that the compounds of Formula

(I) are active as inhibitors of PERK.

This invention also relates to a method of treating cancer, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).

This invention also relates to a method of treating Alzheimer's disease which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).

This invention also relates to a method of treating Parkinson's disease, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I). This invention also relates to a method of treating amyotrophic lateral sclerosis, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).

This invention also relates to a method of treating Huntington's disease, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I). This invention also relates to a method of treating Creutzfeldt-Jakob Disease, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I). This invention also relates to a method of treating progressive supranuclear palsy

(PSP), which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).

This invention also relates to a method of treating dementia, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).

This invention also relates to a method of treating spinal cord injury, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).

This invention also relates to a method of treating traumatic brain injury, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).

This invention also relates to a method of treating ischemic stroke, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I). This invention also relates to a method of treating diabetes, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).

This invention also relates to a method of treating a disease state selected from:, myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias, which comprises administering to a subject in need thereof an effective amount of a PERK inhibiting compound of Formula (I).

This invention also relates to a method of using the compounds of Formula (I) in organ transplantation and in the transportation of organs for transplantation. In a further aspect of the invention there is provided novel processes and novel intermediates useful in preparing the presently invented PERK inhibiting compounds. Included in the present invention are pharmaceutical compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention.

Also included in the present invention are methods of co-administering the presently invented PERK inhibiting compounds with further active ingredients.

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

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Alzheimer's disease.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Parkinson's disease. The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of amyotrophic lateral sclerosis.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Huntington's disease.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Creutzfeldt-Jakob Disease.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of progressive supranuclear palsy (PSP).

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of dementia. The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of spinal cord injury.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of traumatic brain injury.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of diabetes.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disease state selected from:, myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of chronic traumatic encephalopathy (CTE).

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in organ transplantation and in the transportation of organs for transplantation. Included in the present invention are pharmaceutical compositions that comprise a pharmaceutical carrier and a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

The invention also relates to a pharmaceutical composition as defined above for use in therapy.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel compounds of Formula (I) and to the use of compoundsula (I) in the methods of the invention:

is selected from:

bicycloheteroaryl,

substituted bicycloheteroaryl,

heteroaryl, and

substituted heteroaryl,

where said substituted bicycloheteroaryl and said substituted heteroaryl substituted with from one to five substituents independently selected from: fluoro,

chloro,

bromo,

iodo,

C-|-6alkyl,

C-|-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, -NH2, cycloalkyl, Ci -4alkyloxy, -OH, -COOH, -CF ₃ , -N0 ₂ , and

-CN,

-OH,

hydroxyC-|-6alkyl,

-COOH,

tetrazole, cycloalkyl,

oxo,

-OCi_6alkyl,

-CF ₃ ,

-CF ₂ H,

-CFH ₂ ,

-Ci-6alkylOCi-4alkyl, -CONH2,

-CON(H)Ci-3alkyl,

-CH ₂ CH ₂ N(H)C(0)OCH ₂ aryl,

diCi-4alkylaminoCi-4alkyl, aminoCi-6alkyl,

-CN,

heterocycloalkyi,

heterocycloalkyi substituted with from 1 to 4 substituents

independently selected from: C-|-4alkyl, C-|-4alkyloxy, -OH,

-COOH, -CF ₃ , -Ci-4alkylOCi-4alkyl, -N0 ₂ , -NH ₂ and -CN,

-N0 ₂ ,

-NH ₂ ,

-N(H)Ci-3alkyl, and -N(Ci-3alkyl) _2;

2

R is selected from:

C-|-6alkyl,

aryl,

aryl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, cycloalkyl,

Ci_4alkyloxy, -OH, -COOH, -CF ₃ , -Ci-4alkylOCi-4alkyl, -N0 ₂ , -NH ₂ , -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF3,

hydroxyCi-4alkyl, and -CN,

heteroaryl,

heteroaryl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, cycloalkyl,

Ci-4alkyloxy, -OH, -COOH, -CF ₃ , -Ci-4alkylOCi-4alkyl, -N0 ₂ ,

-NH ₂ , -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF3, hydroxyCi-4alkyl, and -CN,

bicycloheteroaryl,

bicycloheteroaryl substituted with from one to five substituents

independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, cycloalkyl, Ci-4alkyloxy, -OH, -COOH, -CF ₃ , -Ci-4alkylOCi-4alkyl,

-N0 ₂ , -NH ₂ , -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF3, hydroxyC-|-4alkyl, and -CN, and

cycloalkyl;

3

R is selected from:

hydrogen,

-NH ₂ ,

-N(H)Ci-3alkyl,

-N(Ci-3alkyl) _2,

-OH,

C-|-6alkyl, and

Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH, -CF ₃ , -Ci-4alkylOC-|-4alkyl, -N0 ₂ , -NH ₂ and -CN;

4 5

R and R are each independently selected from hydrogen and C-|-6alkyl,

or R4 and R5 taken together with the carbon atoms to which they are attached form a 3 or 4 member cycloalkyi, optionally substituted from 1 to 3 times by Ci_4alkyl; and

R is selected from: hydrogen, Ci _4alkyl, -CF3, -C(H)F2, -CH2F, fluoro, chloro,

bromo and iodo;

R ⁷ is selected from: hydrogen, Ci _4alkyl, -CF3, -C(H)F2, -CH2F, fluoro, chloro,

bromo and iodo;

X is CR ^{1 00} or N,

where R ^{1 00} is selected from: hydrogen, -CH3, fluoro, chloro, bromo and iodo;

1 2 1

Y and Y are independently selected from: hydrogn, -CF3 and C-|-4alkyl, or Y

2

And Y are taken together with the carbon to which they are attached to form a C3-C6 cycloalkyi; and

Z is 0 or 1 ; and salts thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (I).

Suitably, in the compounds of Formula (I), X is CR ¹⁰⁰ , where R ^{1 00} is selected from: hydrogen, -CH3, fluoro, chloro, bromo and iodo.

Suitably, in the compounds of Formula (I), X is N.

1

Suitably, in the compounds of Formula (I), R is a substituted thieno[2,3-d]pyrimidine.

Suitably, in the compounds of Formula (I), R is a substituted quinoline.

Suitably, in the compounds of Formula (I), R is a substituted pyridine. 1

Suitably, in the compounds of Formula (I), R is a substituted indazole.

Suitably, in the compounds of Formula (I), R is a substituted quinazoline.

Suitably, in the compounds of Formula (I), R is a substituted benzothiazole.

Suitably, in the compounds of Formula (I), R is a substituted thienopyridine.

2

Suitably, in the compounds of Formula (I), R is C-|-6alkyl.

Suitably, in the compounds of Formula (I), R is selected from: pyrrolo[2,3d]pyrimidin-5 yl and pyrazolo[3,4d] pyrimidin-5-yl.

Suitably, in the compounds of Formula (I), R is selected from: 5-yl pyrrolo[2,3d]pyrimidin-4-amine and 5-yl-pyrazolo[3,4d] pyrimidin-5-yl-4-amine.

Included in compounds of Formula (I) are compounds of Formula (II):

wherein:

R ^{1 0} is selected from:

aryl,

aryl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, cycloalkyi, Ci^alkyloxy, -OH, -COOH, -CF ₃ , -Ci-4alkylOCi_4alkyl,

-N0 ₂ , -NH ₂ , -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF3, hydroxyCi-4alkyl, and -CN,

cycloalkyi,

heteroaryl, and

heteroaryl substituted with from one to five substituents independently

selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, cycloalkyi, Ci-4alkyloxy, -OH, -COOH, -CF ₃ , -Ci-4alkylOCi-4alkyl, -NO2, -NH ₂ , -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF3, hydroxyCi-4alkyl, and -CN,

11

R is selected from:

hydrogen,

-NH ₂ ,

-N(H)Ci-3alkyl,

-N(Ci. ₃ alkyl) _2,

-OH,

C-|-6alkyl, and

Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF ₃ , -Ci-4alkylOC-|-4alkyl, -N0 ₂ , -NH ₂ and -CN;

12 13

R and R are each independently selected from hydrogen and C-|-6alkyl,

or R12 and R^ 3 taken together with the carbon atoms to which they are attached form a 3 or 4 member cycloalkyi, optionally substituted from 1 to 3 times by C-|-4alkyl;

14

R is selected from: hydrogen, C-|-4alkyl, -CF3, -C(H)F ₂ , -CH ₂ F, fluoro and

chloro; 15

R is selected from hydrogen and Ci_6alkyl;

R ¹⁶ is selected from:

hydrogen,

cycloalkyl,

Ci-6alkyl, and

C-|-6alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyloxy, -OH, -CF3 -COOH, -NO2, -NH ₂ and -CN;

17

R is selected from: hydrogen and -CH3;

18

R is selected from: hydrogen, C-|-4alkyl, -CF3, -C(H)F2, -CH2F, fluoro and

chloro;

10 1 1 10 Y and Y are independently selected from: hydrogn, -CF3 and C-|-4alkyl, or Y

1 1

and Y are taken together with the carbon to which they are attached to form a C3-C6 cycloalkyl; and

X is CR ^{1 01} or N,

101

where R is selected from: hydrogen, fluoro and chloro; and salts thereof. This invention also relates to pharmaceutically acceptable salts of the compounds of

Formula (II).

101 101

Suitably, in the compounds of Formula (II), X is CR , where R is selected from: hydrogen, fluoro and chloro.

Suitably, in the compounds of Formula (II), X is N.

Included in the presently invented compounds of Formula (I) are compounds of Formula (III): wherein:

R ²⁰ is selected from:

phenyl optionally substituted with form one to five substituents

independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, cycloalkyl, Ci-4alkyloxy, -OH, -COOH, -CF ₃ , -Ci-4alkylOCi-4alkyl, -N0 ₂ , -NH ₂ , -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF3,

hydroxyCi-4alkyl, and -CN,

cycloalkyl,

heteroaryl, and

heteroaryl substituted with from one to five substituents independently

selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, cycloalkyl, Ci-4alkyloxy, -OH, -COOH, -CF ₃ , -Ci-4alkylOCi-4alkyl, -NO2, -NH ₂ , -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF3,

hydroxyCi-4alkyl, and -CN;

21

R is selected from:

hydrogen,

C-|-6alkyl, and

C-|-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH, -CF ₃ , -Ci-4alkylOCi-4alkyl, -N0 ₂ , -NH ₂ and -CN;

22 23

R and R are each independently selected from hydrogen and C-|-6alkyl, or R22 and R23 taken together with the carbon atoms to which they are attached form a 3 or 4 member cycloalkyi, optionally substituted from 1 to 3 times by C-|-4alkyl;

24

R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;

25

R is selected from hydrogen and Ci-6alkyl;

R is selected from:

hydrogen,

cycloalkyi,

C-|-6alkyl, and

C-|-6alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyloxy, -OH, -CF3 -COOH, -NO2, -IMH2 and -CN;

27

R is selected from: hydrogen and -CH3;

28

R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;

21 22 21 Y and Y are independently selected from: hydrogn, -CF3 and Ci-4alkyl, or Y

22

and Y are taken together with the carbon to which they are attached to form a C3-C6 cycloalkyi; and

X is CR ^{1 02} or N,

102

where R is selected from: hydrogen, fluoro and chloro; and salts thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (III).

102 102

Suitably, in the compounds of Formula (III), X is CR , where R is selected from: hydrogen, fluoro and chloro. Suitably, in the compounds of Formula (III), X is N.

Included in the presently invented compounds of Formula (I) are compounds of Formula (IV):

wherein:

R ³⁰ is selected from:

phenyl optionally substituted with from one to five substituents

independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl,

Ci-4alkyloxy, -OH, -COOH, -CF ₃ , -Ci-4alkylOCi-4alkyl, -N0 ₂ , cycloalkyl, -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF3, -NH ₂ and

-CN, and

cycloalkyl,

heteroaryl, and

heteroaryl substituted with from one to five substituents independently

selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy,

-OH, -COOH, -CF ₃ , -Ci -4alkylOC-|-4alkyl, -N0 ₂ , -NH ₂ , cycloalkyl, -OC(H)F ₂ , -C(H)F ₂ , -OCH ₂ F, -CH ₂ F, -OCF3, and -CN;

31

R is selected from:

hydrogen,

C-|-6alkyl, and

C-|-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-| -4alkyloxy, -OH, -COOH, -CF ₃ , -Ci-4alkylOCi -4alkyl, -N0 ₂ , -NH ₂ and -CN; 32 33

R and R are each independently selected from hydrogen and C-|-6alkyl,

or R32 and R^3 taken together with the carbon atoms to which they are attached form a 3 or 4 member cycloalkyi, optionally substituted from 1 to 3 times by C-|-4alkyl;

34

R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;

35

R is selected from:

hydrogen,

cycloalkyi,

C-|-6alkyl, and

C-|-6alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyloxy, -OH, -CF3 -COOH, -NO2, -IMH2 and -CN;

36

R is selected from: hydrogen and -CH3;

37

R is selected from: hydrogen, methyl, -CF3, fluoro and chloro;

31 32 31

Y and Y are independently selected from: hydrogn, -CF3 and C-|-4alkyl, or Y

32

and Y are taken together with the carbon to which they are attached to form a C3-C6 cycloalkyi; and

X is CR ^{1 03} or N,

where R is selected from: hydrogen, fluoro and chloro; and salts thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (IV).

Suitably, in the compounds of Formula (IV), X is CR , where R is selected from: hydrogen, fluoro and chloro. Suitably, in the compounds of Formula (IV), X is N.

Included in the presently invented compounds of Formula (I) are: 1-(4-(4-Amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-3- fluorophenyl)-3-(2,5- difluorobenzyl) imidazolidin-2-one;

1-(3,5-Dimethylbenzyl)-3-(3-fluoro-4-(2-(methylamino)quin olin-6-yl)phenyl)imidazolidin-

2-one;

1-(3,5-Dimethylbenzyl)-3-(3-fluoro-4-(2-methylquinolin-6- yl)phenyl)imidazolidin-2-one;

1-(4-(4-Amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-((4,6- dimethylpyridin-2-yl)methyl)-4-(hydroxymethyl)imidazolidin-2 -one;

1-(4-(4-Amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-((1-ethyl-1 /-/- pyrrol-2-yl)methyl)imidazolidin-2-one;

1-(4-(4-Chloro-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl )-3-fluorophenyl)-3-(2,5- difluorobenzyl) imidazolidin-2-one;

1- (2,5-difluorobenzyl)-3-(3-fluoro-4-(7-methyl-7/-/-pyrrolo[2, 3-d]pyrimidin-5- yl)phenyl)imidazolidin-2-one; 1-(2,5-difluorobenzyl)-3-(3-fluoro-4-(4-hydroxy-7-methyl-7/- /-pyrrolo[2,3-d]pyrimidin-5- yl)phenyl)imidazolidin-2-one;

2- (4-(4-Amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-3-fl uorophenyl)-4-(2,5- difluorobenzyl)-2,4-diazabicyclo[3.1.0]hexan-3-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) phenyl)-3-(3- cyclopropylpiperidin-1-yl)pyrrolidin-2-one;

4-(4-(3-(2,5-difluorobenzyl)-2-oxoimidazolidin-1-yl)-2-fl uorophenyl)pyridin-2(1 /-/)-one;

6-(4-(3-(2,5-difluorobenzyl)-2-oxoimidazolidin-1-yl)-2-fl uorophenyl)pyridin-2(1 /-/)-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3 -fluorophenyl)-3-(2,3- difluorobenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(5-fluoro-2- methylbenzyl)imidazolidin-2-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fl uorophenyl)-3-((3-fluoro-6- methylpyridin-2-yl)methyl)imidazolidin-2-one; 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)phe nyl)-3-(3- methylbenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(3- methylbenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(3- cyclopropylbenzyl)imidazolidin-2-one;

1-(4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl)-3-benzyl imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3- (cyclohexylmethyl)imidazolidin-2-one;

1-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-6 -methylpyridin-2-yl)-3- benzylimidazolidin-2-one;

1-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4 -methylpyridin-2-yl)-3- benzylimidazolidin-2-one; 1-(4-(4-amino-7-(1-methylpiperidin-4-yl)-7/-/-pyrrolo[2,3-d] pyrimidin-5-yl)-3- fluorophenyl)-3-(3,5-dimethylbenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(4-fluoro-3- methylbenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(3-chloro-2- fluorobenzyl)imidazolidin-2-one;

1-(4-(4-amino-27-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl )-3-fluorophenyl)-3-(3-chloro- 2-fluorobenzyl)imidazolidin-2-one;

1-(5-(4-amino-27-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl )pyridiri-2-yl)-3-(3,5- dimethylbenzyl)imidazolidin-2-one; 1-(4-(4-amino-27-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3 -fluorophenyl)-3-(3-fluoro- 5-(trifluoromethyl)benzyl)imidazolidin-2-one; 1-(4-(3-amino-1-methyl-1 /-/-indazol-4-yl)-3-fluorophenyl)-3-(2,5- difluorobenzyl)imidazolidin-2-one;

1-(5-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pynmidin-5-yl)p yridin-2-yl)-3-(2,5- difluorobenzyl)imidazolidin-2-one;

1-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)py ridin-2-yl)-3-(3-chloro-2- fluorobenzyl)imidazolidin-2-one; 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3- fluorophenyl)-3-(3- ethynylbenzyl)imidazolidin-2-one;

1-(5-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pynmidin-5-yl)p yridin-2-yl)-3-(2,3- difluorobenzyl)imidazolidin-2-one;

1-(4-(4-amino-27-dimethyl-7/-/-pyrrolo[2,3-d]pyrimidin-5- yl)-3-fluorophenyl)-3-(2,3- difluorobenzyl)imidazolidin-2-one;

1-(4-(2-aminoquinazolin-6-yl)-3-fluorophenyl)-3-(3,5-dime thylbenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) phenyl)-3-(3,5- dimethylbenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ph enyl)-3-((4,6-dimethylpyridin- 2-yl)methyl)imidazolidin-2-one;

1-(3,5-dimethylbenzyl)-3-(3-fluoro-4-(2-methylbenzo[d]thi azol-6-yl)phenyl)imidazolidin-

2-one; 1-(4-(2-aminobenzo[d]thiazol-6-yl)-3-fluorophenyl)-3-(3,5-di methylbenzyl)imidazolidin-2- one;

1-(4-(4-amino-7-(1-methylpiperidin-4-yl)-7 - -pyrrolo[2,3-d]pyrimidin-5-yl)-3- fluorophenyl)-3-(2,5-difluorobenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(3- (difluoromethyl)benzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(5- (difluoromethyl)-2-fluorobenzyl)imidazolidin-2-one; 1-(3,5-dimethylbenzyl)-3-(3-fluoro-4-(2-(methylamino)quinazo lin-6- yl)phenyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-methylphenyl)-3-(3,5- dimethylbenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-methylphenyl)-3-(3- (trifluoromethyl)benzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) phenyl)-3-benzyl-4,4- dimethylimidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3- d]pyrimidin-5-yl)-3-fluorophenyl)-3-(3- chlorobenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-methylphenyl)-3-(2,5- difluorobenzyl)imidazolidin-2-one;

1-(5-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pynmidin-5-yl)p yridin-2-yl)-3-(3,5- dimethylbenzyl)imidazolidin-2-one;

1-(3,5-dimethylbenzyl)-3-(3-fluoro-4-(2-(methylamino)benz o[d]thiazol-6- yl)phenyl)imidazolidin-2-one; 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3- fluorophenyl)-3-(3- (difluoromethoxy)benzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3- d]pyrimidin-5-yl)-3-fluorophi

(cyclopentylmethyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(2-fluoro-5- (trifluoromethyl)benzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3 -fluorophenyl)-3-((1-methyl- 1 H-pyrrol-2-yl)methyl)imidazolidin-2-one;

1-(4-(4-amino-27-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl )-3-methylphenyl)-3-(3,5- dimethylbenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-(2,2-difluoroethyl)-7/-/-pyrrolo[2,3-d]py rimidin-5-yl)-3-fluorophenyl)-3- (2,5-difluorobenzyl)imidazolidin-2-one; 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)phe nyl)-3-((6- (trifluoromethyl)pyridin-3-yl)methyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) phenyl)-3-((6- (trifluoromethyl)pyridin-2-yl)methyl)imidazolidin-2-one;

1-(4-(4-amino-2,7-dimethyl-7/-/-pyrrolo[2,3-d]pyrimidin-5 -yl)-3-fluorophenyl)-3-(2,5- difluorobenzyl)imidazolidin-2-one; 1-(4-(4-amino-2,7-dimethyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl )-3-fluorophenyl)-3-(3,5- dimethylbenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) 3-fluorophenyl)-3-(1-(3,5- dimethylphenyl)ethyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(2-fluoro-5- methylbenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(3-fluoro-5- methylbenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(2,5- dimethylbenzyl)imidazolidin-2-one; 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3- fluorophenyl)-3-(2-fluoro-3- methylbenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) 3-fluorophenyl)-3-(3,5- dimethylphenethyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(2- methylbenzyl)imidazolidin-2-one)imidazolidin-2-one ;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(5-chloro-2- fluorobenzyl)imidazolidin-2-one;

1-(4-(4-amino-2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidi n-5-yl)-3-fluorophenyl)-3-(2,5- difluorobenzyl)imidazolidin-2-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fl uorophenyl)-3-(2-chloro-5- fluorobenzyl)imidazolidin-2-one; 1-(4-(4-amino-2-methoxy-7-methyl-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)-3-fluorophenyl)-3- (2,5-difluorobenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(5- cyclopropyl-2-fluorobenzyl)imidazolidin-2-one;

1-(4-(4-amino-2,7-dimethyl-7/-/-pyrrolo[2,3-d]pyrimidin-5 -yl)-3-fluorophenyl)-3-(2,5- dimethylbenzyl)imidazolidin-2-one; 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3- fluorophenyl)-3-((6- (hydroxymethyl)-4-methylpyridin-2-yl)methyl)imidazolidin-2-o ne;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3 -fluorophenyl)-3-(3,5- diethylbenzyl)imidazolidin-2-one;

1-(4-(4-amino-27-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl )-3-fluorophenyl)-3-(3-chloro- 2-fluorobenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ph enyl)-3-benzylimidazolidin-2- one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3- benzylimidazolidin-2-one; 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3- fluorophenyl)-3-(1- phenylethyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl) -3-fluorophenyl)-3-(3,5- difluorobenzyl)imidazolidin-2-one;

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

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3 -fluorophenyl)-3- (cyclopropylmethyl)imidazolidin-2-one;

1-(4-(4-aminothieno[3,2-c]pyridin-3-yl)phenyl)-3-benzylim idazolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pynmidin-5-yl)-3- fluorophenyl)-3-(3,5- dimethylbenzyl)imidazolidin-2-one; 1-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrid in-2-yl)-3- benzylimidazolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ph enyl)-3-(2,5- difluorobenzyl)imidazolidin-2-one;

4-(4-(3-(2,5-difluorobenzyl)-2-oxoimidazolidin-1-yl)-2-fl uorophenyl)-1-methylpyridin- 2(1 H)-one; 6-(4-(3-(2,5-difluorobenzyl)-2-oxoimidazolidin-1-yl)-2-fluor ophenyl)-1-methylpyridin- 2(1 H)-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3 -fluorophenyl)-3-(3-fluoro-5- (trifluoromethyl)benzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pynmidin-5-yl)-3- fluorophenyl)-3-(2,3,5- trifluorobenzyl)imidazolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pynmidin-5-yl)-3- fluorophenyl)-3-(2,3,6- trifluorobenzyl)imidazolidin-2-one;

1- (4-(4-amino-6,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3- fluorophenyl)-3-(2,5- difluorobenzyl)imidazolidin-2-one; 2-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pynmidin-5-yl)-3-flu orophenyl)-4-(2,5- difluorobenzyl)-6,6-dimethyl-2,4-diazabicyclo[3.1.0]hexan-3- one;

2- (4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluo rophenyl)-4-(3-chloro-2- fluorobenzyl)-2,4-diazabicyclo[3.1.0]hexan-3-one;

2- (4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidiri-5-yl)-3-flu orophenyl)-4-(2,3,6- trifluorobenzyl)-2,4-diazabicyclo[3.1.0]hexan-3-one;

3- (4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluo rophenyl)-1-(2,5- difluorobenzyl)-4-methylimidazolidin-2-one;

2-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)py ridin-2-yl)-4-(2,5- difluorobenzyl)-2,4-diazabicyclo[3.1.0]hexan-3-one; and

1-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)py ridin

dimethylbenzyl)imidazolidin-2-one; and salts thereof including pharmaceutically acceptable salts thereof.

The skilled artisan will appreciate that salts, including pharmaceutically acceptable salts, of the compounds according to Formula (I) may be prepared. Indeed, in certain embodiments of the invention, salts including pharmaceutically-acceptable salts of the compounds according to Formula (I) may be preferred over the respective free or unsalted compound. Accordingly, the invention is further directed to salts, including pharmaceutically- acceptable salts, of the compounds according to Formula (I). The salts, including pharmaceutically acceptable salts, of the compounds of the invention are readily prepared by those of skill in the art.

The compounds according to Formula (I) may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in a compound of Formula (I), or in any chemical structure illustrated herein, if not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula (I) containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.

The compounds according to Formula (I) may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula (I), or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula (I) whether such tautomers exist in equilibrium or predominately in one form. The compounds of Formula (I) or salts, including pharmaceutically acceptable salts, thereof may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof. For compounds of the invention that are in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing vaiable amounts of water.

The skilled artisan will further appreciate that certain compounds of Formula (I) or salts, including pharmaceutically acceptable salts thereof that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

Definitions

"Alkyl" refers to a hydrocarbon chain having the specified number of "member atoms". For example, C-1-C5 alkyl refers to an alkyl group having from 1 to 6 member atoms. Alkyl groups may be saturated, unsaturated, straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, ethylene, propyl (n-propyl and isopropyl), butene, butyl (n-butyl, isobutyl, and t-butyl), pentyl and hexyl.

"Alkoxy" refers to an -O-alkyl group wherein "alkyl" is as defined herein. For example, C-|-

C4alkoxy refers to an alkoxy group having from 1 to 4 member atoms. Representative branched alkoxy groups have one, two, or three branches. Examples of such groups include methoxy, ethoxy, propoxy, and butoxy. "Aryl" refers to an aromatic hydrocarbon ring. Aryl groups are monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring member atoms, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 member atoms, such as phenyl, naphthalene, tetrahydronaphthalene and biphenyl. Suitably aryl is phenyl. "Bicycloheteroaryl" refers to two fused aromatic rings containing from 1 to 6 heteroatoms as member atoms. Bicycloheteroaryl groups containing more than one heteroatom may contain different heteroatoms. Bicycloheteroaryl rings have from 6 to 1 1 member atoms. Bicycloheteroaryl includes: 1 /-/-pyrrolo[3,2-c]pyridine, 1/-/-pyrazolo[4,3-c]pyridine, 1 H- pyrazolo[3,4-d]pyrimidine, 1 H-pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, thieno[3,2- c]pyridine, thieno[2,3-d]pyrimidine, furo[2,3-c]pyridine, furo[2,3-d]pyrimidine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5- c] pyridine, imidazo[4.5-b]pyridine, furopyridinyl and napthyridinyl.

Suitably "Bicycloheteroaryl" includes: 1 H-pyrazolo[3,4-d]pyrimidine, 1 H-pyrrolo[2,3- d] pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, thieno[3,2-c]pyridine, thieno[2,3-d]pyrimidine, furo[2,3-c]pyridine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5-c]pyridine, imidazo[4.5-b]pyridine, furopyridinyl and napthyridinyl. Suitably 1 H-pyrazolo[3,4-d]pyrimidine, 1 H-pyrrolo[2,3-d]pyrimidine, thieno[3,2-c]pyridine, thieno[2,3-d]pyrimidine, indazolyl, quinolinyl, quinazolinyl or benzothiazolyl. Suitably 1 H- pyrazolo[3,4-d]pyrimidine, thieno[2,3-d]pyrimidine or 1 H-pyrrolo[2,3-d]pyrimidine. Suitably 1 H- pyrrolo[2,3-d]pyrimidine.

"Cycloalkyl", unless otherwise defined, refers to a saturated or unsaturated non aromatic hydrocarbon ring having from three to seven carbon atoms. Cycloalkyl groups are monocyclic ring systems. For example, C3-C7 cycloalkyl refers to a cycloalkyl group having from 3 to 7 member atoms. Examples of cycloalkyl as used herein include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptyl.

"Halo" refers to the halogen radicals fluoro, chloro, bromo, and iodo. "Heteroaryl" refers to a monocyclic aromatic 4 to 8 member ring containing from 1 to 7 carbon atoms and containing from 1 to 4 heteroatoms, provided that when the number of carbon atoms is 3, the aromatic ring contains at least two heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl includes: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl. Suitably, "heteroaryl" includes: pyrazole, pyrrole, isoxazole, pyridine, pyrimidine, pyridazine, and imidazole.

"Heterocycloalkyl" refers to a saturated or unsaturated non-aromatic ring containing 4 to 12 member atoms, of which 1 to 1 1 are carbon atoms and from 1 to 6 are heteroatoms. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups are monocyclic ring systems or a monocyclic ring fused with an aryl ring or to a heteroaryl ring having from 3 to 6 member atoms. Heterocycloalkyl includes: pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, oxetanyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4- dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, 1 ,3oxazolidin-2-one, hexahydro-1 H- azepin, 4,5,6,7,tetrahydro-1 H-benzimidazol, piperidinyl, 1 ,2,3,6-tetrahydro-pyridinyl and azetidinyl.

"Heteroatom" refers to a nitrogen, sulphur or oxygen atom.

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:

Ac (acetyl);

Ac ₂ 0 (acetic anhydride); ACN (acetonitrile);

AIBN (azobis(isobutyronitrile));

BINAP (2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl);

BMS (borane - dimethyl sulphide complex);

Bn (benzyl);

Boc (tert-Butoxycarbonyl);

Boc ₂ 0 (di-te/f-butyl dicarbonate);

BOP (Benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate);

CAN (cerric ammonium nitrate);

Cbz (benzyloxycarbonyl);

CSI (chlorosulfonyl isocyanate);

CSF (cesium fluoride);

DABCO (1 ,4-Diazabicyclo[2.2.2]octane);

DAST (Diethylamino)sulfur trifluoride);

DBU (1 ,8-Diazabicyclo[5.4.0]undec-7-ene);

DCC (Dicyclohexyl Carbodiimide);

DOE (1 ,2-dichloroethane);

DCM (dichloromethane);

DDQ (2,3-Dichloro-5,6-dicyano-1 ,4-benzoquinone);

ATP (adenosine triphosphate);

Bis-pinacolatodiboron (4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1 ,3,2-dioxaborolane);

BSA (bovine serum albumin);

C18 (refers to 18-carbon alkyl groups on silicon in HPLC stationary phase)

CH ₃ CN (acetonitrile) Cy (cyclohexyl);

DCM (dichloromethane);

DIPEA (Hunig's base, A/-ethyl-A/-(1-methylethyl)-2-propanamine); Dioxane (1 ,4-dioxane);

DMAP (4-dimethylaminopyridine);

DME (1 ,2-dimethoxyethane);

DMEDA (Λ/,Λ/'-dimethylethylenediamine);

DMF (A/./V-dimethylformamide);

DMSO (dimethylsulfoxide);

DPPA (diphenyl phosphoryl azide);

EDC (A/-(3-dimethylaminopropyl)-/\/'ethylcarbodiimide);

EDTA (ethylenediaminetetraacetic acid);

EtOAc (ethyl acetate) ;

EtOH (ethanol);

Et ₂ 0 (diethyl ether);

HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid);

HATU (0-(7-Azabenzotriazol-1-yl)-/\/,/\/,/\/',A/'-tetramethyluron ium hexafluorophosphate); HOAt (1-hydroxy-7-azabenzotriazole);

HOBt (1-hydroxybenzotriazole);

HOAc (acetic acid);

HPLC (high pressure liquid chromatography);

HMDS (hexamethyldisilazide);

Hunig's Base (A/,A/-Diisopropylethylamine);

I PA (isopropyl alcohol);

Indoline (2,3-dihydro-1/-/-indole) ;

KHMDS (potassium hexamethyldisilazide) ;

LAH (lithium aluminum hydride) ;

LDA (lithium diisopropylamide) ;

LHMDS (lithium hexamethyldisilazide)

MeOH (methanol); MTBE (methyl tert-butyl ether);

mCPBA (m-chloroperbezoic acid);

NaHMDS (sodium hexamethyldisilazide);

NBS (/V-bromosuccinimide);

PE (petroleum ether);

Pd ₂ (dba) ₃ (Tris(dibenzylideneacetone)dipalladium(O);

Pd(dppf)CI ₂ .DCM Complex([1 , 1 '-

Bis(diphenylphosphino)ferrocene]dichloropalladium(ll).dic hloromethane complex);

PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate);

PyBrOP (bromotripyrrolidinophosphonium hexafluorophosphate);

RPHPLC (reverse phase high pressure liquid chromatography);

RT (room temperature);

Sat. (saturated)

SFC (supercritical fluid chromatography);

SGC (silica gel chromatography);

SM (starting material);

TCL (thin layer chromatography);

TEA (triethylamine);

TEMPO (2,2,6,6-Tetramethylpiperidine 1-oxyl, free radical);

TFA (trifluoroacetic acid); and

THF (tetrahydrofuran).

All references to ether are to diethyl ether and brine refers to a saturated aqueous solution of NaCI. Compound Preparation

The compounds according to Formula I are prepared using conventional organic synthetic methods. A suitable synthetic route is depicted below in the following general reaction schemes. All of the starting materials are commercially available or are readily prepared from commercially available starting materials by those of skill in the art.

The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.

As used in the Schemes, "x" and "r" groups represent corresponding positional groups on any of Formulas I to IV. All of the compounds of Formula (I) can be prepared generally as described in the Schemes using appropriate substitutions for starting materials.

Compounds of the invention were prepared according to Scheme 1. Substituted urea derivative B was prepared by reacting corresponding aniline A with chloroethylisocyanate using organic solvent preferably chloroform, the urea derivative B was reacted with base such as cesium carbonate to obtain A/-aryl cyclic urea intermediate C. Disubstituted cyclic urea derivative D can be obtained by alkylation of intermediate C using substituted benzyl bromides or cycloalkyi bromides or alkyl halides in presence of base such as cesium carbonate or reacting with corresponding alcohol using Mitsunobu condition. After conversion to the boronate ester E, palladium catalyzed Suzuki-Miyaura reaction with the bicycloheteroaryl bromide E1 produced the compound F, which represents the structure of the compounds of the invention F. In few examples of the invention, boronate ester formation and suzuki-miyaura reaction were performed in-situ and in some examples boronate ester was isolated and performed Suzuki-Miyaura reaction. Scheme 1.

B

r1 = H, F, Me, CI

r2 = Me, H

l

r10, r1 1 = H, Me r12 = CI, H, OH

In another aspect of the invention, compounds F were prepared by boronate ester formation of bicycloheteroaryl E1 followed by Suzuki-Miyaura coupling with bromo aryl imidazolidinone D as described in general Scheme 2. Scheme 2.

r1 = H, F, Me, CI

r2 = Me, H

r3 = substituted aryl or heteroaryl or alkyl or cycloalkyl x1 = CH, N

Suzuki-Miyaura coupling

aryl

Compounds of the invention with methyl or gem-dimethyl substituted at the 4-position of the imidazolidinone were prepared according to Scheme 3. lmidazolidine-2,4-dione O was protected with p-methoxybenzyl amine followed by selective reduction of P using reducing agents such as sodium borohydride in presence of boron trifluoride etherate to give imidazolidinone derivative Q. Alkylation was performed on Q using substituted benzyl bromide C1 in presence of base such as sodium hydride to obtain R. Deprotection of p-methoxybenzyl group was performed using TFA in anisole to obtain substituted benzyl imidazolidinone S. Arylation was performed on compound S to give intermediate U. Boronate ester formation and Suzuki-Miyaura coupling were performed similarly described in Scheme 2 to obtain compounds of the present invention W. Scheme 3.

Compounds of the invention with methyl or gem-dimethyl substituted at the 4-position of the imidazolidinone and Λ/1-fluorophenyl imidazolidinone were prepared according to scheme 4. /V-Boc-imidazolidinone intermediate Z was prepared in two steps from amino acid Y by treating Y with boc anhydride followed by reacting with DPPA. /V-arylimidazolidinone Z3 was obtained by arylation of Z followed by deprotection of boc group. Alkylation and Suzuki reactions were performed similar to the general Scheme 1 to obtain compounds of the present invention Z6.

Scheme 4.

r3 = aryl or heteroaryl

or alkyl or cycloalkyl

Compounds of the invention with hydroxymethyl substitution at the 4-position of the imidazolidinone were prepared according to Scheme 5. Phenyl carbamate Z9 was prepared by reacting substituted aniline Z7 with phenyl carbonochloridate Z8 using base such as pyridine. The intermediate Z8 was treated with methyl 2-amino-3-hydroxypropanoate Z10 in presence of base such as DMAP to give hydroxymethyl-imidazolidine-dione Z11. Reduction was performed using sodiumborohydride and borontrifluoride ethyrate to give 4-hydroxymethyl imidazolidinone derivative Z12. Protection of hydroxyl group with TBDMS followed by alkylation using C1 gave trisubstituted imidazolidinone intermediate Z14. Boronate ester formation followed by Suzuki-Miyaura reaction with heteroaryl bromide X gave intermediate Z16. OTBDMS deprotection was performed to give compounds of the present invention Z17. Scheme 5.

aryl or heteroaryl or alkyl or cycloalkyl

Compounds of the invention with cycloalkyl fused imidazolidinone derivatives were prepared according to Scheme 6. Cyclopropane dicarboxylic acid Z19 was prepared by treating Z18 with water. The dicarboxylic acid was converted to corresponding acid chloride Z20 followed by reacting with sodium azide to give cyclopropanedicarbonyl azide Z21. Intermediate Z21 upon heating in organic solvent such as toluene followed by refluxing with tert-BuOH afforded cyclopropane fused imidazolidinone compound Z23. Alkylation of imidazolidinone was performed using C1 in presence of base such as NaH to give /V-alkyllated imidazolidinone intermediate Z24. Intermediate Z24 was treated with hydrochloric acid for Boc deprotection followed by /V-arylation using Z1 to give intermediate Z26. Boronate ester formation and Suzuki reactions were performed similar to the general Scheme 1 to obtain compounds of the present invention Z28. Scheme 6. toluene

Z18 Z19 Z20 Z21

Cis

The bicycloheteroaryl halide E1 used in the present invention are prepared by using methods and procedures described in Schemes 7 to 12 or procured from commercial sources.

Z29 Z30 Z31 To a stirred solution of 4-bromo-2-iodoaniline (1.0 g, 3.35 mmol) in DMF (15 mL) was added ethanethioamide (0.25 g, 3.35 mmol, 1.0 equiv), copper oxide (0.19 g, 2.34 mmol, 0.7 equiv), 1 -1 '-bis diphenylphosphino ferrocene (0.04 g, 0.067 mmol, 0.02 equiv.) and tris(dibenzylideneacetone)dipalladium(0) (0.03 g, 0.033 mmol, 0.01 equiv.). The reaction mixture was bubbled with nitrogen gas for 10 minutes and heated to 60°C & stirred for 4 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was extracted with ethyl acetate and dried over sodium sulphate. The organic layer was evaporated to obtain crude product which was purified over Silica gel flash Column Chromatography. The compound eluted out as a mixture in 5% MeOH in DCM. The fractions containing the compound were evaporated to obtain 6-bromo-2-methylbenzo[c]thiazole as yellow solid (0.5 g, crude) which was used as such. LC-MS (ES) m/z = 228.0, 230.0 [M+H] ⁺

Scheme 8. 6-Bromo- V-methylquinazolin-2-amine

Step 1 : 5-Bromo-2-fluorobenzaldehyde (4.0 g, 19.7 mmol, 1.0 equiv) and guanidine carbonate (2.68 g, 29.7 mmol, 1.51 equiv) were dissolved in DMA (20 mL) and heated to 140°C & stirred for overnight. After completion of starting material, reaction mixture was poured onto ice cold water. The solid was filtered, washed with diethyl ether and dried to get 6-bromoquinazolin-2- amine (3.0 g, 68%) as off white solid. LCMS (ES) m/z = 234.0, 236.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ 6.96 (s, 2H), 7.34 (d, J = 8.8 Hz, 1 H), 7.74 - 7.77 (m, 1 H), 8.03 (d, J = 2.0 Hz, 1 H), 9.07 (s, 1 H).

Step 2: To a stirred solution of 6-bromoquinazolin-2-amine (0.75 g, 3.33 mmol, 1.0 equiv) in DCM/DMF (34 mL/2 mL) was added tert-butyl nitrite (0.6 mL, 4.99 mmol, 1.5 equiv), tetrabutylammonium chloride (0.37 g, 1.33 mmol, 0.4 equiv) and trimethylsillyl chloride (0.64 mL, 4.99 mmol, 1.5 equiv) at 0°C and stirred at room temperature for 15 min. The reaction mixture was heated to 50°C & stirred for 1 h. After completion of starting material, reaction mixture was diluted with DCM (30 mL) and water (300 mL). Two layers were separated and aqueous layer extracted with DCM (40 mL). The organics were combined and dried over Na ₂ S0 ₄ , filtered, and concentrated to give 6-bromo-2-chloroquinazoline (0.8 g, Crude). Crude product was used directly for next stage without purification. LCMS (ES) m/z = 243.0 [M+H] ⁺ .

Step 3: To a stirred solution of 6-bromo-2-chloroquinazoline (0.8 g, 3.3 mmol, 1.0 equiv) in THF (10 mL) was added methyl amine (2M in THF) (6.5 mL, 13.2 mmol, 4.0 equiv) in steel bomb and heated to 80°C for overnight. The reaction mixture was cooled to room temperature and concentrated to get crude compound. Crude product was purified by flash chromatography using Silica gel and compound was eluted with 30% EtOAc in Hexane. Fractions containing compound were concentrated to obtain 6-bromo-Ay-methylquinazolin-2-amine (0.21 g, 27%) as off white solid. LCMS (ES) m/z = 238.0, 240.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ 2.87 (d, J = 5.2 Hz, 3H), 7.41 (d, J = 9.2 Hz, 1 H), 7.46 (br. s., 1 H), 7.75 (dd, J = 2.0, 8.8 Hz, 1 H), 8.03 (d, J = 2.4 Hz, 1 H), 9.05 (s, 1 H).

Scheme 9. 6-Bromo- V-methylbenzor lthiazol-2-amine

To a stirred solution of 6-bromo-2-chlorobenzo[c]thiazole (1.0g, 4.0 mmol, 1.0 equiv) in THF (20 mL) was added methyl amine(2M in THF) (8.1 mL, 16.0 mmol, 4.0 equiv) in steel bomb and heated to 80 °C for overnight. The reaction mixture was cooled to room temperature and concentrated to obtain 6-bromo-Ay-methylbenzo[c]thiazol-2-amine (1.1 g, crude) as an off white solid. LCMS (ES) m/z = 243.0, 245.0 [M+H] ⁺ .

Scheme 10. 5-Bromo-2-chloro-7-methyl-7H-pyrrolor2,3- lpyrimidin-4-amine and 5- bromo-2-methoxy-7-methyl-7H-pyrrolor2,3- lpyrimidin-4-amine

Step 1 : To a stirred solution of 2,4-dichloro-7/-/-pyrrolo[2,3-c]pyrimidine (2 g, 10.638 mmol) in DMF (20 mL) was added 60 % NaH (0.63 g, 15.957 mmol, 1.5 equiv) at 0 °C and stirred for 30 min at room temperature. Methyl iodide (0.79 mL, 12.765 mol, 1.2 equiv) was added and allowed to stir at room temperature for 3 h. The reaction was quenched with ice water (200 mL) and the precipitated solid was filtered and dried in vacuo to obtain 2,4-dichloro-7-methyl- 7H-pyrrolo[2,3-c]pyrimidine as an off white solid (2.06 g, 96 %). LCMS (ES) m/z = 202.1 , 204.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 3.80 (s, 3H), 6.66 (d, J = 3.2 Hz, 1 H), 7.73 (d, J = 3.2 Hz, 1 H).

Step 2: To a stirred solution of 2,4-dichloro-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidine (2.06 g, 10.198 mmol) in dichloromethane (20 mL) was added /V-bromosuccinimide (2.17 g, 12.237 mmol) in one portion at room temperature, and the reaction was stirred overnight. The reaction mixture was concentrated and water was added to the residue. The precipitated solid was filtered and dried under vacuo to obtain 5-bromo-2,4-dichloro-7-methyl-7/-/-pyrrolo[2,3- cdpyrimidine as an off white solid (2.76 g, 96 %). LCMS (ES) m/z = 279.9, 281.9 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 3.84 (s, 3H), 7.24 (s, 1 H).

Step 3: A suspension of 5-bromo-2,4-dichloro-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidine (2.2 g, 7.831 mmol) in NH ₄ OH (20 mL) and 1 ,4-dioxane (5 mL) was heated in a stainless steel autoclave at 95 °C for 18 h. The reaction mixture was cooled to room temperature and the suspension was filtered. The cake was washed with water (3 x 20 mL), and dried under vacuo to give 5-bromo-2-chloro-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-ami ne as an off white solid (2 g, 98 %). LCMS (ES) m/z = 261.0, 263 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 3.59 (s, 3H), 6.80 - 7.80 (br. s., 2H), 7.36 (s, 1 H).

Step 4: Run 1 ; To a stirred solution of 5-bromo-2-chloro-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4- amine (0.1 g, 0.383 mmol) in methanol (10 mL) was added 0.5 M sodium methoxide in methanol (3.8 mL, 1.915 mmol, 5 equiv) at room temperature. The reaction was stirred at 100 °C for overnight in a sealed tube. The reaction mixture was cooled to room temperature & concentrated. Water was added to the residue and extracted with dichloromethane (30 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated to dryness to afford 5- bromo-2-methoxy-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amin e as off white solid (0.1 g, crude). LCMS (ES) m/z = 257.0, 259.0 [M+H] ⁺ .

Run-2: To a stirred solution of 5-bromo-2-chloro-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-ami ne (0.5 g, 1.915 mmol) in methanol (10 mL) was added 0.5 M sodium methoxide in methanol (19 mL, 9.578 mmol) at room temperature. The reaction was stirred at 100 °C for overnight in sealed tube. The reaction mixture was cooled to room temperature & concentrated. Water was added to the residue and extracted with dichloromethane (50 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated to dryness. The crude product was purified by flash column chromatography with silica gel cartridge using 30% EtOAc in hexane. The collected fractions with pure product were combined and concentrated in vacuo to afford 5-bromo-2- methoxy-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine as off white solid (0.33 g, 55.93 % combined yield from run1 & 2). LCMS (ES) m/z = 257.0, 259.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 3.55 (s, 3H), 3.79 (s, 3H), 6.46 - 6.82 (br. s., 2H), 7.14 (s, 1 H).

Scheme 11. 5-Bromothienor2,3- lpyrimidin-4-amine

Z43 Z44 Z45 Z46

ep

Step 1 : To a stirred solution of methyl 2-aminothiophene-3-carboxylate (10 g, 63.694 mmol) in formamide (10 mL) was heated to 190 °C and stirred for 8 h. Reaction mixture was cooled to room temperature & stirred for overnight. The reaction mixture was poured on to ice water (300 mL) and stirred for 10 min. The precipitate was filtered and washed with water (50 mL) and dried under vacuo to give thieno[2,3-d]pyrimidin-4(1/-/)-one as brown solid (5.5g g, 57 %). LCMS (ES) m/z = 153.1 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 7.38 (d, J = 5.6 Hz, 1 H), 7.56 (d, J = 6 Hz, 1 H), 8.10 (s, 1 H), 12.42 (s, 1 H).

Step 2: To a stirred solution of thieno[2,3-d]pyrimidin-4(1/-/)-one (3 g, 19.736 mmol) in acetic acid (30 mL) was added bromine (3 mL) at room temperature, and the reaction mixture was stirred for 2h. The reaction mixture was concentrated under reduced pressure. The residue was washed with water (2 x 10 mL) and dried to give 6-bromothieno[2,3-c]pyrimidin-4(1/-/)-one as light brown color solid (4.5 g, 98 %). LCMS (ES) m/z = 231.0, 233.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (s, 1 H), 8.12 (s, 1 H), 12.61 (br. s., 1 H).

Step 3: 6-Bromothieno[2,3-c]pyrimidin-4(1/-/)-one (4.5 g, 19.480 mmol) in phosphoryl chloride (80 mL) was refluxed for 6h. The reaction mixture was cooled to room temperature and concentrated. The solid was washed with cold water (50 mL) & hexane (100 mL) and dried to give 6-bromo-4-chlorothieno[2,3-d]pyrimidine as brown solid (4 g, 82 %). LCMS (ES) m/z = 248.9, 250.9 [M+H] ⁺ . H NMR (400 MHz, CDCI ₃ ) δ ppm 7.48 (s, 1 H), 8.81 (s, 1 H).

Step 4: To a stirred solution of 6-bromo-4-chlorothieno[2,3-c]pyrimidine (3 g, 12.048 mmol) in THF (120 mL) was added 2M LDA solution in THF/heptane/ethylbenzene (9 mL, 18.072 mmol) at -78 °C under nitrogen. The reaction mixture was stirred for 1 h at -78 °C, a mixture of 3.75 mL water and 15 mL THF was added slowly. The mixture was warmed to 0 °C, poured onto water (180 mL). The reaction mixture was extracted with dichloromethane (2 x 50 mL). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo to give crude product. The crude product was purified by flash column chromatography with 80 g silica column and 10% EtOAc in Hexanes as eluent to give 5-bromo-4-chlorothieno[2,3- cdpyrimidine as yellow solid (1.7 g, 56%). LCMS (ES) m/z = 248.9, 250.9 [M+H] ⁺ . H NMR (400 MHz, CDCI ₃ ) δ ppm 7.66 (s, 1 H), 8.87 (s, 1 H).

Step 5: A suspension of 5-bromo-4-chlorothieno[2,3-c]pyrimidine (1.7 g, 6.827 mmol) in NH ₄ OH (60 mL) was heated in a stainless steel autoclave at 100 °C for 18 h. The reaction mixture was cooled to room temperature and filtered. The solid cake was washed with water (3 x 20 mL), and dried under vacuo to give 5-bromothieno[2,3-c]pyrimidin-4-amine as light yellow solid (1.3 g, 82 %). LCMS (ES) m/z = 230.0, 232.0 [M+H] ⁺ . H NMR (400 MHz, DMSO- d6) δ ppm 7.16 - 7.56 (br. s., 2H), 7.76 (s, 1 H), 8.31 (s, 1 H).

Scheme 12. 5-Bromo-7-(2,2-difluoroethyl)-7H-pyrrolor2,3- lpyrimidin-4-amine

Step 1 : To a stirred solution of 4-chloro-7/-/-pyrrolo[2,3-c]pyrimidine (6.0 g, 39.1 mmol, 1.0 equiv) in DMF (70 mL) was added NBS (6.95 g, 39.1 mmol, 1.0 equiv) slowly at room temperature. The reaction mixture was stirred for 2 h at room temperature. After consumption of the starting material, the reaction mixture was quenched with water, and the solid that formed was filtered and dried to give the 5-bromo-4-chloro-7/-/-pyrrolo[2,3-c]pyrimidine as off white solid (11.0 g, crude). LCMS (ES) m/z = 232.0, 234.0 [M+H] ⁺ . H NMR (400 MHz, DMSO- <J6) δ ppm 7.91 (s, 1 H), 8.59 (s, 1 H), 12.92 (s, 1 H). Step 2: To a stirred solution of 5-bromo-4-chloro-7/-/-pyrrolo[2,3-c]pyrimidine (3.2 g, 13.8 mmol, 1.0 equiv) in DMF (45 ml_) was added K ₂ C0 ₃ (3.82 g, 27.6 mmol, 2.0 equiv) & 1 , 1- difluoro-2-iodoethane (1.33 ml_, 15.14 mmol, 1.1 equiv) slowly at room temperature. The reaction mixture was hated to 60 °C and stirred for 24 h. After consumption of the starting material, the reaction mixture was evaporated, water was added and then extracted with EtOAc. The organic layer was washed with brine and dried over sodium sulfate and concentrated to give crude product. The crude product was purified by flash column chromatography using silica gel column, compound was eluted at 13 % EtOAc in Hexane. The fractions containing product were evaporated to give 5-bromo-4-chloro-7-(2,2-difluoroethyl)- 7H-pyrrolo[2,3-c]pyrimidine as off white solid (1.7 g, 41.6 %). LCMS (ES) m/z = 297.0, 299.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 4.70 - 4.79 (m, 1 H), 6.42 (t, J = 54.4 Hz, 1 H), 7.99 (s, 1 H), 8.70 (s, 1 H).

Step 3: A solution of 5-bromo-4-chloro-7-(2,2-difluoroethyl)-7/-/-pyrrolo[2,3-c]py rimidine (0.5 g, 1.7 mmol, 1.0 equiv) in aq. NH ₄ OH (9.0 ml_) and 1 ,4-dioxane (3.0 ml_) in a sealed stainless steel autoclave at 100 °C was stirred for 16 h. After completion of the starting material, the reaction mixture was cooled to room temperature and the solid was filtered. The solid was washed with water and dried to give 5-bromo-7-(2,2-difluoroethyl)-7/-/-pyrrolo[2,3-c]pyrimidin-4 - amine as off white solid (0.3 g, 64.2 %). LCMS (ES) m/z = 277.0, 279.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 4.51 - 4.59 (m, 2 H), 6.21 - 6.48 (m, , 1 H), 6.76 (br. s., 2H), 7.40 (s, 1 H), 8.10 (s, 1 H).

Substituted benzyl chlorides/bromides used in present invention were either procured from commercial sources or prepared by following procedures similar to the Schemes described below.

Scheme 13. 2-(bromomethyl)-4,6-dimethylpyridine

Z56 Z57

To a stirred solution of 2,4,6-trimethylpyridine (1.0 g, 8.26 mmol, 1.0 equiv.) in carbon tetrachloride (15 ml_) was added NBS (1.46 g, 8.26 mmol, 1.0 equiv.) followed by dibenzoyl peroxide (0.5 g, 2.06 mmol, 0.25 equiv.). The reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to room temperature and evaporated to obtain crude compound. The crude product was purified over silica gel flash column chromatography. The compound eluted out in 15 % EtOAc: Hexanes. The pure fractions were evaporated to obtain 2-(bromomethyl)-4,6-dimethylpyridine (0.7 g, 42.5%) as an orange oil. LCMS (ES) m/z = 200.0, 202.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.27 (s, 3H), 2.39 (s, 3H), 4.57 (s, 2H), 7.0 (s, 1 H), 7.15 (s, 1 H).

Scheme 14. 1-(bromomethyl)-3-cyclopropylbenzene

Z58 Z59 Z60 _Z61

Step 1 : To a stirred solution of methyl 3-bromobenzoate (3.0 g, 13.950 mmol, 1.0 equiv) in toluene (24 mL) and water (6 mL) (4: 1) was added cyclopropyl boronic acid (1.79 g, 20.900 mmol, 1.5 equiv), potassium phosphate (5.92 g, 27.900 mmol, 2.0 equiv) and tricyclohexylphosphine (0.39 g, 1.390 mmol, 0.1 equiv) at one portion and degassed with Ar gas for 5 min. Pd(OAc) ₂ (0.15 g, 0.69 mmol, 0.05 equiv), was added and the reaction mixture was stirred for 3 h at 100 C. After completion of the reaction, the reaction was cooled to room temperature, quenched with water and extracted with ethyl acetate (2 ^χ 100 mL). The organics were combined and washed with brine solution (60 mL) and dried over Na ₂ S0 ₄ , filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by using flash chromatography with 100 - 200 silica gel (24 g column) & using 5% EtOAc in n-Hexane as mobile phase to afford the titled product methyl 3- cyclopropylbenzoate as oily liquid (2.2 g, 89.0 %). LC-MS (ES) m/z = 177.1 [M-H] ⁺ . H NMR (400 MHz, DMSO-cfe) δ ppm 0.64 - 0.75 (m, 2 H), 0.96 - 1.04 (m, 2 H), 1.97 - 2.31 (m, 1 H), 3.83 (s, 3 H), 7.33 (d, J = 7.2 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.64 (s, 1 H), 7.71 (d, J = 7.6 Hz, 1 H).

Step 2: To a stirred solution of 3-cyclopropylbenzoate (2.0 g, 12.567 mmol, 1.0 equiv) in ethanol (20 mL) was added 2.0 M Lithium borohydride in THF (11.3 mL, 22.700 mmol, 2.0 equiv) at 0 °C and stirred the reaction mixture for 1 h at room temperature. After completion of the reaction, the reaction mixture was quenched with ice cold water (30 mL) and extracted with DCM (2 x 30 mL). The organics were combined and dried over Na ₂ S0 ₄ , filtered, and evaporated the solvent under reduced pressure to afford the crude product (3- cyclopropylphenyl)methanol as light green liquid (1.2 g, 75.0%). H NMR (400 MHz, DMSO- d _e ) δ ppm 0.60 - 0.67 (m, 2 H), 0.87 - 0.93 (m, 2 H), 1.85 - 1.91 (m, 1 H), 4.44 (t, J = 5.6 Hz, 2 H), 5.06 (t, J = 5.6 Hz, 1 H), 6.91 (d, J = 7.2 Hz, 1 H), 7.00 (s, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 7.16 (t, J = 8.0 Hz, 1 H).

Step 3: To a stirred solution of (3-cyclopropylphenyl)methanol (1.0 g, 6.756 mmol, 1.0 equiv) in diethyl ether (20 mL) was added phosphorous tribromide (0.95 mL, 10.135 mmol, 1.5 equiv). The reaction mixture was stirred for 1 h at room temperature. After completion of the reaction, the reaction mixture was quenched with ice cold water (20 mL) and extracted with diethyl ether (2 x 20 mL). The organics were combined and dried over Na ₂ S0 ₄ , filtered, and evaporated the solvent under reduced pressure to afford the crude product 1-(bromomethyl)-3- cyclopropylbenzene as pale yellow liquid (0.9 g). H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.65 (d, J = 5.2 Hz, 2 H), 0.94 (d, J = 6.8 Hz, 2 H), 1.87 - 1.93 (m, 1 H), 4.64 (s, 2 H), 6.99 (d, J = 6.8 Hz, 1 H), 7.15 (s, 1 H), 7.20 - 7.26 (m, 2 H). Scheme 15. 2-(Bromomethyl)-3-fluoro-6-methylpyridine

Step 1 : To a stirred solution of 2-bromo-3-fluoro-6-methylpyridine (5.0 g, 15.788 mmol, 1.0 equiv) in DMF (12 mL) was added copper cyanide (2.3 g, 15.788 mmol, 1.0 equiv) in one portion at room temperature and the reaction mixture was stirred for overnight at 110 °C. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water (80 mL) and extracted with ethyl acetate (2 ^χ 150 mL). The organics were combined and dried over Na ₂ S0 ₄ , filtered, and evaporated the solvent under reduced pressure to afford the crude product. The crude product was purified by using flash chromatography with 100 - 200 silica gel (40g column), product was eluted with 5% EtOAc in n-Hexane mobile phase. Fractions containing product were concentrated to afford the title product 3-fluoro-6- methylpicolinonitrile as dark brown liquid (3.5 g, 98.0%). LCMS (ES) m/z = 137.1 [M+H] ⁺ . H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.69 (s, 3 H), 7.92 (s, 2 H). Step 2: A stirred solution of 3-fluoro-6-methylpicolinonitrile (3.3 g, 24.241 mmol, 1.0 equiv) in aq. hydrochloric acid (30 mL) was refluxed for overnight. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in water (50 mL) and extracted with 5% MeOH in DCM (2 *150 mL). The organics were combined and dried over Na ₂ S0 ₄ , filtered and evaporated the solvent. The residue was triturated with n-pentane to afford the product 3-fluoro-6-methylpicolinic acid as yellow solid (3.7 g, 97.8%). LCMS (ES) m/z = 156.1 [M+H] ⁺ . H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.45 (s, 3 H), 7.35 (s, 1 H), 7.71 (t, J = 9.2 Hz, 1 H), 8.94 (br. s., 1 H).

Step 3: To a stirred solution of 3-fluoro-6-methylpicolinic acid (2.0 g, 12.89 mmol, 1.0 equiv) in THF (20 mL) was added borane dimethylsulfide (6.11 mL, 64.462 mmol, 5.0 equiv) at 0 °C and stirred the reaction mixture for 2 h at room temperature. After completion of the reaction, the reaction mixture was quenched with methanol (20 mL) and evaporated the solvent under reduced pressure. The residue was extracted with ethyl acetate (2 ^χ 50 mL). The organics were combined and dried over Na ₂ S0 ₄ , filtered, and evaporated the solvent under reduced pressure to afford the crude product. The crude product was purified by using flash chromatography with 100 - 200 silica gel (24 g column) and eluted with 2.0% MeOH in DCM as mobile phase to afford the titled product (3-fluoro-6-methylpyridin-2-yl)methanol as colorless liquid (0.45 g, 25%). LCMS (ES) m/z = 142.1 [M+H] ⁺ . H NMR (400 MHz, CDCI ₃ ) δ ppm 2.25 - 2.63 (m, 2 H), 2.73 (s, 3 H), 4.38 (br. s., 1 H), 7.51 (s, 2 H).

Step 4: To a stirred solution of (3-fluoro-6-methylpyridin-2-yl)methanol (0.3 g, 2.125 mmol, 1.0 equiv) in diethyl ether (15 mL) was added phosphorous tribromide (0.3 mL, 3.188 mmol, 1.5 equiv) at room temperature and stirred the reaction mixture for 1.5 h. After completion of the reaction, the reaction mixture was quenched with ice cold water (20 mL) and extracted with diethyl ether (2 x 10 mL). The organics were combined and dried over Na ₂ S0 ₄ , filtered, and evaporated the solvent under reduced pressure to afford the crude product 2-(bromomethyl)-3- fluoro-6-methylpyridine as pale yellow liquid (0.35 g). LCMS (ES) m/z = 204.0, 206.0 [M+H] ⁺ .

Scheme 16. 1 -(Bromomethyl)-3-(difluoromethoxy)benzene

Z67 Z68 Z69 Step 1 : A stirred solution of 3-(difluoromethoxy)benzaldehyde (1.0 g, 5.81 mmol, 1 equiv), in MeOH (25 mL) was cooled to 0 °C, NaBH ₄ (0.440 g, 11.62 mmol, 2.0 equiv) was slowly added in portion wise. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. After completion of starting material, the reaction mixture was evaporated and added water, extracted with DCM. The organic layer was washed with brine and dried over sodium sulfate and concentrated to give (3-(difluoromethoxy)phenyl)methanol as colorless liquid (1.0 g, crude). H NMR (400 MHz, DMSO-d6) δ ppm 4.50 (d, J = 5.2 Hz, 2 H), 5.27 (d, J = 5.2 Hz, 1 H), 7.01 (d, J = 7.2 Hz, 1 H), 7.11 (s, 1 H), 7.18 (t, J = 7.6 Hz, 1 H), 7.36 (t, J = 8.0 Hz, 1 H).

Step 2: Run-1 ; To a stirred solution of (3-(difluoro methoxy)phenyl)methanol (0.5 g, 2.87 mmol, 1 equiv), in DCM (30 mL) was slowly added PPh ₃ (1.131 g, 4.31 mmol, 1.5 equiv) and the reaction mixture was cooled to 0 °C, CBr ₄ (1.43 g, 4.31 mmol, 1.5 equiv) was added. The reaction mixture was slowly warmed to room temperature and stirred for 3 h at room temperature. The reaction mixture was evaporated to give crude product. The crude product was purified by flash column chromatography using silica gel column, compound was eluted at 3 % EtOAc in Hexane. Fractions containing product were concentrated to give 1- (bromomethyl)-3-(difluoromethoxy)benzene as colorless liquid (0.380 g, 56 %). H NMR (400 MHz, DMSO-d6) δ ppm 4.70 (s, 2 H), 7.12 (d, J = 7.6 Hz, 1 H), 7.23 (t, J = 74.0 Hz, 1 H), 7.27 (s, 1 H), 7.32 (d, J = 7.6 Hz, 1 H), 7.42 (t, J = 7.2 Hz, 1 H).

Run-2; To a stirred solution of (3-(difluoromethoxy)phenyl)methanol (0.5 g, 2.87 mmol, 1 equiv), in DCM (30 mL) was slowly added PPh ₃ (1.131 g, 4.31 mmol, 1.5 equiv) and the reaction mixture was cooled to 0°C, CBr ₄ (1.43 g, 4.31 mmol, 1.5 equiv) was added. The reaction mixture was slowly warmed to room temperature and stirred for 3 h at room temperature. The reaction mixture was evaporated to give crude product. The crude product was purified by flash column chromatography using Silica gel column, compound was eluted at 3 % EtOAc in Hexane. Fractions containing product were concentrated to give 1- (bromomethyl)-3-(difluoromethoxy)benzene as colorless liquid (0.410 g, 60 %). H NMR (400 MHz, DMSO-d6) δ ppm 4.70 (s, 2 H), 7.22 (t, J = 74.0 Hz, 1 H), 7.26 (s, 1 H), 7.31 (d, J = 7.6 Hz, 1 H), 7.41 (t, J = 8.0 Hz, 1 H). Scheme 17. (6-(Bromomethyl)-4-methylpyridin-2-yl)methanol

Z70 Z71 Z72 Z73

Step 1 : To a Suspension of 60% NaH (1 g, 26.200 mmol, 3 equiv) in 35 mL of toluene under argon, was slowly added diethyl malonate (4.19 g, 26.200 mmol, 3 equiv) in 5 mL of toluene. The reaction mixture was heated to reflux. After complete dissolution of the resulting malonate salt, dimethyl 4-chloropyridine-2, 6-dicarboxylate (2 g, 8.733 mmol, 1 equiv) was added. The reaction mixture was refluxed for 3 h. The hot supernatant solution was removed by decantation and 40 mL of 4N HCI was added to the residue. The mixture was heated to reflux for overnight. The reaction mixture was cooled to room temperature and the aq. phase was washed with ether and the aqueous was evaporated to dryness to afford 4-methylpyridine-2,6- dicarboxylic acid hydrochloride as yellow powder (2 g, crude). LCMS (ES) m/z = 182.1 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 2.47 (s, 3H), 8.06 (s, 2H), 11.60 - 13.70 (br. s., 2H).

Step 2: To a stirred solution of 4-methylpyridine-2,6-dicarboxylic acid hydrochloride (1.5 g, 6.912 mmol) in tetrahydrofuran (20 mL) was added borane dimethylsulfide (3.9 mL, 41.474 mmol, 6 eqiv) at 0 °C, and the reaction was stirred at room temperature for overnight. The reaction mixture was quenched with methanol at 0 °C and concentrated under vacuo to obtain (4-methylpyridine-2,6-diyl)dimethanol hydrochloride as brown gummy solid (1.5 g, crude). LCMS (ES) m/z = 154.1 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 2.38 (s, 3H), 5.30 -5.90 (br. s., 2H), 4.57(s, 4H), 7.33 (s, 2H).

Step 3: Run-1 ; To a solution of (4-methylpyridine-2,6-diyl)dimethanol hydrochloride (0.5 g, 2.645 mmol) in 48% HBr in water (5 mL) was refluxed at 100 °C for 1 h. The resulting mixture was cooled and basified with saturated sodium bicarbonate, extracted with dichloromethane (2 x 50 mL). Organic layers were combined and dried over Na ₂ S0 ₄ , filtered, and concentrated under vacuum to give (6-(bromomethyl)-4-methylpyridin-2-yl)methanol (0.2 g, crude) as brown liquid. LCMS (ES) m/z = 216.0, 218.0 [M+H] ⁺ .

Run-2; To a solution of (4-methylpyridine-2,6-diyl)dimethanol hydrochloride (1.5 g, 7.936 mmol) in 48% HBr in water (10 mL) was refluxed at 100°C for 1 h. The resulting mixture was cooled and basified with saturated sodium bicarbonate, and extracted with dichloromethane (2 x 100 mL). Organic layers were combined and dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo to afford crude product. The crude product (run-1 and Run-2) was purified by flash column chromatography with silica gel cartridge using gradient elution of 0% to 5% MeOH in DCM. The collected fractions with pure product were combined and concentrated in vacuo to afford (6-(bromomethyl)-4-methylpyridin-2-yl)methanol as colorless liquid (0.21 g, combined yield of run 1 and run 2). LC-MS (ES) m/z = 216.0, 218.0 [M+H] ⁺ . H NMR (400 MHz, DMSO- cB) δ ppm 2.30 (s, 3H), 4.48 (s, 2H), 4.58 (s, 2H), 5.20 - 5.50 (br. s., 1 H), 7.21 (s, 2H).

Scheme 18. 1-(Bromomethyl)-3,5-diethylbenzene

Step 1 : To a stirred solution of 3,5-dibromobenzoic acid (2 g, 7.168 mmol) in tetrahydrofuran (20 mL) was added borane dimethylsulfide (3.4 mL, 35.842 mmol, 5 eq.) at 0 °C, and the reaction mixture was stirred at room temperature for overnight. The reaction mixture was quenched with methanol at 0 °C and concentrated under vacuo to obtain (3,5- dibromophenyl)methanol as an off white solid (1.8 g, 94%). H NMR (400 MHz, DMSO-d6) δ ppm 4.47 (d, J = 6 Hz, 2H), 5.39 (t, J = 6 Hz, 1 H), 7.49 (s, 2H), 7.65 (s, 1 H).

Step 2: To a mixture of (3,5-dibromophenyl)methanol (1 g, 3.759 mmol, 1 equiv) and PdCI ₂ (dppf).CH ₂ Cl ₂ complex (0.21 g, 0.263 mmol, 0.07 equiv) in 10 mL of dry THF at -70 °C was added 1 M diethyl zinc in hexane (15 mL). The resulting mixture was allowed to warm to room temperature, and stirred at 45 °C for overnight. To drive the reaction to completion, additional 11.3 mL of 1 M diethyl zinc in hexane was added with continued stirring at 45 °C for overnight. After cooling, the reaction mixture was added to a stirred mixture of dilute HCI and EtOAc. Organic layer was separated, washed with water, dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo to afford crude product. The crude product was purified by flash column chromatography with silica gel cartridge using gradient elution of 0 to 10% EtOAc in Hexane. The collected fractions with pure product were combined and concentrated in vacuo to afford (3,5-diethylphenyl)methanol as colorless liquid (0.2 g, 32%). LC-MS (ES) m/z = 147.2 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J = 7.2 Hz, 6H), 2.50 - 2.56 (m, 4H), 4.41 (d, J = 5.2 Hz, 2H), 5.01 (t, J = 5.6 Hz, 1 H), 6.87 (s, 1 H), 6.93 (s, 2H). Step 3: To a stirred solution of (3,5-diethylphenyl)methanol (0.2 g, 1.219 mmol) in dry THF (10 mL) was added triphenylphosphine (0.47 g, 1.829 mmol, 1.5 eqvi). The reaction mixture was stirred for 5 min, tetrabromomethane (0.6 g, 1.829 mmol, 1.5 eqvi) was added, and the reaction mixture was stirred at room temperature under nitrogen atmosphere for overnight. The reaction mixture was concentrated in vacuo to afford crude product. The crude was purified by flash column chromatography with silica gel cartridge using gradient elution of 0 to 5% EtOAc in Hexane. The collected fractions with pure product were combined and concentrated in vacuo to afford 1-(bromomethyl)-3,5-diethylbenzene as colorless liquid (0.3 g, crude). H NMR (400 MHz, CDCI ₃ ) δ ppm 1.23 (t, J = 7.6 Hz, 6H), 2.59 - 2.65 (m, 4H), 4.46 (s, 2H), 6.96(s, 1 H), 7.04 (s, 2H).

Scheme 19.

Z78 Z79 Z80 Z81

Step 1 : Run 1 ; A mixture of methyl 5-bromo-2-fluorobenzoate (0.5 g, 2.145 mmol, 1 equiv), cyclopropylboronic acid (0.18 g, 2.145 mmol, 1 equiv) and cesium carbonate (1.74 g, 5.364 mmol, 2.5 equiv) in 10 mL of 1 ,4-dioxane and 2 mL of water was degassed with nitrogen for 10 min, PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.175 g, 0.214 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 100 °C for overnight in sealed vessel. The reaction mixture was cooled to room temperature, filtered through Celite and the filtrate was dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo to afford crude product. The crude was purified by flash column chromatography with silica gel cartridge using gradient elution of 0 to 3 % EtOAc in hexane. The collected fractions with pure product were combined and concentrated in vacuo to afford methyl 5-cyclopropyl-2-fluorobenzoate as light green liquid (0.27 g). LC-MS (ES) m/z = 195.1 [M+H] ⁺ .

Run 2: A mixture of methyl 5-bromo-2-fluorobenzoate (2 g, 8.583 mmol, 1 equiv), cyclopropylboronic acid (0.73 g, 8.583 mmol, 1 equiv) and cesium carbonate (6.9 g, 21.459 mmol, 2.5 equiv) in 20 mL of 1 ,4-dioxane and 5 mL of water was degassed with nitrogen for 10 min, PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.7 g, 0.858 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 100 °C for overnight in sealed vessel. The reaction mixture was cooled to room temperature, filtered through Celite and the filtrate was dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo to afford crude product. The crude was purified by flash column chromatography with silica gel cartridge using gradient elution of 0 to 3 % EtOAc in hexane. The collected fractions with pure product were combined and concentrated in vacuo to afford methyl 5-cyclopropyl-2-fluorobenzoate as light green liquid (1.3 g, 78 % combined yield of run 1 & 2). LC-MS (ES) m/z = 195.1 [M+H] ⁺ . H NMR (400 MHz, CDCI ₃ ) δ ppm 0.66 - 0.68 (m, 2H), 0.94 - 1.02 (m, 2H), 1.86 - 1.93(m, 1 H), 3.91 (s, 3H), 6.98 - 7.02 (m, 1 H), 7.18 - 7.22 (m, 1 H), 7.61 (dd, J = 2, 7.2 Hz, 1 H).

Step 2: To a stirred solution of methyl 5-cyclopropyl-2-fluorobenzoate (1.57 g, 8.092 mmol) in Ethanol (15 ml_) was added 2M lithium borohydride in THF (8 ml_, 16.185 mmol, 2 equiv) at room temperature, and the reaction mixture was stirred at room temperature for overnight.

The reaction mixture was quenched with water, extracted with ethyl acetate (2 x 100 ml_).

Organic layers were combined and dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo to give (5-cyclopropyl-2-fluorophenyl) methanol (1.4 g, crude) as a colorless liquid. LCMS (ES) m/z = 149.2 [M+H] ⁺ -18.

Step 3: To a solution of (5-cyclopropyl-2-fluorophenyl)methanol (1.4 g, 8.433 mmol) in diethyl ether (10 ml_) was added phosphorus tribromide (1.2 ml_, 12.650 mmol, 1.5 equiv) at room temperature and the reaction was stirred at room temperature for 3 h. The reaction mixture was quenched with water, basified with saturated sodium bicarbonate & extracted with diethyl ether (2 x 100 ml_). Organic layers were combined and dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo to afford 2-(bromomethyl)-4-cyclopropyl-1-fluorobenzene as light brown liquid (1 g, crude). H NMR (400 MHz, CDCI ₃ ) δ ppm 0.62 - 0.69 (m, 2H), 0.93 - 0.97 (m, 2H), 1.82 - 1.90 (m, 1 H), 4.47 (s, 2H), 6.90 - 6.99 (m, 2H), 7.07 - 7.09 (m, 1 H).

Scheme 20.

Z82 Z83 Z84

Step 1 : To a stirred solution of methyl 6-(trifluoromethyl)nicotinaldehyde (2 g, 11.428 mmol) in

Ethanol (20 ml_) was added sodium borohydride (064 g, 17.142 mmol, 1.5 equiv) at 0 °C, and the reaction was stirred at room temperature for 2h. The reaction mixture was concentrated and diluted with water (20 ml_), extracted with ethyl acetate (2 x 50 ml_). Organic layers were combined and dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo to give (6- (trifluoromethyl)pyridin-3-yl)methanol (1.8 g, crude) as a colorless liquid. LCMS (ES) m/z = 178.1 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 4.64 (d, J = 6 Hz, 2H), 5.51 (t, J = 5.6 Hz, 1 H), 7.83 (d, J = 8 Hz, 1 H), 7.98 (d, J = 7.6 Hz, 1 H), 8.69 (s, 1 H).

Step 2: To a solution of (6-(trifluoromethyl)pyridin-3-yl)methanol (1.8 g, 10.169 mmol) in 48% HBr in water (10 mL) was refluxed at 100 °C for 6h. The resulting mixture was concentrated and diluted with EtOAc (100 mL) washed with saturated sodium bicarbonate dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo to afford crude product. The crude product was purified by flash column chromatography with silica gel cartridge using gradient elution of 0 to 20% EtOAc in hexane. The fractions containing pure product were combined and concentrated in vacuo to afford 5-(bromomethyl)-2-(trifluoromethyl)pyridine as yellow liquid (1.5 g, 62%). LC-MS (ES) m/z = 240.0, 242.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 4.50 (s, 2H), 7.68 (d, J = 8 Hz, 1 H), 7.91 (d, J = 7.6 Hz, 1 H), 8.73 (s, 1 H).

Methods of Use

The compounds according to Formula (I) and pharmaceutically acceptable salts thereof are inhibitors of PERK. These compounds are potentially useful in the treatment of conditions wherein the underlying pathology is attributable to (but not limited to) activation of the UPR pathway, for example, neurodegenerative disorders, cancer, cardiovascular and metabolic diseases. Accordingly, in another aspect the invention is directed to methods of treating such conditions.

Suitably, the present invention relates to a method for treating or lessening the severity of breast cancer, including inflammatory breast cancer, ductal carcinoma, and lobular carcinoma.

Suitably the present invention relates to a method for treating or lessening the severity of colon cancer.

Suitably the present invention relates to a method for treating or lessening the severity of pancreatic cancer, including insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, and glucagonoma. Suitably the present invention relates to a method for treating or lessening the severity of skin cancer, including melanoma, including metastatic melanoma.

Suitably the present invention relates to a method for treating or lessening the severity of lung cancer including small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.

Suitably the present invention relates to a method for treating or lessening the severity of cancers selected from the group consisting of brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers and testicular cancer.

Suitably the present invention relates to a method for treating or lessening the severity of pre-cancerous syndromes in a mammal, including a human, wherein the pre-cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplasia syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.

Suitably the present invention relates to a method for treating or lessening the severity of neurodegenerative diseases/injury, such as Alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, Parkinson disease, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, and other diseases associated with UPR activation including: diabetes, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, fatty liver disease, liver steatosis, liver fibrosis chronic and acute diseases of the lung, lung fibrosis, chronic and acute diseases of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, frontotemporal dementias, tauopathies, Pick's disease, Neimann-Pick's disease, amyloidosis cognitive impairment, atherosclerosis, ocular diseases, and arrhythmias.

Suitably the present invention relates to a method preventing organ damage during and after organ transplantation and in the transportation of organs for transplantation. The method of preventing organ damage during and after organ transplantation will comprise the in vivo administration of a compound of Formula (I). The method of preventing organ damage during the transportation of organs for transplantation will comprise adding a compound of Formula (I) to the solution housing the organ during transportation.

The compounds of this invention inhibit angiogenesis which is implicated in the treatment of ocular diseases. Nature Reviews Drug Discovery 4, 711-712 (September 2005). Suitably the present invention relates to a method for treating or lessening the severity of ocular diseases/angiogenesis. In embodiments of methods according to the invention, the disorder of ocular diseases, including vascular leakage can be: edema or neovascularization for any occlusive or inflammatory retinal vascular disease, such as rubeosis irides, neovascular glaucoma, pterygium, vascularized glaucoma filtering blebs, conjunctival papilloma; choroidal neovascularization, such as neovascular age-related macular degeneration (AMD), myopia, prior uveitis, trauma, or idiopathic; macular edema, such as post surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, macular edema secondary to diabetes, and macular edema secondary to retinovascular occlusive disease (i.e. branch and central retinal vein occlusion); retinal neovascularization due to diabetes, such as retinal vein occlusion, uveitis, ocular ischemic syndrome from carotid artery disease, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, or Eale's Disease; and genetic disorders, such as VonHippel-Lindau syndrome. In some embodiments, the neovascular age-related macular degeneration is wet age- related macular degeneration. In other embodiments, the neovascular age-related macular degeneration is dry age-related macular degeneration and the patient is characterized as being at increased risk of developing wet age-related macular degeneration.

The methods of treatment of the invention comprise administering an effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt, thereof to a patient in need thereof. The invention also provides a compound according to Formula (I) or a pharmaceutically-acceptable salt thereof for use in medical therapy, and particularly in therapy for: cancer, pre-cancerous syndromes, Alzheimer's disease, neuropathic pain, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute diseases of the liver, fatty liver disease, liver steatosis, liver fibrosis, chronic and acute diseases of the lung, lung fibrosis, chronic and acute diseases of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, frontotemporal dementias, tauopathies, Pick's disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. Thus, in further aspect, the invention is directed to the use of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disorder characterized by activation of the UPR, such as cancer.

By the term "treating" and derivatives thereof as used herein, in reference to a condition means: (1) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

Prophylactic therapy is appropriate when a subject has, for example, a strong family history of cancer or is otherwise considered at high risk for developing cancer, or when a subject has been exposed to a carcinogen. As used herein, the term "effective amount" and derivatives thereof means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" and derivatives thereof means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

As used herein, "patient" or "subject" refers to a human or other animal. Suitably the patient or subject is a human.

The compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered by any suitable route of administration, including systemic administration. Systemic administration includes oral administration, and parenteral administration. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.

The compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Additionally, the compounds of Formula (I) or pharmaceutically-acceptable salts thereof may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound. Where a -COOH or -OH group is present, pharmaceutically acceptable esters can be employed, for example methyl, ethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics.

The compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of cancer or pre-cancerous syndromes.

By the term "co-administration" as used herein is meant either simultaneous administration or any manner of separate sequential administration of a PERK inhibiting compound, as described herein, and a further active agent or agents, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. The term further active agent or agents, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered orally.

Typically, any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 ^th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism. Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented PERK inhibiting compounds are chemotherapeutic agents.

Suitably, the pharmaceutically active compounds of the invention are used in combination with a VEGFR inhibitor, suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonam ide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt thereof, which is disclosed and claimed in in International Application No. PCT/U S01/49367, having an International filing date of December 19, 2001 , International Publication Number WO02/059110 and an International Publication date of August 1 , 2002, the entire disclosure of which is hereby incorporated by reference, and which is the compound of Example 69. 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonam ide can be prepared as described in International Application No. PCT/US01/49367. Suitably, 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidi nyl]amino]^ methylbenzenesulfonamide is in the form of a monohydrochloride salt. This salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001.

5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrim idinyl]amino]-2- methylbenzenesulfonamide is sold commercially as the monohydrochloride salt and is known by the generic name pazopanib and the trade name Votrient ^® . Pazopanib is implicated in the treatment of cancer and ocular diseases/angiogenesis.

Suitably the present invention relates to the treatment of cancer and ocular diseases/angiogenesis, suitably age-related macular degeneration, which method comprises the administration of a compound of Formula (I) alone or in combination with pazopanib. In one embodiment, the cancer treatment method of the claimed invention includes the co-administration a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti- microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.

Suitably, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of neurodegenerative diseases/injury.

Suitably, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of diabetes.

Suitably, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of cardiovascular disease. Suitably, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of ocular diseases. Suitably, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful for preventing organ damage during and after organ transplantation and in the transportation of organs for transplantation. Compositions

The pharmaceutically active compounds within the scope of this invention are useful as PERK inhibitors in mammals, particularly humans, in need thereof. The present invention therefore provides a method of treating cancer, neurodegeneration and other conditions requiring PERK inhibition, which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as PERK inhibitors. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, topical, subcutaneous, intradermal, intraocular and parenteral. Suitably, a PERK inhibitor may be delivered directly to the brain by intrathecal or intraventricular route, or implanted at an appropriate anatomical location within a device or pump that continuously releases the PERK inhibitor drug.

The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical compositions are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.

Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 500 mg/kg of active compound, preferably 0.001 - 100 mg/kg. When treating a human patient in need of a PERK inhibitor, the selected dose is administered preferably from 1-6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermal^, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Suitably oral dosage units for human administration preferably contain from 0.5 to 1 ,000 mg of active compound. Oral administration, which uses lower dosages, is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular PERK inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.

When administered to prevent organ damage in the transportation of organs for transplantation, a compound of Formula (I) is added to the solution housing the organ during transportation, suitably in a buffered solution.

The method of this invention of inducing PERK inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective PERK inhibiting amount of a pharmaceutically active compound of the present invention. The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as a PERK inhibitor. The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in therapy.

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating cancer, pre-cancerous syndromes, Alzheimer's disease, neuropathic pain, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, Parkinson disease, diabetes, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute diseases of the liver, fatty liver disease, liver steatosis, liver fibrosis, chronic and acute diseases of the lung, lung fibrosis, chronic and acute diseases of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, frontotemporal dementias, tauopathies, Pick's disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, ocular diseases, and arrhythmias.

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in preventing organ damage during the transportation of organs for transplantation. .

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

The invention also provides for a pharmaceutical composition for use in the treatment of cancer which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In addition, the pharmaceutically active compounds of the present invention can be coadministered with further active ingredients, such as other compounds known to treat cancer, or compounds known to have utility when used in combination with a PERK inhibitor.

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

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

EXAMPLES

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

Example 1

1-(4-(4-Amino-7-methyl-7H-pyrrolor2,3- lpyrimidin-5-yl)-3-fluorophenyl)-3-(2,5- difluorobenzyl) imidazolidin-2-one

Step 1 : To a stirred solution of 4-bromo-3-fluoroaniline (500.0 g, 2.63 mol) in Chloroform (6 L) was added 1-chloro-2-isocyanatoethane (336.68 mL, 3.95 mol, 1.5 equiv) at room temperature. The reaction mixture was refluxed for 1 h and cooled to room temperature. The precipitated solid was filtered and washed with n-pentane to give 1-(4- bromofluorophenyl)-3-(2-chloroethyl) urea (610 g, 79 %) as a white solid. H NMR (400 MHz, DMSO-d6) δ ppm 3.39 - 3.43 (m, 2H), 3.65 (t, J = 6.2 Hz, 2H), 6.53 (t, J = 5.7 Hz, 1 H), 7.04 (dd, J = 1.8, 8.7 Hz, 1 H), 7.50 (t, J = 8.4 Hz, 1 H), 7.60 (dd, J = 2.4, 12 Hz, 1 H), 9.03 (s, 1 H).

Step 2: To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(2-chloroethyl)urea (610.0 g, 2.07 mol) in acetonitrile (7 L) was added Cs ₂ C0 ₃ (1.35 kg, 4.13 mol, 2.0 equiv) at room temperature. The reaction mixture was refluxed for 12 h. The reaction mixture was cooled to room temperature and the solvents were evaporated. The crude product was diluted with ethyl acetate (1 L) and water (1 L). Two layers were separated and aqueous layer was extracted with ethyl acetate. Organic layers were combined and dried over Na ₂ S0 ₄ , filtered, and concentrated to give 1-(4-bromo-3-fluorophenyl)imidazolidin-2-one (481 g, 90 %) as brown solid. LCMS (ES) m/z = 259.02, 261.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/6) δ ppm 3.40 (t, J = 8.8 Hz, 2H), 3.81 - 3.85 (m, 2H), 7.22 (br. s., 1 H), 7.26 - 7.29 (m, 1 H), 7.58 (t, J = 8.8, 1 H), 7.70 (dd, J = 2.8, 12.4 Hz, 1 H). Step 3: To a stirred suspension of 60% NaH (2 g, 50.96 mmol, 1.2 equiv) in DMF (150 ml_) was added 1-(4-bromo-3-fluorophenyl)imidazolidin-2-one (1 1 g, 42.47 mmol, 1 equiv) at 0 °C, & stirred for 30 min and then 2-(bromomethyl)-1 ,4-difluorobenzene (9.7 g, 46.71 mmol, 1.1 equiv) was added at 0 °C. The reaction mixture was stirred for 3.5 h at room temperature and quenched with ice water. The precipitate formed was filtered, washed with water and dried to give 1-(4-bromo-3-fluorophenyl)-3-(2,5-difluorobenzyl)imidazolidi n- 2-one as off white powder (15 g, 92 %). LCMS (ES) m/z = 385.0, 387.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 3.42 (t, J = 7.6 Hz, 2H), 3.81 (t, J = 7.6 Hz, 2H), 4.42 (s, 2H), 7.14 - 7.31 (m, 4H), 7.57 - 7.62 (m, 1 H), 7.68 - 7.72 (m, 1 H).

Step 4: A mixture of 1-(4-bromo-3-fluorophenyl)-3-(2,5-difluorobenzyl)imidazolidi n-2-one (10 g, 25.974 mmol, 1 equiv), bis(pinacolato)diboron (9.8 g, 38.961 mmol, 1.5 equiv) and potassium acetate (7.6 g, 77.922 mmol, 3 equiv) in 250 ml_ of 1 ,4-dioxane was degassed with nitrogen for 15 min, PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (1.05 g, 1.298 mmol, 0.05 equiv) was added and the reaction mixture was stirred at 100 °C for overnight in sealed vessel. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by flash column chromatography with 80 g silica gel cartridge using gradient elution of 10 to 50% EtOAc in hexane. The collected fractions with pure product were combined and concentrated in vacuo to give 1-(2,5-difluorobenzyl)-3-(3-fluoro-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)imidazolidin-2-one as off white solid (5.43 g). LC-MS (ES) m/z = 433.2 [M+H] ⁺ .

Step 5: Run 1 ; A mixture of 1-(2,5-difluorobenzyl)-3-(3-fluoro-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)imidazolidin-2-one (0.5 g, 1.157 mmol, 1 equiv), 5-bromo- 7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-4-amine (0.31 g, 1.388 mmol, 1.2 equiv), K ₃ P0 ₄ (0.49 g, 2.314 mmol, 2.0 equiv) and Pd ₂ (dba) ₃ (0.05 g, 0.057 mmol, 0.05 equiv) in 15 mL of 1 ,4- dioxane and 5 mL of water in a sealed tube was bubbled with nitrogen for 15 min, tri-(f- butyl)phosphonium tetrafluoroborate (0.03 g, 0.115 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 100 °C for overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite and the filtrate was concentrated in vacuo to afford crude product (1 g, crude). LC-MS (ES) m/z = 453.2 [M+H] ⁺ .

Run 2: A mixture of 1-(2,5-difluorobenzyl)-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)imidazolidin-2-one (5 g, 11.574 mmol, 1 equiv), 5-bromo-7- methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (2.6 g, 1 1.574 mmol, 1 equiv), K ₃ P0 ₄ (4.9 g, 23.148 mmol, 2.0 equiv) and Pd ₂ (dba) ₃ (0.52 g, 0.578 mmol, 0.05 equiv) in 100 mL of 1 ,4- dioxane and 30 mL of water in a sealed tube was bubbled with nitrogen for 15 min, tri-(f- butyl)phosphonium tetrafluoroborate (0.33 g, 1.115 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 100 °C for overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite and the filtrate was concentrated in vacuo to afford crude product. The crude product from run-1 and run-2 was purified by flash column chromatography with 80 g silica gel cartridge using gradient elution of 0 to 2 % MeOH in DCM. The collected fractions with pure product were combined and concentrated in vacuo. The solid obtained was triturated with ether (3 x 30 ml_) and dried to afford 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3- fluorophenyl)-3-(2,5-difluorobenzyl)imidazolidin-2-one as off white solid (4.14 g, 72 %, combined yield of run 1 and run 2). LC-MS (ES) m/z = 453.2 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 3.44 (t, J = 8 Hz, 2H), 3.72 (s, 3H), 3.87 (t, J = 7.6 Hz, 2H), 4.44 (s, 2H), 5.92 (br. s., 2H), 7.16 - 7.29 (m, 4H), 7.31 - 7.38 (m, 1 H), 7.40 - 7.41 (m, 1 H), 7.69 (d, J = 13.2 Hz, 1 H), 8.12 (s, 1 H). 99.86% of purity by HPLC @ 254 nM. Run 3: To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(2,5- difluorobenzyl)imidazolidin-2-one (450 mg, 1.16 mmol) in 1 ,4-dioxane (18 ml_) was added bis(pinacolato)diboron (300 mg, 1.16 mmol, 1 equiv), and potassium acetate (340 mg, 3.48 mmol, 3 equiv). The reaction mixture was degassed with N ₂ for 5 min. PdCI ₂ (dppf)- CH ₂ CI ₂ adduct (48 mg, 0.058 mmol, 0.05 equiv) was added and degassed with N ₂ for additional 5 min. The reaction mixture was stirred for 16 h at 100°C in a sealed vessel. The reaction was cooled to room temperature, 5-bromo-7-methyl-7/-/-pyrrolo[2,3- <^pyrimidin-4-amine (260 mg, 1.16 mmol, 1.0 equiv), saturated aqueous NaHC0 ₃ (6 ml_) and PdCI ₂ (dppf)-CH ₂ CI ₂ adduct (48 mg, 0.058 mmol, 0.05 equiv) were added and the reaction mixture was degassed with N ₂ for 5 min. The vessel was sealed and the reaction mixture was stirred for 16 h at 100°C. The reaction mixture was cooled to room temperature & filtered through celite and the filtrate was extracted with ethyl acetate. The organic layer was dried over Na ₂ S0 ₄ and concentrated to obtain dark oily compound. The crude product was purified over silica gel flash column chromatography using 2% MeOH in DCM as mobile phase. Compound containing pure fractions were evaporated to obtain 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-3- fluorophenyl)-3-(2,5- difluorobenzyl) imidazolidin-2-one (70 mg, 13.5 %) as an off white solid. LCMS (ES) m/z = 453.2 [M+H] ⁺ . H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.46 (t, J = 8.0 Hz, 2H), 3.73 (s, 3H), 3.88 (t, J = 7.6 Hz, 2H), 4.46 (s, 2 H), 5.94 (br. s., 2H), 7.19 - 7.26 (m, 4H), 7.31- 7.40 (m, 1 H), 7.42-7.45 (m, 1 H), 7.70 (d, J = 13.2 Hz, 1 H), 8.13 (s, 1 H). Example 2:

1 -(3,5-Dimethylbenzyl)-3-(3-fluoro-4-(2-(methylamino)quinolin -6- yl)phenyl)imidazolidin-2-one

Z90 Z91 Z92

Step 1 : A stirred solution of 6-bromoquinolin-2(1 /-/)-one (1.0 g, 4.4 mmol, 1.0 equiv) in phosphorous oxychloride (15 mL) was heated to 100°C for 15 h. The solvent was completely evaporated and water was added to the residue. The precipitated solid was filtered and dried under vacuum to obtain 6-bromo-2-chloroquinoline (1.0 g, 92 %) as pink solid. LCMS (ES) m/z = 241.0, 243.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.41 (d, J = 8.4 Hz, 1 H), 7.79 - 7.82 (m, 1 H), 7.89 (d, J = 9.2 Hz, 1 H), 7.98 - 7.99 (m, 1 H), 8.02 (d, J = 8.8 Hz, 1 H). Step 2: A suspension of 6-bromo-2-chloroquinoline (0.8 g, 3.3 mmol, 1.0 equiv.) in 15 mL methyl amine solution in THF was heated to 100°C in a stainless steel autoclave for 24 h. The reaction mixture was cooled to room temperature and evaporated completely to obtain crude product as a gummy solid. The crude was stirred in n-pentane for 1 h. The precipitated solid was filtered and dried under vacuum to obtain 6-bromo-/V- methylquinolin-2-amine (0.7 g, 90%) as off white solid. LCMS (ES) m/z = 237.0, 239.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.08 (d, J = 5.6 Hz, 3H), 4.74 (br. s., 1 H), 6.63 (d, J = 8.8 Hz, 1 H), 7.59 - 7.54 (m, 2H), 7.71 - 7.69 (m, 2H).

Step 3: To a stirred solution of 1-(4-bromo-3-fluorophenyl) imidazolidin-2-one (500 mg, 1.92 mmol) in DMF (8 mL) was added sodium hydride (92 mg, 2.31 mmol, 1.2 equiv) at 0°C. The reaction mixture was stirred for 15 min. 1-(bromomethyl)-3, 5-dimethylbenzene (42 mg, 2.12 mmol, 1.1 equiv) in DMF (2 mL) was added drop wise and the reaction mixture was gradually allowed to warm to room temperature and stirred for 4 h. Water was added and the solid was filtered, washed with n-pentane and dried under vacuum to obtain 1-(4-bromo-3-fluorophenyl)-3- (3,5-dimethylbenzyl)imidazolidin-2-one (500 mg, 69.5 %) as off white solid. LCMS (ES) m/z = 377.0, 379.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.24 (s, 6H), 3.34 (t, J = 8.0 Hz, 2H), 3.79 (t, J = 7.6 Hz, 2H), 4.30 (s, 2H), 6.88 - 6.90 (m, 3H), 7.30 - 7.32 (m, 1 H), 7.58 - 7.62 (m, 1 H), 7.71 - 7.75 (m, 1 H). Step 4: To a mixture of 6-bromo-/V-methylquinolin-2-amine (0.25 g, 1.05 mmol, 1 equiv) in 1 ,4-dioxane was added bis(pinacolato)diboron (0.27 g, 1.05 mmol, 1 equiv), and potassium acetate (0.31 g, 3.16 mmol, 3 equiv). The reaction mixture was degassed with N ₂ for 5 min. PdCl ₂ (dppf).CH ₂ Cl ₂ adduct (0.043 g, 0.05 mmol, 0.05 equiv) was added and degassed with N ₂ for further 5 min. The reaction mixture was stirred for 3 h at 100°C in a sealed vessel. The reaction was cooled to room temperature, 1-(4-bromo-3- fluorophenyl)-3-(3,5-dimethylbenzyl)imidazolidin-2-one (0.4 g, 1.05 mmol, 1.0 equiv), saturated aqueous NaHC0 ₃ (6 mL), and PdCI ₂ (dppf). CH ₂ CI ₂ adduct (0.043 g, 0.05 mmol, 0.05 equiv) were added and the reaction mixture was degassed with N ₂ for 5 min. The vessel was sealed and the reaction mixture was stirred for 16 h at 100°C. The reaction mixture was cooled to room temperature and filtered through celite and the filtrate was extracted with ethyl acetate. The organic layer was dried over Na ₂ S0 ₄ and concentrated to obtain dark oily compound. The crude product was purified over silica gel flash column chromatography. The compound eluted in 30% EtOAc in Hexanes. The fractions containing pure product were evaporated to obtain 1-(3,5-dimethylbenzyl)-3-(3- fluoro-4-(2-(methylamino)quinolin-6-yl)phenyl)imidazolidin-2 -one (0.25 g, 52 %) as off white solid. LCMS (ES) m/z = 455.2 [M+H] ⁺ . H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.25 (s, 6H), 2.90 (d, J =4.4 Hz, 3H), 3.37 (t, J = 8.0 Hz, 2H), 3.85 (t, J = 7.6 Hz, 2H), 4.32 (s, 2 H), 6.75 (d, J = 8.8 Hz, 1 H), 6.90 (br. s., 3H), 7.04 - 7.03 (m, 1 H), 7.43 - 7.40 (m, 1 H), 7.58 - 7.53 (m, 2H), 7.66 - 7.62 (m, 1 H), 7.70 - 7.67 (m, 1 H), 7.77 (s, 1 H), 7.87 (d, J = 9.2 Hz, 1 H).

Example 3:

1 -(3,5-Dimethylbenzyl)-3-(3-fluoro-4-(2-methylquinolin-6-yl)p henyl)imidazolidin-2- one

Step 1 : To a stirred solution of 4-bromoaniline (0.2 g, 1.16 mmol, 1.0 equiv) in acetic acid (2 mL) was added ethoxyethene (0.45 mL, 4.8 mmol, 3.0 equiv) and heated to 100°C & stirred for overnight. After completion of starting material, reaction mixture was concentrated. Crude product was neutralized with saturated NaHC0 ₃ solution and extracted with DCM (20 mL). The organics were combined and washed with brine solution, dried over Na ₂ S0 ₄ , filtered, and concentrated to obtain crude product. Crude product was purified by flash chromatography on silica gel. The compound was eluted with 30% EtOAc in Hexane. Fractions containing required product were concentrated to give 6-bromo-2-methylquinoline (0.051 g, 20%) as off white solid. LC-MS (ES) m/z = 222, 224 [M+H] ⁺ , H NMR (400 MHz, CDCI ₃ ) δ ppm 2.72 (s, 3H), 7.30 (d, J = 8.4 Hz, 1 H), 7.72 - 7.75 (m, 1 H), 7.87 - 7.96 (m, 3H). Step 2: To a mixture of 6-bromo-2-methylquinoline (0.5 g, 2.25 mmol, 1.0 equiv), bis(pinacolato)diboron (0.68 g, 2.7 mmol, 1.2 equiv), and potassium acetate (0.55 g, 5.62 mmol, 2.5 equiv) was added 1 ,4-dioxane (15 mL), and the mixture was degassed with N ₂ for 10 min. PdCl ₂ (dppf).CH ₂ Cl ₂ complex (0.183 g, 0.22 mmol, 0.1 equiv) was added and again degassed with N ₂ for 10 min. The reaction mixture was stirred for 3 h at 100°C in a sealed vessel. The reaction was cooled to room temperature. 1-(4-bromo-3- fluorophenyl)-3-(3,5-dimethylbenzyl)imidazolidin-2-one (0.848 g, 2.25 mmol, 1 equiv) and saturated aqueous NaHC0 ₃ (4 mL) were added, and N ₂ gas was bubbled through the mixture for 10 min. PdCl ₂ (dppf).CH ₂ Cl ₂ complex (0.183 g, 0.22 mmol, 0.1 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100°C. The reaction mixture was cooled and filtered through celite bed, the celite pad was washed with DCM (100 mL), and the filtrate was dried over Na ₂ S0 _4, filtered and concentrated to give crude product. The crude compound was purified by flash column chromatography using silica gel column and 50% EtOAc/Hexane as mobile phase. It was repurified by preparative HPLC. Preparative HPLC method - Inertsil ODS (250 mm x 20 mm x 3.5μηι), Mobile Phase: (A)/(B)-0.01 % TFA in water/Acetonitrile; Flow rate: 21 ml/min. Fractions obtained from prep HPLC were concentrated and neutralized using saturated NaHC0 ₃ solution and extracted with DCM (2 x 50 mL). The combined DCM layers were washed with brine solution, dried over Na ₂ S0 ₄ , filtered, and concentrated to give 1-(3,5-dimethylbenzyl)-3-(3-fluoro-4-(2-methylquinolin-6-yl) phenyl)imidazolidin-2-one (0.07 g, 8.0%) as off white solid. LCMS (ES) m/z = 440.2 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 6H), 2.66 (s, 3H), 3.38 (t, J = 8.4 Hz, 2H), 3.87 (t, J = 6.8 Hz, 2H), 4.33 (s, 2H), 6.91 (s, 3H), 7.42 - 7.48 (m, 2H), 7.63 (t, J = 8.8 Hz, 1 H), 7.71 - 7.75 (m, 1 H), 7.86 - 7.88 (m, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 8.07 (s, 1 H), 8.29 (d, J = 8.4 Hz, 1 H). HPLC: 99.76 % purity at 254 nM.

Example 4:

1 -(4-(4-Amino-7-methyl-7H-pyrrolor2,3-dlpyrimidin-5-yl)-3-flu orophenyl)-3-((4,6- dimethylpyridin-2-yl)methyl)-4-(hvdroxymethyl)imidazolidin-2 -one

Step 1 : To a stirred solution of 4-bromo-3-fluoroaniline (5 g, 26.31 mol) in EtOAc (50 mL) was added pyridine (2.3mL, 28.94 mol, 1.1 equiv) and phenyl carbonochloridate (3.6MI, 28.94 mmol, 1.1 equiv) at 0°C. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was washed with water (2 x 50 mL), organic solvent was dried over sodium sulphate, filtered and concentrated to obtain crude product. Crude compound was triturated with n-hexane to give phenyl (4-bromo-3- fluorophenyl)carbamate (5.5 g, 70 %) as off white solid. H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.20 -7.27 (m, 4H), 7.41 (t, J = 8.0 Hz, 2H), 7.53 (dd, J =2.0, 11.6 Hz, 1 H), 7.62 (t, J = 8.4 Hz, 1 H), 10.55 (s, 1 H).

Step 2: To a stirred solution of phenyl (4-bromo-3-fluorophenyl)carbamate (5.5 g, 17.74 mmol) in dichloromethane (60 ml_) was added methyl 2-amino-3-hydroxypropanoate (3.16 g, 26.61 mmol, 1.5 equiv) and dimethyl amino pyridine (5.4 g, 44.35 mmol, 2.5 equiv) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was washed with 5 % HCI (50 ml_) and water (50 ml_), organic solvent was separated and dried over sodium sulphate, filtered & concentrated to obtain crude product. Crude compound was purified by flash column chromatography, with silica gel column using 70 % EtOAc in n-hexane as eluent. Pure fractions were concentrated to give 3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl) imidazolidine-2,4- dione (3.0 g, 56 %) as off white solid. LC-MS (ES) m/z = 303.0, 305.0. [M+H] ⁺ . H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.63 - 3.73 (m, 1 H), 3.74 - 3.77 (m, 1 H), 4.21 (s, 1 H), 5.15(t, J = 5.6 Hz, 1 H), 7.22 (dd, J = 2.0, 8.8 Hz, 1 H), 7.41 (dd, J = 2.0, 10.4 Hz, 1 H), 7.80 - 7.83 (m, 1 H), 8.50 (s, 1 H).

Step 3: To a stirred solution of NaBH ₄ (0.25g, 6.60 mmol) in THF (15 ml_) was added BF ₃ -OEt ₂ (3.25 ml_, 26.4 mmol, 4 equiv) at 0 °C & stirred for 15 min. A solution of 3-(4- bromo-3-fluorophenyl)-5-(hydroxymethyl) imidazolidine-2,4-dione (1g, 3.3mmol) in THF (5 ml_) was added to the reaction mixture and stirred for 30 min. The reaction mixture warmed to room temperature and stirred for overnight. The reaction mixture was quenched with MeOH and 1 N HCI slowly over 15 min. The reaction mixture was concentrated to obtain crude product. The crude product was purified by flash column chromatography, with silica gel column using 4 % MeOH in DCM as mobile phase. Pure fractions were concentrated to give 1-(4-bromo-3-fluorophenyl)-4-(hydroxymethyl) imidazolidin-2-one (0.465 g, 48 %) as off white solid. LC-MS (ES) m/z = 291.0, 293.0. [M+H] ⁺ . H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.30 - 3.42 (m, 2H), 3.56 - 3.58 (m, 1 H), 3.68 - 3.71 (m,1 H), 3.84 - 3.88 (m, 1 H), 4.91 (t, J = 5.4 Hz, 1 H), 7.24 (dd, J = 2.0, 8.8 Hz, 1 H), 7.28 (s, 1 H), 7.55(t, J = 8.6 Hz, 1 H), 7.69 (dd, J = 2.0, 12.4 Hz, 1 H).

Step 4: To a stirred solution of 1-(4-bromo-3-fluorophenyl)-4-(hydroxymethyl) imidazolidin-2-one (0.45g, 1.55 mmol) in DMF (10 ml_) was added Imidazole (0.075 g, 1.71 mmol, 0.05 equiv), dimethyl amino pyridine (0.019 g, 0.155 mmol, 1 equiv) and TBDMS-Chloride (0.258 g, 1.71 mmol, 1.1 equiv) and resulted mixture was stirred at room temperature for 12 h. Reaction mixture was concentrated to obtain crude product. The crude product was purified by flash column chromatography; with silica gel column using 20% EtOAc in n-hexane as mobile phase. Pure fractions were concentrated to give 1-(4-bromo-3-fluorophenyl)-4-(((tertbutyldimethylsilyl)oxy)m ethyl)imidazolidin-2-one (0.26 g, 41 %) as semi solid. LC-MS (ES) m/z = 403.0, 405.0 [M+H] ⁺ . H NMR (400 MHz, CDCI3) δ ppm 3.30 - 3.42 (m, 2H), 3.56 - 3.58 (m, 1 H), 3.68 - 3.71 (m,1 H), 3.84 - 3.88 (m, 1 H), 4.91 (t, J = 5.4 Hz, 1 H), 7.24 (dd, J = 2.0, 8.8 Hz, 1 H), 7.28 (s, 1 H), 7.55 (t, J = 8.6 Hz, 1 H), 7.69 (dd, J = 2.0, 12.4 Hz, 1 H).

Step 5: To a stirred solution of 1-(4-bromo-3-fluorophenyl)-4-(((tertbutyldimethylsilyl)oxy)- methyl)imidazolidin-2-one (0.25g, 0.62 mmol) in DMF (10 mL) was cooled to 0°C, NaH (0.027 g, 0.68 mmol, 1.1 equiv) was added and stirred for 15 min at 0°C. 2- (bromomethyl)-4,6-dimethylpyridine (0.136 g, 0.68 mmol, 1.1 equiv) was added and the resulted mixture was stirred at room temperature for 1 h. Ice cold water (20 mL) was added, and extracted with EtOAc (2 x 50 mL). Organic layer was washed with cold water (2 x 50 mL) and brine solution (20 mL). Organic layer was dried over sodium sulphate, filtered and concentrated to give crude compound. Crude product was purified by flash column chromatography; with silica gel column using 10-25 % EtOAc in n-hexane as mobile phase. Pure fractions were concentrated to give 1-(4-bromo-3-fluorophenyl)-4- (((tert-butyldimethylsilyl)oxy)methyl)-3-((4,6-dimethylpyrid in-2-yl)methyl)imidazolidin-2-one (0.32 g, 92 %) as semi solid. LC-MS (ES) m/z = 522.1 , 524.0 [M+H] ⁺ .

Step 6: A mixture of 1-(4-bromo-3-fluorophenyl)-4-(((tert-butyldimethylsilyl)oxy) methyl)-3- ((4,6-dimethylpyridin-2-yl)methyl)imidazolidin-2-one (0.3 g, 0.57 mmol, 1 equiv), bis(pinacolato)diboron (0.15 g, 0.57 mmol, 1.0 equiv) and potassium acetate (0.167 g, 1.71 mmol, 3 equiv) in 10 mL of 1 ,4-dioxane was degassed with nitrogen for 15 min. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.046 g, 0.057 mmol, 0.01 equiv) was added and the reaction mixture was stirred at 100°C for overnight in sealed vessel. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by flash column chromatography with 24 g silica gel cartridge using gradient elution of 0- 20% EtOAc in hexane. The collected fractions with pure product were combined and concentrated in vacuo to afford 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((4,6- dimethylpyridin-2-yl)methyl)-1-(3-fluoro-4-(4,4,5,5-tetramet hyl-1 ,3,2-dioxaborolan-2- yl)phenyl)imidazolidin-2-one (0.3 g, crude) as gummy compound. LC-MS (ES) m/z = 570.3 [M+H] ⁺ .

Step 7: A mixture of 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((4,6-dimethylpyr idin-2- yl)methyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)imidazolidin- 2-one (0.3 g, 0.52 mmol, 1 equiv), 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.12 g, 0.52 mmol, 1 equiv), K ₃ PO4 (0.22 g, 1.04 mmol, 2.0 equiv) and Pd ₂ (dba) ₃ (0.024 g, 0.026 mmol, 0.05 equiv) in 12 mL of 1 ,4-dioxane and 4 mL of water in a sealed tube was bubbled with nitrogen for 15 min. Tri-(f-butyl)phosphonium tetrafluoroborate (0.015 g, 0.052 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 100°C for 6h in a sealed vessel. The reaction mixture was cooled to room temperature, filtered through celite and the filtrate was concentrated in vacuo to afford crude product. The crude product was purified by flash column chromatography with 24 g silica gel cartridge using gradient elution of 0-3 % MeOH in DCM. The collected fractions with pure product were combined and concentrated in vacuo to afford 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3- d]pyrimidin-5-yl)-3-fluorophenyl)-4-(((tert-butyldimethylsil yl)oxy)methyl)-3-((4,6- dimethylpyridin-2-yl)methyl) imidazolidin-2-one (0.15 g, crude) as off white solid. LC-MS (ES) m/z = 590.2 [M+H] ⁺ .

Step 8: Run1 : To a stirred solution of 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin- 5-yl)-3-fluorophenyl)-4-(((tert-butyldimethylsilyl)oxy)methy l)-3-((4,6-dimethylpyridin-2- yl)methyl)imidazolidin-2-one (0.02 g, 0.03 mmol, 1 equiv) in THF (5 mL) was added tetra butyl ammonium fluoride (0.084 mL, 0.084 mmol, 2.5 equiv, 1 M in THF) at 0°C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (5 mL). Organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford crude product (0.021g, crude). LC- MS (ES) m/z = 476.1 [M+H] ⁺ .

Run 2: To a stirred solution of 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3- fluorophenyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((4 ,6-dimethylpyridin-2- yl)methyl)imidazolidin-2-one (0.13 g, 0.22 mmol, 1 equiv) in THF (10 mL) was added tetra butyl ammonium fluoride (0.55 mL 1 M in THF, 0.55 mmol, 2.5 equiv) at 0°C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (10 mL). Organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford crude product. The crude product was purified by flash column chromatography with 24 g silica gel cartridge using gradient elution of 0-5% MeOH in DCM and the fractions containing desired product were combined and concentrated in vacuo to afford 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3- d]pyrimidin-5-yl)-3-fluorophenyl)-3-((4,6-dimethylpyridin-2- yl)methyl)-4- (hydroxymethyl)imidazolidin-2-one as off white solid (0.035 g, 28 %, combined yield of run 1 and run 2). LC-MS (ES) m/z = 476.1 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H), 2.37 (s, 3H), 3.40 - 3.50 (m, 1 H), 3.68 - 3.69 (m, 2H), 3.71 (s, 3H), 3.85 (br. s., 1 H), 3.97 - 4.00 (m, 1 H), 4.35 - 4.40 (m, 1 H), 4.50 - 4.54 (m, 1 H), 5.52 - 5.53 (m, 1 H), 6.00 (br. s., 2H), 6.98 (d, J = 8.8 Hz, 2H), 7.24 (s, 1 H), 7.32 - 7.37 (m, 1 H), 7.38 - 7.39 (m, 1 H), 7.71 (dd, J = 2.0, 13.2 Hz, 1 H), 8.12 (s, 1 H). 99.78% purity by HPLC @ 252 nM. Example 5:

1 -(4-(4-Amino-7-methyl-7H-pyrrolor2,3-dlpyrimidin-5-yl)-3-flu orophenyl)-3-((1-ethyl-

1H-pyrrol-2-yl)methyl)imidazolidin-2-one

Z105 Z106 Z107 Z108

Step 4

Step 1 : To a stirred solution of 1 H-pyrrole-2-carbaldehyde (2.0 g, 21.3 mmol, 1 equiv), in DMF (45 mL) was added K ₂ C0 ₃ (5.88 g, 42.6 mmol, 2 equiv) at room temperature. The reaction mixture was cooled to 0°C, and added Ethyl Iodide (2.05 mL, 25.53 mmol, 1.2 equiv) slowly at 0°C. The reaction mixture was stirred for 16 h at room temperature. After completion of starting material, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 1 -ethyl- 1/-/-pyrrole-2-carbaldehyde as brown oil (2.7 g, crude), LC-MS (ES) m/z = 124.1 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 1.24 - 1.28 (m, 3 H), 4.25 - 4.35(m, 2 H), 6.20 - 6.26 (m, 1 H), 6.99 - 7.01 (m, 1 H), 7.29 (s, 1 H), 9.49 (s, 1 H).

Step 2: To a stirred solution of 1 -ethyl- 1/-/-pyrrole-2-carbaldehyde (2.6 g, 21.1 1 mmol, 1 equiv), in MeOH (35 mL) was added NaBH ₄ (1.6 g, 42.22 mmol, 2.0 equiv) slowly in portion wise at 0°C. After the addition, the reaction mixture was slowly warmed to room temperature and stirred for 3h at room temperature. The reaction mixture was evaporated; water was added to the residue and extracted with DCM. The organic layer was washed with brine and dried over sodium sulfate & concentrated to give (1-ethyl-1 H- pyrrol-2-yl) methanol as brown oil (1.7 g, crude). H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (t, J = 6.8 Hz, 3 H), 3.91 (q, J = 7.6 Hz, 14.4 Hz, 2 H), 4.37 (d, J = 5.2 Hz, 2 H), 4.79 (t, J = 5.2 Hz, 1 H), 5.86 (s, 2 H), 6.69 (s, 1 H).

Step 3: To a stirred solution of 1-(4-bromo-3-fluorophenyl)imidazolidin-2-one (1.65 g, 6.4 mmol, 1 equiv), in THF (50 mL) was added (1-ethyl-1 H-pyrrol-2-yl)methanol (0.8 g, 6.4 mmol, 1 equiv) and PPh ₃ (3.36 g, 12.8 mmol, 2 equiv) at room temperature. DEAD (2.0 mL, 12.8 mmol, 2 equiv) was added slowly to the reaction mixture at 0°C. The reaction mixture was stirred for 3h at room temperature. After consumption of starting material, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine and dried over sodium sulfate and concentrated to give crude product. The crude product was purified by flash column chromatography using silica gel column. The compound was eluted at 15 - 20 % EtOAc in Hexane. Fractions containing compound were concentrated to give 1-(4-bromo-3-fluorophenyl)-3-((1-ethyl- 1H-pyrrol-2-yl)methyl)imidazolidin-2-one as pale yellow solid (0.250 g, 10.7 %). LC-MS (ES) m/z = 366.0, 368.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t, J = 19.2 Hz, 3 H), 3.29 - 3.32 (m, 2 H), 3.74 (t, J = 8.8 Hz, 2 H), 3.85 - 3.90 (m, 2 H), 4.34 (s, 2 H), 5.92 (t, J = 3.2 Hz, 1 H), 5.97 (d, J = 1.6 Hz, 1 H), 6.74 (t, J = 2.0 Hz, 1 H), 7.26 - 7.29 (m, 1 H), 7.58 (t, J = 8.4 Hz, 1 H), 7.67 - 7.71 (m, 1 H).

Step 4: To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-((1 -ethyl- 1 /-/-pyrrol-2- yl)methyl)imidazolidin-2-one (0.250 g, 0.683 mmol, 1.0 equiv) in dioxane (10 mL), was added bis(pinacolato)diboron (0.174 g, 0.683 mmol, 1.0 equiv), potassium acetate (0.209 g, 2.05 mmol, 3.0 equiv), and degassed with Argon for 10 min. PdCl ₂ (dppf).CH ₂ Cl ₂ complex (0.028 g, 0.0342 mmol, 0.05 equiv) was added and again degassed with Argon for 10 min. The reaction mixture was stirred for 7 h at 100°C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin- 4-amine (0.156 g, 0.683 mmol, 1.0 equiv) and saturated aqueous NaHC0 ₃ (2.5 mL) was added, and argon gas was bubbled through the mixture for 10 min. PdCl ₂ (dppf).CH ₂ Cl ₂ complex (0.028 g, 0.0342 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100°C. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was dried over Na ₂ S0 ₄ and concentrated to give crude product. The crude product was purified by flash column chromatography using Silica gel column, compound was eluted at 3.0 % MeOH in DCM. Compound containing pure fractions were concentrated to give 1-(4-(4-amino-7-methyl- 7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-3-fluorophenyl)-3-((1-eth yl-1 /-/-pyrrol-2- yl)methyl)imidazolidin-2-one (0.023 g, 7.7 % yield) as white solid. LCMS (ES) m/z = 434.4 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (t, J = 6.8 Hz, 3H), 3.31 (s , 2H), 3.71 (s, 3H), 3.80 (t, J = 8.8 Hz, 2H), 3.87 - 3.92 (m, 2H), 4.37 (s, 2H), 5.93 (br. s., 2H), 5.98 (s, 1 H), 6.75 (s, 1 H) 7.24 (s, 1 H), 7.32 - 7.38 (m, 2H), 7.67 (d, J = 13.2 Hz, 1 H), 8.12 (s, 1 H).

Examples 6, 7, and 8:

1 -(4-(4-Chloro-7-methyl-7H-pyrrolor2,3-dlpyrimidin-5-yl)-3-fl uorophenyl)-3-(2,5- difluorobenzyl) imidazolidin-2-one (6);

1 -(2,5-difluorobenzyl)-3-(3-fluoro-4-(7-methyl-7H-pyrrolor2,3 -dlpyrimidin-5- yl)phenyl)imidazolidin-2-one (7);

1 -(2,5-difluorobenzyl)-3-(3-fluoro-4-(4-hvdroxy-7-methyl-7H-p yrrolor2,3-dlpyrimidin-

5-yl)phenyl)imidazolidin-2-one (8)

Step 1 : To a stirred solution of 4-chloro-7/-/-pyrrolo[2,3-d]pyrimidine (4 g, 26.143 mmol) in THF (40 mL) was added potassium tertiary butoxide (3.8 g, 33.986 mmol, 1.3 equiv) at 0°C. The reaction mixture was allowed to stir at room temperature for 20 min. Methyl iodide (2.4 mL, 39.215 mol, 1.5 equiv) was added at 0°C to the reaction mixture and stirred for 4h at room temperature. The solvent was evaporated, diluted with ice water (50 mL) and the precipitated solid was filtered & dried in vacuo to give 4-chloro-7-methyl- 7H-pyrrolo[2,3-d]pyrimidine as off white solid (3.6 g, 83 %). LCMS (ES) m/z = 168.1 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 3.84 (s, 3H), 6.62 (d, J = 3.2 Hz, 1 H), 7.72 (d, J = 3.2 Hz, 1 H), 8.62 (s, 1 H).

Step 2: To a stirred solution of 4-chloro-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidine (3.6 g, 21.556 mmol) in dimethyl formamide (50 mL) was added /V-iodosuccinimide (4.8 g, 21.556 mmol) in one portion at room temperature and the reaction mixture was stirred overnight. Ice water (100 mL) was added to the reaction mixture and the resulting precipitate was filtered, washed with water (100 mL) and dried under vacuum to obtain 4- chloro-5-iodo-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidine as off white solid (5.2 g, crude). LCMS (ES) m/z = 293.9 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 3.81 (s, 3H), 7.95 (s, 1 H), 8.62 (s, 1 H).

Step 3: To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(2,5- difluorobenzyl)imidazolidin-2-one (1.0 g, 2.6 mmol, 1.0 equiv), was added bis(pinacolato)diboron (0.66 g, 2.6 mmol, 1.0 equiv), & potassium acetate (0.764 g, 7.8 mmol, 3.0 equiv), and the reaction mixture was degassed with Argon for 10 min, PdCl ₂ (dppf).CH ₂ Cl ₂ complex (0.106 g, 0.13 mmol, 0.05 equiv) was added and again degassed with Argon for 10 min. The reaction mixture was stirred for 5h at 100°C in a sealed vessel. The reaction mixture was cooled to room temperature. 4-chloro-5-iodo-7- methyl-7/-/-pyrrolo[2,3-d]pyrimidine (0.762 g, 2.6 mmol, 1.0 equiv) and saturated aqueous NaHC0 ₃ (8.0mL) were added and Argon gas was bubbled through the mixture for 10 min. PdCl ₂ (dppf).CH ₂ Cl ₂ complex (0.106 g, 0.13 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100°C. The reaction mixture was cooled to room temperature & filtered through celite. The filtrate was dried over Na ₂ S0 ₄ and concentrated to give crude product. The crude product was purified by flash column chromatography using silica gel column, compound was eluted at 32 - 35 % EtOAc in Hexanes. Compound containing pure fractions were concentrated to give 1-(4- (4-chloro-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluo rophenyl)-3-(2,5- difluorobenzyl)imidazolidin-2-one (0.055 g). Impure fractions were combined and evaporated to give and addtioanl 0.1 10g of 1-(4-(4-chloro-7-methyl-7/-/-pyrrolo[2,3- d]pyrimidin-5-yl)-3-fluorophenyl)-3-(2,5-difluorobenzyl)imid azolidin-2-one, which was 89% purity by LCMS and used in the next step without further purification) as off white solid. LCMS (ES) m/z = 472.1 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 0.66 (d, J = 4.0 Hz, 2 H), 0.93 (d, J = 6.80 Hz, 2 H), 1.92 (m, 1 H), 2.16 - 2.24 (m, 1 H), 2.49 - 2.66 (m, 1 H), 3.74 (s, 3 H), 3.90 - 3.98 (m, 3 H), 5.97 (br. S., 2 H), 7.44 (d, J = 7.60 Hz, 1 H), 7.05 (d, J = 8.80 Hz, 2 H), 7.22 (t, J = 7.60 Hz, 1 H), 7.30 (s, 1 H), 7.42 (t, J = 8.80 Hz, 1 H), 7.59 (d, J = 8.40 Hz, 1 H), 7.83 (d, J = 1 1.60 Hz, 1 H), 8.14 (s, 1 H).

Step 4: To a stirred solution of 1-(4-(4-chloro-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3 - fluorophenyl)-3-(2,5-difluorobenzyl)imidazolidin-2-one (0.1 10 g, 89% purity by LCMS)) in MeOH (10 mL) was added 10% Pd/C (0.015 g, contains 50% moisture) and the mixture was degassed using nitrogen and then replaced with H ₂ bladder. The reaction mixture was stirred for 16 h at room temperature. After consumption of the starting material, the reaction mixture was filtered through celite bed. The solvent was concentrated to give crude product. The crude product was purified by flash column chromatography using Silica gel column, compound was eluted at 2 - 3 % MeOH in DCM. Fractions containing pure compound was concentrated to give 1-(2,5-difluorobenzyl)-3-(3-fluoro-4-(7-methyl- 7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)imidazolidin-2-one as off white solid (0.05 g, 48.9 %). LCMS (ES) m/z = 438.1 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 3.45 (t, J = 8.0 Hz, 2H), 3.86 - 3.90 (m, 5H), 4.45 (s, 2H), 7.18 - 7.30 (m, 3H), 7.42 (d, J = 8.0 Hz, 1 H), 7.69 - 7.76 (m, 2H), 7.89 (s, 1 H), 8.85 (s, 1 H), 9.16 (br. S., 1 H).

Step 5: To a stirred solution of 4-chloro-5-iodo-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidine (0.6 g, 2.045 mmol, 1.0 equiv) in 1 ,4-dioxane (7.0 mL) and water (7.0 mL) was added NaOH pellets (0.408 g, 10.222 mmol, 5.0 equiv) and stirred for 5 min. The reaction mixture was heated to 100°C and stirred for 4 h. The reaction mixture was concentrated; the residue was diluted with water and acidified with 1 N HCI. The precipitate was filtered and dried to give 5-iodo-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-4-ol as off white solid (0.520 g, crude ). LCMS (ES) m/z = 276.0 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 3.65 (s, 3 H), 7.26 (s, 1 H), 7.87 (s, 1 H), 1 1.89 (s, 1 H).

Step 6: To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(2,5- difluorobenzyl)imidazolidin-2-one (0.5 g, 1.3 mmol, 1.0 equiv) in DMF (15 mL) was added bis(pinacolato)diboron (0.33 g, 1.3 mmol, 1.0 equiv), and potassium acetate (0.382 g, 3.9 mmol, 3.0 equiv), and the mixture was degassed with Argon for 10 min. PdCl ₂ (dppf).CH ₂ Cl ₂ complex (0.053 g, 0.065 mmol, 0.05 equiv) was added and again degassed with Argon for 10 min. The reaction mixture was stirred for 5h at 100°C in a sealed vessel. The reaction was cooled to room temperature, 5-iodo-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-4-ol (0.357 g, 1.3 mmol, 1.0 equiv) and saturated aqueous NaHC0 ₃ (5.0ml_) were added and Argon gas was bubbled through the mixture for 10 min. PdCl ₂ (dppf).CH ₂ Cl ₂ complex (0.053 g, 0.065 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100°C. The reaction mixture was cooled to room temperature & filtered through celite. The filtrate was diluted with water and extracted with EtOAc. The organic layer was dried over Na ₂ S0 _4, filtered & concentrated to give crude product. The crude product was purified by flash column chromatography using Silica gel column, compound was eluted at 2.7 - 3.0 % MeOH in DCM. Fractions containing pure product was concentrated to give 1-(2,5-difluorobenzyl)- 3-(3-fluoro-4-(4-hydroxy-7-methyl-7/-/-pyrrolo[2,3-c]pyrimid in-5-yl)phenyl)imidazolidin-2- one (0.064 g, 10.87 %) as white solid. LCMS (ES) m/z = 454.1 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 3.43 (t, J = 8.0 Hz, 2H), 3.73 (s , 3H), 3.85 (t, J = 8.0 Hz, 2H), 4.43 (s, 2H), 7.18 - 7.31 (m, 5H), 7.61 (d, J = 14.4 Hz, 1 H), 7.89 (d, J = 3.2 Hz, 1 H), 7.96 (t, J = 9.2 Hz, 1 H), 11.86 (s, 1 H).

Example 9:

2-(4-(4-Amino-7-methyl-7H-pyrrolor2,3- lpyrimidin-5-yl)-3-fluorophenyl)-4-(2,5- difluorobenzyl)-2,4-diazabicyclor3.1.01hexan-3-one

9

O

Z113 Z114 Z115 Z116 Z117

H ° Step 6 V Step 7 V St

Z119 Z120

Step 1 : 3-Oxabicyclo[3.1.0]hexane-2,4-dione (5.5 g, 49mmol, 1.0 equiv) was taken in H ₂ 0 (40 mL) and heated to 80 °C for overnight. The reaction mixture was concentrated under reduced pressure and co-distilled the water traces with toluene to get dry cyclopropane- 1 ,2-dicarboxylic acid (6.0 g, 94 %) as white solid. LC-MS (ES) m/z = 131.1 [M+H] ⁺ , H NMR (400 MHz, DMSO) δ ppm 1.06 - 1.11 (m, 1 H), 1.22 - 1.27 (m, 1 H), 1.93 - 1.97 (m, 2H), 12.20 (br. S., 2H).

Step 2: Cyclopropane-1 ,2-dicarboxylic acid (3.5 g, 26.9 mmol, 1.0 equiv) and PCI ₅ (16.82 g, 80.7 mmol, 3.0 equiv) were mixed and heated to 90 °C for 6h. The reaction mixture was cooled to room temperature and filtered to remove the excess PCI ₅ and washed with Et ₂ 0. Filtrate was concentrated under reduced pressure to give cyclopropane-1 ,2- dicarbonyl dichloride (3.5 g, crude) as colorless oil. H NMR (400 MHz, DMSO) δ ppm 1.60 - 1.64 (m, 1 H), 1.76 - 1.79 (m, 1 H), 2.87 - 2.90 (m, 2H).

Step 3: Caution - acyl azides are dangerous and potentially explosive. For saftey, all experiements involving acyl azides should be performed with appropriate protection and blast shielding. Cyclopropane- 1 ,2-dicarbonyl dichloride (3.5 g, 21 mmol, 1.0 equiv) in acetone (30 mL) was added dropwise with stirring to a cooled (ice-salt bath) aqueous solution (30 mL) of NaN ₃ (4.09 g, 62 mmol, 3.0 equiv)). After complete addition, the reaction the reaction mixture was stirred at 0 °C for 3h. The reaction mixture was diluted with cold water and extracted with Et ₂ 0 (3 x 100 mL). The combined organic layer was washed with cold water and brine solution, dried over Na ₂ S0 ₄ , filtered and evaporated by keeping the bath temperature below 30°C to obtain cyclopropane-1 ,2-dicarbonylazide (2.6 g, Crude) as colorless oil, which was directly forwarded for next stage. H NMR (400 MHz, DMSO) δ ppm 1.40 - 1.45 (m, 1 H), 1.51 - 1.53 (m, 1 H), 2.33 - 2.37 (m, 2H).

Step 4: Caution - acyl azides are dangerous and potentially explosive. For saftey, all experiements involving acyl azides should be performed with appropriate protection and blast shielding. Cyclopropane-1 ,2-dicarbonylazide (2.6 g, 14.4 mmol, 1.0 equiv) in toluene was heated to 100°C for 15h. The disappearance of starting material was monitored by TLC and the reaction mixture was concentrated to give 1 ,2- diisocyanatocyclopropane (2.6 g, crude), which is used directly for next stage without purification.

Step 5: 1 ,2-Diisocyanatocyclopropane (2.6 g, 20 mmol, 1.0 equiv) in tert-BuOH (30 mL) was heated to 80°C for 15h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with Et ₂ 0 and dried to obtain solid to give the required product tert-butyl 3-oxo-2,4-diazabicyclo[3.1.0]hexane-2-carboxylate (0.8 g crude). LC-MS (ES) m/z = 143.1 (M+H) ⁺ -56

Step 6: Run 1 ; To a mixture of tert-butyl 3-oxo-2,4-diazabicyclo[3.1.0]hexane-2- carboxylate and 2,4-diazabicyclo[3.1.0]hexan-3-one (0.2 g, 1.0 mmol, 1.0 equiv) in DMF (5.0 mL) was added NaH(60 % in oil) (0.04g, 1.1 mmol, 1.1 equiv) at 0 °C and stirred for 30 min. 2,5-Difluorobenzylbromide (0.15 mL, 1.1 mmol, 1.1 equiv) was added and stirred for 2h at 0°C. After completion of starting material, reaction mixture was quenched with ice water and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water, brine solution & dried over Na ₂ S0 ₄ , filtered, and concentrated under reduced pressure to get crude product. Crude product was purified by flash chromatography on silica gel and compound was eluted with 20% EtOAc in Hexane. Fractions containing desired product were concentrated to give tert-butyl 4-(2,5- difluorobenzyl)-3-oxo-2,4-diazabicyclo[3.1.0]hexane-2-carbox ylate (0.1g, 31.2%) as white solid. LC-MS (ES) m/z = 269.0 (M+H) ⁺ -56. H NMR (400 MHz, DMSO) δ ppm 0.29 - 0.31 (m, 1 H), 0.70 - 0.74 (m, 1 H), 1.44 (s, 9H), 3.11 - 3.15 (m, 1 H), 3.57 - 3.67 (m, 1 H), 4.41 (s, 2H), 7.16 - 7.29 (m, 3H).

Run 2; To a mixture of tert-butyl 3-oxo-2,4-diazabicyclo[3.1.0]hexane-2-carboxylate and 2,4-diazabicyclo[3.1.0]hexan-3-one (0.6g, 3.0 mmol, 1.0 equiv) in DMF (10.0 mL) was added NaH (60 % in oil) (0.16g, 3.93 mmol, 1.3 equiv) at 0 °C and stirred for 30 min. 2,5- Difluorobenzylbromide (0.5 mL, 3.93 mmol, 1.3 equiv) was added and stirred for 2h at 0°C. After completion of starting material, the reaction mixture was quenched with ice water and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water, brine solution & dried over Na ₂ S0 ₄ , filtered, and concentrated under reduced pressure to give crude product. Crude product was purified by flash chromatography on silica gel and compound was eluted with 20% EtOAc in Hexane. Fractions containing desired product were concentrated to give tert-butyl 4-(2,5-difluorobenzyl)-3-oxo-2,4- diazabicyclo[3.1.0]hexane-2-carboxylate (0.32g, 32.6%) as white solid. LC-MS (ES) m/z = 269.1 (M+H) ⁺ -56.

Step 7: To a stirred solution of tert-butyl 4-(2,5-difluorobenzyl)-3-oxo-2,4- diazabicyclo[3.1.0]hexane-2-carboxylate (0.41 g, 1.26 mmol, 1.0 equiv) in MeOH (10 mL) was added (4M) HCI in dioxane (2 mL) at 0 °C and stirred for 3h. After consumption of starting material, the reaction mixture was concentrated under reduced pressure and the residue was triturated with Et ₂ 0 to give 2-(2,5-difluorobenzyl)-2,4- diazabicyclo[3.1.0]hexan-3-one (0.3 g, Crude) as off-white solid. LC-MS (ES) m/z = 225.1 (M+H) ⁺ .

Step 8: To a stirred solution of 2-(2,5-difluorobenzyl)-2,4-diazabicyclo[3.1.0]hexan-3-one (0.3 g, 1.34 mmol, 1.0 equiv) and 1-bromo-2-fluoro-4-iodobenzene (0.484 g, 1.60 mmol, 1.2 equiv) in EtOAc (20 mL) was added cesium fluoride (0.51 g, 3.35 mmol, 2.5 equiv), Ν,Ν' -dimethylethylenediamine (0.029 mL, 0.268 mmol, 0.2 equiv) and Cul (0.051 g, 0.268 mmol, 0.2 equiv) and the resulting mixture was stirred for 15h at room temperature. The reaction mixture was diluted with EtOAc (3 x 50 mL), washed with water (10 mL), brine solution (10 mL), dried over Na ₂ S0 _4, filtered and concentrated under reduced pressure to give crude product. Crude product was purified by flash chromatography on silica gel and compound was eluted with 30% EtOAc in Hexane. Fractions containing product were concentrated to give 2-(4-bromo-3-fluorophenyl)-4-(2,5-difluorobenzyl)-2,4- diazabicyclo[3.1.0]hexan-3-one (0.29g, 55%) as off white solid. LC-MS (ES) m/z = 397.0, 398.9 [M+H] ⁺ . H NMR (400 MHz, CDCI ₃ ) δ ppm 0.27 - 0.30 (m, 1 H), 0.82 - 0.87 (m, 1 H), 3.16 - 3.20 (m, 1 H), 3.37 - 3.41 (m, 1 H), 4.56 (d, J = 2.8 Hz, 2H), 6.94 - 6.99 (m, 1 H), 7.01 - 7.10 (m, 2H), 7.29 - 7.32 (m, 1 H), 7.48 (t, J = 8.8 Hz, 1 H), 7.54 - 7.57 (m, 1 H).

Step 9: To a mixture of 2-(4-bromo-3-fluorophenyl)-4-(2,5-difluorobenzyl)-2,4- diazabicyclo[3.1.0]- hexan-3-one (0.28 g, 0.7 mmol, 1.0 equiv), bis(pinacolato)diboron (0.22 g, 0.846 mmol, 1.2 equiv), and potassium acetate (0.173 g, 1.76 mmol, 2.5 equiv) was added 1 ,4-dioxane (10 ml_), and the mixture was degassed with N ₂ for 10 minutes. PdCl ₂ (dppf).CH ₂ Cl ₂ complex (0.057 g, 0.07 mmol, 0.1 equiv) was added and again degassed with N ₂ for 10 minutes. The reaction mixture was stirred for 15 h at 100°C in a sealed vessel. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to give crude product. Crude product was purified by flash chromatography on silica gel and compound was eluted with 25% EtOAc in Hexane. Fractions containing product were concentrated to give 2-(2,5-difluorobenzyl)-4-(3-fluoro- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-2,4-diazabicyclo[3.1.0]hexan- 3-one (0.2g, 64%) as off white solid. LC-MS (ES) m/z = 445.1 [M+H] ⁺ .

Step 10: 2-(2,5-Difluorobenzyl)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)-2,4-diazabicyclo[3.1.0]hexan-3-one (0.19 g, 0.43 mmol, 1.0 equiv), 5-bromo-7- methyl-7/-/-pyrrolo[2,3-d]pyrimidin-4-amine (0.097 g, 0.43 mmol, 1.0 equiv) and potassium phosphate (0.183 g, 0.86 mmol, 2 equiv) in 1 ,4-dioxane: water (10 ml_ : 3.0 ml_) was degassed with N ₂ for 15 minutes, added Pd ₂ (dba) ₃ ( 0.0196 g, 0.022 mmol, 0.05 equiv) & Tri-tert-butylphosphonium tetrafluoroborate ( 0.0124 g, 0.043 mmol, 0.1 equiv). The reaction mixture was further degassed for 5 minutes. The vial was sealed and the reaction mixture was heated to 100°C and stirred for 5h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was dried over Na ₂ S0 ₄ , concentrated to obtain crude compound. Crude product was purified by flash column chromatography using silica gel column and compound was eluted at 2% MeOH in DCM. Fractions containing pure product were concentrated to give 2-(4-(4-amino-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-5-yl)-3-fluorophenyl)-4-(2,5-difluor obenzyl)-2,4- diazabicyclo[3.1.0]hexan-3-one (0.02g, 10 %) as off white solid. LCMS (ES) m/z = 465.1 [M+H] ⁺ . H NMR (400 MHz, DMSO-d6) δ ppm 0.21 - 0.23 (m, 1 H), 0.81 - 0.86 (m, 1 H), 3.32 - 3.36 (m, 1 H), 3.72 (s, 4H), 4.52 (q, J = 15.6 Hz, 2H), 5.95 (br. S., 2H), 7.20 - 7.30 (m, 4H), 7.37 (t, J = 8.4 Hz, 1 H), 7.48 - 7.51 (m, 1 H), 7.64 - 7.68 (m, 1 H), 8.12 (s, 1 H).

Compounds 10 to 91 were prepared generally according to the above schemes and using procedures analogous to those described for Examples 1 to 9, using

apporpriately substituted starting materials. As is appreciated by those skilled in the art, these analogous procedures may involve variations in general reaction conditions.

Table 1.

zolidin-2-one (s, 1H).

2- one 8.12 (s, 1H).

- Compounds 92 to 98 are prepared generally according to the above schemes and using procedures analogous to those described for Examples 1 to 9, using apporpriately substituted starting materials. As is appreciated by those skilled in the art, these analogous procedures may involve variations in general reaction conditions.

Table 2.

d]pyrimidin-5- yl)pyridin-2-yl)-3- (2,5- dimethylbenzyl)im

idazolidin-2-one

Example 99: PERK Enzyme Assay Compounds of the invention were assayed for PERK enzyme inhibitory activity with modifications to previously reported conditions (Axten et al. J. Med. Chem., 2012, 55, 7193-7207). Briefly, various concentrations of compounds (maximum 1 % DMSO) were dispensed into 384-well plates containing GST-PERK enzyme. After 30-60 minutes of compound pre-incubation, ATP and biotin-elF2a were added and after 60 minutes the reaction was quenched. After 2 hrs, a fluorescence plate reader was used to measure inhibition and IC50s were calculated.

Enzyme assay protocol for PKR-Like Endoplasmic Reticulum Kinase (PERK) - HTRF - % Inhibition

Assay Buffer contains HEPES (pH7.5) 10mM, CHAPS 2mM, MgCI2 5mM and DTT 1 mM in water

Detection Buffer contains HEPES (pH7.5) 10mM and CHAPS 2mM in water

Assay Plate Preparation:

1. Enzyme Preparation:

4X Enzyme solution was prepared immediately prior to adding to compound plates.

3nM of GST-PERK in Assay buffer. Final [PERK] in 10 μΙ assay volume = 0.75nM

2. Substrate Preparation:

4X Substrate solution was prepared immediately prior to adding to compound plates.

4X Substrate solution in assay buffer 2000μΜ ATP and 160 nM Biotin-elF2a

Final [ATP] in 10 μΙ assay

Final [biotin-elF2a] in 10 μΙ assay volume =40 nM.

3. Quench/Detection Solution:

16 nM elF2 Phospho-Antibody 16 nM Eu anti-Rabbit IgG

160 nM Streptavidin-APC

60 mM EDTA

Final concentration in 10 μΙ_ assay volume: 4 nM elF2 Phospho-Antibody, 4 nM Eu anti-Rabbit IgG 40 nM Streptavidin-APC

The activity of compounds in the PERK enzyme assay was determined at PERK Enzyme (500 μΜ ATP) IC50 (nM).

Example 100 - Capsule Composition

An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table 3, below.

Table 3

INGREDIENTS AMOUNTS

1-(4-(4-Amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl) -3- 7 mg

fluorophenyl)-3-(2,5-difluorobenzyl) imidazolidin-2-one

(Compound of Example 1)

Lactose 53 mg

Talc 16 mg

Magnesium Stearate 4 mg

Example 101 - Injectable Parenteral Composition

An injectable form for administering the present invention is produced by stirring 1.7% by weight of 1-(3,5-Dimethylbenzyl)-3-(3-fluoro-4-(2-(methylamino)quinoli n-6- yl)phenyl)imidazolidin-2-one (Compound of Example 2) in 10% by volume propylene glycol in water.

Example 102 Tablet Composition

The sucrose, calcium sulfate dihydrate and a PERK inhibitor as shown in Table 4 below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid;, screened and compressed into a tablet. Table 4

INGREDIENTS AMOUNTS

1-(4-(4-Amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrirnidin-5-yl )-3- 12 mg

fluorophenyl)-3-((4,6-dimethylpyridin-2-yl)methyl)-4- (hydroxymethyl)imidazolidin-2-one (Compound of

Example 4)

calcium sulfate dihydrate 30 mg

sucrose 4 mg

starch 2 mg

talc 1 mg

stearic acid 0.5 mg

Biological Activity Compounds of the invention are tested for activity against PERK in the above assay.

The compounds of Examples 1 to 91 were tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 μΜ ATP) IC50 (nM) value: < 8 μΜ against PERK, except for Examples 2, 3, 6 to 8, 11 , 12, 20, 35, 38, 43, 46, 50, 57, 66, 69, 87, and 88, which exhibited IC50 > 10 μΜ.

The compound of Example 74 was tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a PERK Enzyme (500 μΜ ATP) IC50 (nM) value of 526.6 against PERK.

While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.