EP3116877A1

EP3116877A1 - Chemical compounds acting as perk inhibitors

Info

Publication number: EP3116877A1
Application number: EP15714943.6A
Authority: EP
Inventors: Jeffrey M. Axten; Jesus Raul Medina
Original assignee: GlaxoSmithKline Intellectual Property No 2 Ltd
Current assignee: GlaxoSmithKline Intellectual Property No 2 Ltd
Priority date: 2014-03-11
Filing date: 2015-03-11
Publication date: 2017-01-18
Also published as: WO2015136463A1; JP2017507967A

Abstract

The invention is directed to substituted pyrrolidinone derivatives. Specifically, the invention is directed to compounds according to Formula X: wherein R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, and R⁴⁷ are defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer and diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt- Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, myocardial infarction, neurodegeneration, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias, more specifically cancers of the breast, colon, pancreas and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

Description

CHEMICAL COMPOUNDS ACTING AS PERK INHIBITORS

FIELD OF THE INVENTION

The present invention relates to substituted pyrrolidinone 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 associated with activated unfolded protein response pathways, such as Alzheimer's disease, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt- Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, neurodegeneration, atherosclerosis, ocular diseases, and arrhythmias.

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 (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. Cellualr responses include transcriptional reprogramming to increase the level of chaperone proteins to enhance protein re-folding, degradation of the mis-folded proteins, and translational arrest to decrease the burden of client proteins entering the ER (Ron, D. 2002), (Harding et al., 2002). These pathways also regulate cell survival by modulating apoptosis (Ma and Hendershot, 2004), (Feldman et al., 2005), and autophagy (Rouschop et al. 2010), and can trigger cell death under conditions of prolonged ER stress (Woehlbier and Hetz, 2011).

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). This site is also phosphorylated by other EIF2AK family members [(general control non-derepressed 2 (GCN2), PKR, and heme-regulated kinase (HRI)] in response to different stimuli, and by pharmacological inducers of ER stress such as thapsigargin and tunicamycin.

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 decrease in translation initiation and global protein synthesis (Harding et al. 2002). Paradoxically, translation of specific mRNAs is enhanced when the UPR is activated and elF2a is phosphorylated. The transcription factor ATF4, which is regulated by PERK, has 5'-upstream open reading frames (uORFs) that normally represses ATF4 synthesis. However, when PERK is activated under stress and P-elF2a inhibits elF2B, low levels of ternary complex allows for selective enhanced translation of ATF4 (Jackson et al. 2010). Therefore, when ER stress ensues due to the presence of misfolded proteins, PERK activation causes an increase in ATF4 translation, which transcriptionally upregulates downstream target genes such as CHOP (transcription factor C/EBP homologous protein), which modulates cellular survival pathways and induces apoptotic genes.

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) and prion diseases including Creutzfeldt-Jakob Disease (CJD), (Doyle et al. 2011), (Paschen 2004), (Salminen et al. 2009). 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 malfolded protein stress is under control of PERK. A cell enduring ER stress may restore proteostasis and return to normal, or if the stress is insurmountable, sustained PERK activation may lead to cell death through ATF4/CHOP signaling coupled with the inability to synthesize vital proteins because of the persistent translational repression. Activated PERK and associated biological markers of PERK activation are detected in post-mortem brain tissue of Alzheimer's disease patients and in human prion disease (Ho et al. 2012), (Hoozemans et al, 2009) (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 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. Inhibitors of PERK may be therapeutically useful for the treatment of a variety of human diseases such as Alzheimer's disease and frontotemporal dementias, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), spinal cord injury, traumatic brain injury, stroke , Creutzfeldt-Jakob Disease (CJD) and related prion diseases, such as fatal familial insomnia (FFI), Gerstmann-Straussler-Scheinker Syndrome, and vanishing white matter (VWM) disease. Inhibitors of PERK may also be useful for effective treatment of cancers, particularly those derived from secretory cell types, such as pancreatic and neuroendocrine cancers, multiple myeloma, or for use in combination as a chemosensitizer to enhance tumor cell killing. A PERK inhibitor may also be useful for myocardial infarction, cardiovascular disease, atherosclerosis (McAlpine et. al, 2010), and arrhythmias. A PERK inhibitor is expected to have diverse utility in the treatment of numerous diseases in which the underlying pathology and symptoms are associated with dysregulaton of the unfolded protein response.

References

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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 useful in the methods of the invention.

It is also an object of the present invention to provide a method for treating neurodegenerative diseases, cancer, and other diseases associated with activated unfolded protein response pathways such as: Alzheimer's disease, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, neurodegeneration, atherosclerosis, ocular diseases, and arrhythmias, that comprises administering inhibitors of PERK activity. SUMMARY OF THE INVENTION

The invention is directed to substituted pyrrolidinone derivatives. Specifically, the invention is directed to compounds according to Formula X:

wherein R⁴ , R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, and R⁴⁷, are defined below.

The present invention also relates to the discovery that the compounds of Formula (X) are active as inhibitors of PERK.

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

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

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

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

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

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

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

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

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. DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel compounds of Formula (X):

is selected from:

bicycloheteroaryl,

substituted bicycloheteroaryl,

heteroaryl, and

substituted heteroaryl,

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

halo,

C-|-6alkyl,

C-|-4alkyloxy,

-OH,

hydroxyC-|-4alkyl,

-COOH,

tetrazole,

-CF₃,

-Ci-4alkylOCi-4alkyl, -CONH2, -CON(H)Ci-3alkyl,

-CH₂CH₂N(H)C(0)OCH₂aryl,

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

-CN,

heterocycloalkyl,

heterocycloalkyl substituted with from 1 to 4 substituents

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

-COOH, -CF₃, -Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN,

-N0₂,

-NH₂,

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

elected from:

aryl,

aryl substituted with form one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, cycloalkyi, C-|-4alkyloxy, -OH,

-COOH, -CF₃, -Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN,

heteroaryl,

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

Ci-4alkyloxy, -OH, -COOH, -CF₃, -Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to five substituents

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

Ci-4alkyloxy, -OH, -COOH, -CF₃, -Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN;

R⁴³ is selected from:

-H,

-NH₂,

-OH,

-CN,

Ci-6alkoxy, Ci-6alkyl, and

C-|-6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH, -CF₃, -Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN;

44

R is selected from:

-NH₂,

-N(H)Ci.₃alkyl,

-N(Ci.₃alkyl)_2,

-OH,

Ci-6alkyl, and

C-|-6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF₃, -Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN;

45

R is selected from:

C-|-6alkyl, and

46

R is selected from: H, fluoro, chloro, bromo and iodo; or R5 and are optionally taken together to form a 5 to 6 member saturated or unsaturated ring containing up to one other heteroatom selected from oxygen and nitrogen; and

47

R is selected from: H, C-|-4alkyl, -CF3, fluoro, chloro, bromo and iodo; and salts thereof.

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

Included in the presently invented compounds of Formula (X) are compounds of Formula (XI):

wherein:

R⁵⁰ is selected from:

aryl,

aryl substituted with form one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH,

-CF₃, -Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN,

heteroaryl, and

heteroaryl substituted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH,

-COOH, -CF₃, -Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN;

51

R is selected from: H and CH3_;

52

R is selected from: -NH₂,

-N(H)Ci-3alkyl,

-N(Ci-3alkyl)₂,

-OH,

Ci-6alkyl, and

Ci-6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH, -CF₃, -Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN;

53

R is selected from: H, C-|-4alkyl, -CF3, fluoro and chloro; and

54

R is selected from:

C-|-6alkyl, and

C-|-6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF₃, -Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN; and salts thereof.

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

Included in the presently invented compounds of Formula (X) are compounds of Formula (XII):

wherein:

60

R is selected from: H and CH3;

61

R is phenyl optionally substituted with form one to five substituents independently selected from:

fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH, -CF3,

-Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN; and

62

R is selected from: H, methyl, -CF3, fluoro and chloro; and salts thereof.

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

Included in the presently invented compounds of Formula (X) are compounds of Formula (XIII):

R is selected from: H and CH3;

71

fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH, -CF3,

-Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN; and

72

R is selected from: H, methyl, -CF3, fluoro and chloro; and salts thereof. This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (XIII).

Included in the presently invented compounds of Formula (X) are compounds of

Formula (I):

wherein:

R is selected from:

bicycloheteroaryl,

substituted bicycloheteroaryl,

heteroaryl, and

substituted heteroaryl,

halo,

C-|-6alkyl,

C-|-4alkyloxy,

-OH,

hydroxyC-|-4alkyl,

-COOH,

tetrazole,

-CF₃,

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

-CON(H)Ci-3alkyl,

-CH₂CH₂N(H)C(0)OCH₂aryl,

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

-NO2,

-NH₂,

-N(H)Ci-3alkyl,

-N(Ci-3alkyl)₂, and

-CN;

2

R is selected from:

aryl,

aryl substituted with form one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH,

-CF₃, -Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN,

heteroaryl, and

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

-COOH, -CF₃, -Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN;

3

R is selected from:

-H,

-NH₂,

-OH,

-CN,

C-|-6alkyl, and

C-|-6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH, -CF₃, -Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN;

4

R is selected from:

-NH₂,

-N(H)Ci-3alkyl,

-N(Ci.₃alkyl)₂,

-OH,

Ci-6alkyl, and

5

R is selected from: C-|-6alkyl, and

R is selected from: H, fluoro, chloro, bromo and iodo;

or R5 and R6 are optionally taken together to form a 5 to 6 member saturated or unsaturated ring containing up to one other heteroatom selected from oxygen and nitrogen; and

R⁷ is selected from: H, fluoro, chloro, bromo and iodo; and salts thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (I). Included in the presently invented compounds of Formula (I) are compounds of Formula (II):

wherein:

R¹⁰ is selected from:

aryl,

-CF₃, -Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN,

heteroaryl, and

-COOH, -CF₃, -Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN;

11

R is selected from: H and CH3_;

12

R is selected from:

-NH₂,

-N(H)Ci.₃alkyl,

-N(Ci.₃alkyl)_2,

-OH,

Ci-6alkyl, and

C-|-6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF₃, -Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN; 13

R is selected from: H, fluoro and chloro; and

14

R is selected from: C-|-6alkyl, and

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

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

wherein:

20

R is selected from: H and CH3; _and

21

fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH, -CF3,

-Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN, and salts thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (III). Included in the presently invented compounds of Formula (I) are compounds of Formula (IV):

wherein:

30

R is selected from: H and CH3; _and

31

fluoro, chloro, bromo, iodo, C-|-4alkyl, C-|-4alkyloxy, -OH, -COOH, -CF3,

-Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN, and salts thereof.

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

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

1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-phenylpyrrolidin-

2-one;

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

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(2,5- difluorophenyl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(3- (trifluoromethyl)phenyl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)phenyl)-3-(2- (trifluoromethyl)phenyl)pyrrolidin-2-one;

1-(4-(4-amino-1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3- phenylpyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3- phenylpyrrolidin-2-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3- phenylpyrrolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-(^pyrimidin-5-yl)phenyl)-3-phenylpyrrolidin-

2-one;

1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrirTiidin-5-yl)phenyl)-3-(3,5- dimethylphenyl)pyrrolidin-2-one;

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

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-3-(rri- tolyl)pyrrolidin-2-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3-(3- fluorophenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)phenyl)-3-(3,5-difluoro phenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3-(3,5- difluorophenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)phenyl)-3-(2,3-difluoro phenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrirTiidin-5-yl)-3-fluorophenyl)-3-(2,3- difluorophenyl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrimidin-5-yl)-3-fluorophenyl)-3-(3,4- difluorophenyl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-<^pyrimidin-5-yl)-3-fluorophenyl)-3-(3,4- difluorophenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3-(2,5- difluorophenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrimidin-5-yl)-2-fluorophenyl)-3-(3,5- difluorophenyl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-3-fluorophenyl)-3-(3- (trifluoromethyl)phenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-<^pyrimidiri-5-yl)phenyl)-3-(3,5-dimethoxy phenyl)pyrrolidin-2-one;

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

1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-3-fluorophenyl)-3-(3- cyclopropylphenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-3-(2- methyl-1 H-indol-3-yl)pyrrolidin-2-one; 1-( -(4-amino-7-isopropyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-3-(3,5- difluorophenyl)pyrrolidin-2-one;

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

1-4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3- phenylpyrrolidin-2-one;

1-4-(4-amino-7-(1-methylpiperidin-4-yl)-7/-/-pyrrolo[2,3-d]pyrirriidiri-5-yl)-3- fluorophenyl)-3-(3,5-difluorophenyl)pyrrolidin-2-one;

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

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

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-(^pyrimidin-5-yl)phenyl)-3-(5-methylthiazol- 2-yl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-fluoropyridin-2- yl)pyrrolidin-2-one; 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(6-methylpyridin-

2- yl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrirTiidin-5-yl)phenyl)-3-(4,6- dimethylpyrimidin-2-yl)- pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-<^pyrimidiri-5-yl)phenyl)-3-(4,6-dimethyl pyridin-2-yl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrirTiidin-5-yl)phenyl)-3-(6- (trifluoromethyl) pyridin-2-yl)pyrrolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-3-(6- (trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-<^pyrimidiri-5-yl)phenyl)-3-(2,6-dimethyl pyrimidin-4-yl)pyrrolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)phenyl)-3-hydroxy-3-(6- (trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-<^pyrimidiri-5-yl)phenyl)-3-methoxy-3-(6- (trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one;

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

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-<^pyrimidiri-5-yl)phenyl)-3-(1/-/-indol-1- yl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-(^pyrimidin-5-yl)phenyl)-3-(3,5-dimethyl-1 H- pyrazol-1-yl)pyrrolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-(^pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)-

3- (3,5-difluorophenyl)pyrrolidin-2-one; and

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-<^pyrimidiri-5-yl)-3-methylphenyl)-3-(3,5- difluorophenyl)pyrrolidin-2-one; and salts thereof including pharmaceutically acceptable salts thereof.

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

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

2-one;

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

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

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

1-(4-(4-amino-1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3- phenylpyrrolidin-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 X may be prepared. Indeed, in certain embodiments of the invention, salts including pharmaceutically-acceptable salts of the compounds according to Formula X may be preferred over the respective free or unsatled compound. Accordingly, the invention is further directed to salts, including pharmaceutically-acceptable salts, of the compounds according to Formula X.

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

The compounds according to Formula X may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula X, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula X whether such tautomers exist in equilibrium or predominately in one form.

The compounds of Formula X or salts, including pharmaceutically acceptable salts, thereof may exist in solid or liquid form. 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 invention includes all such solvates.

The skilled artisan will further appreciate that certain compounds of Formula X 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. The invention includes all such polymorphs.

Definitions

"Alkyl" refers to a hydrocarbon chain having the specified number of "member atoms". For example, C-1-C4 alkyl refers to an alkyl group having from 1 to 4 member atoms.

Alkyl groups may be saturated, unsaturated, straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, ethylene, propyl (n-propyl and isopropyl), butene, and butyl (n-butyl, isobutyl, and t-butyl).

"Alkoxy" refers to an -O-alkyl group wherein "alkyl" is as defined herein. 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 11 member atoms. Bicycloheteroaryl includes: 1 /-/-pyrrolo[3,2-c]pyridine, 1 /-/-pyrazolo[4,3- c]pyridine, 1 H-pyrazolo[3,4-d]pyrimidine, 1 H-pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3- d]pyrimidine, thieno[3,2-c]pyridine, thieno[2,3-d]pyrimidine, furo[2,3-c]pyridine, furo[2,3- d]pyrimidine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5-c]pyridine, imidazo[4.5- b]pyridine, furopyridinyl and napthyridinyl.

Suitably "Bicycloheteroaryl" refers to two fused aromatic rings containing from 1 to 6 heteroatoms as member atoms. Bicycloheteroaryl groups containing more than one heteroatom may contain different heteroatoms. Bicycloheteroaryl rings have from 6 to 11 member atoms. Bicycloheteroaryl includes: 1 H-pyrazolo[3,4-d]pyrimidine, 1 H-pyrrolo[2,3- d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, thieno[3,2-c]pyridine, thieno[2,3-d]pyrimidine, furo[2,3-c]pyridine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5-c]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, 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.

"Cycloalkyi" refers to a saturated or unsaturated non aromatic hydrocarbon ring having from three to seven carbon atoms. Cycloalkyi groups are monocyclic ring systems. For example, C3-C7 cycloalkyi refers to a cycloalkyi group having from 3 to 7 member atoms.

Examples of cycloalkyi as used herein include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.

"Halo" refers to the halogen radicals fluoro, chloro, bromo, and iodo.

"Heteroaryl" refers to a monocyclic aromatic 4 to 8 member ring containing from 1 to 7 carbon atoms and containing from 1 to 4 heteroatoms, provided that when the number of carbon atoms is 3, the aromatic ring contains at least two heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl includes: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl. 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 11 are carbon atoms and from 1 to 6 are heteroatoms. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups are monocyclic ring systems or a monocyclic ring fused with an aryl ring or to a heteroaryl ring having from 3 to 6 member atoms. Heterocycloalkyl includes: pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, oxetanyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1 ,3- dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, 1 ,3oxazolidin-2-one, hexahydro-1 H-azepin, 4,5,6,7,tetrahydro-1 H-benzimidazol, piperidinyl, 1 ,2,3,6-tetrahydro-pyridinyl and azetidinyl.

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

"Pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

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

Ac (acetyl);

Ac₂0 (acetic anhydride);

ACN (acetonitrile);

AIBN (azobis(isobutyronitrile));

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

BMS (borane - dimethyl sulphide complex);

Bn (benzyl);

Boc (tert-Butoxycarbonyl);

Boc₂0 (di-terf-butyl dicarbonate);

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

CAN (cerric ammonium nitrate);

Cbz (benzyloxycarbonyl);

CSI (chlorosulfonyl isocyanate);

CSF (cesium fluoride);

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

DAST (Diethylamino)sulfur trifluoride);

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

DCC (Dicyclohexyl Carbodiimide);

DCE (1 ,2-dichloroethane);

DCM (dichloromethane);

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

ATP (adenosine triphosphate);

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

BSA (bovine serum albumin); C18 (refers to 18-carbon alkyl groups on silicon in HPLC stationary phase)

CH₃CN (acetonitrile) Cy (cyclohexyl);

DCM (dichloromethane);

DIPEA (HCinig's base, A/-ethyl-A/-(1-methylethyl)-2-propanamine);

Dioxane (1 ,4-dioxane);

DMAP (4-dimethylaminopyridine);

DME (1 ,2-dimethoxyethane);

DM EDA (Λ/,Λ/'-dimethylethylenediamine);

DMF (A/,A/-dimethylformamide);

DMSO (dimethylsulfoxide);

DPPA (diphenyl phosphoryl azide);

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

EDTA (ethylenediaminetetraacetic acid);

EtOAc (ethyl acetate);

EtOH (ethanol);

Et₂0 (diethyl ether);

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

HATU (0-(7-Azabenzotriazol-1-yl)-/V,/\/,/\/',/\/-tetramethyluronium hexafluorophosphate); HOAt (1-hydroxy-7-azabenzotriazole);

HOBt (1-hydroxybenzotriazole);

HOAc (acetic acid);

HPLC (high pressure liquid chromatography);

HMDS (hexamethyldisilazide);

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

I PA (isopropyl alcohol);

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

LAH (lithium aluminum hydride) ;

LDA (lithium diisopropylamide) ;

LHMDS (lithium hexamethyldisilazide)

MeOH (methanol);

MTBE (methyl tert-butyl ether);

mCPBA (m-chloroperbezoic acid);

NaHMDS (sodium hexamethyldisilazide);

NBS (/V-bromosuccinimide);

PE (petroleum ether);

Pd₂(dba)₃ (Tris(dibenzylideneacetone)dipalladium(O);

Pd(dppf)CI₂.DCM Complex([1 ,1 '-

Bis(diphenylphosphino)ferrocene]dichloropalladium(ll).dichloromethane complex); PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate); PyBrOP (bromotripyrrolidinophosphonium hexafluorophosphate);

RPHPLC (reverse phase high pressure liquid chromatography);

RT (room temperature);

Sat. (saturated)

SFC (supercritical fluid chromatography);

SGC (silica gel chromatography);

SM (starting material);

TCL (thin layer chromatography);

TEA (triethylamine);

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

TFA (trifluoroacetic acid); and

THF (tetrahydrofuran). All references to ether are to diethyl ether and brine refers to a saturated aqueous solution of NaCI.

Compound Preparation

The compounds according to Formula X are prepared using conventional organic synthetic methods. A suitable synthetic route is depicted below in the following general reaction schemes.

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 Wley & 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.

Compounds of the invention were prepared according to Scheme 1. 2-aryl-4- pentenoic acids B were prepared by alkylation of an arylacetic acid A dianion with allyl bromide according to a reported procedure (Organic Letters, 2009, 17, 3858, supplementary material p26). Reaction of the 2-aryl-petenoic acid B with substituted 4- bromoaniline and a coupling reagent to form an amide bond, such as HATU, afforded the pentenamide C. The pentenamide C was then cyclized to the pyrrolidinone ring using a two step process. The alkene was first oxidized with Nal0₄ and catalytic Os0₄ to the hydroxypyrrolidinone D, which was reduced with triethylsilane and TFA to give the pyrrolidinone E. After conversion to the boronate ester F, palladium catalyzed Suzuki- Miyaura reaction with the bicycloheteroaryl bromide G produced the compound H, which represents the structure of the compounds of the invention. Scheme 1

yl-4-yl-piperidine

Compounds of the invention substituted at the 3-position of the pyrrolidinone were prepared according to Scheme 2. The aryl pyrrolidinone E was deprotonated with a strong base (LDA or LHMDS) and alkylated with a suitable electrophile, such as an alkyl halide to give I, which was then converted to the boronate ester J. The Suzuki-Miyaura coupling of J with the bicycloheteroaryl bromide G afforded the compounds of the invention represented by the structure K.

Scheme 2

X = CH, N In another invention of the compounds substituted at the 3-position of the pyrrolidinone were prepared according to Scheme 3. Pyrrolidinone L was /V-alkylated with suitable aryl halide L1 using the reported literature (Tetrahedron Letters, 50, 7293-7296; 2009 ) to give /V-arylpyrrolidinone M. The aryl pyrrolidinone M was deprotonated with a strong base (NaHMDS or LiHMDS or LDA) and alkylated with a suitable electrophile, such as an aryl or heteroaryl halide according to the reported literature (Organic Letters, 8(7), 1447- 1450; 2006) to give E or N. Compound N was O alkylated using base such as NaH and methyl iodide to give compound O. Pyrrolidinone compound E or O were then converted to the boronate ester P or F. The Suzuki-Miyaura coupling of P or F with the bicycloheteroaryl bromide G afforded the compounds of the invention represented by the structure Q.

Scheme 3

Compounds of the invention represented by structure U were prepared according to Scheme 4. Deprotonation of methylarylacetate R using strong base such as LDA or BuLi followed by reacting with bromoacetonitrile provided compound S, which was hydrogenated using Raney-Ni or Pd/C in presence of hydrogen to give pyrrolidinone compound T. /V-arylation of T was performed using L1 following reported literature (Tetrahedron Letters, 50, 7293-7296; 2009 ) to give /V-arylpyrrolidinone E, which was then converted to the boronate ester F. The Suzuki-Miyaura coupling of F with the bicycloheteroaryl bromide G1 afforded the compounds of the invention represented by the structure U.

Scheme 4

X = CH, N

XI = H, F

X3 = S, NMe Compounds of the invention substituted at the 3-position of the pyrrolidinone were prepared according to Scheme 5. Lactone V was reacted with PBr3, Br2 followed by thionylchloride at ambient to elevated temperature followed by addition of base such as triethylamine and substituted aniline V1 to give compound W, which was further treated with base such as NaH to give 3-bromopyrrolidinone X. In some cases of the present invention, reaction was performed in situ to give compound X using potassium phosphate and sodium hydroxide instead of NaH and without isolating W. Nucleophilic displacement of 3-bromopyrrolidinone X with heterocycles using bases such as sodium hydride afforded 3-substituted pyrrolidinone Y, which was then converted to the boronate ester Y1. The Suzuki-Miyaura coupling of Y1 with the bicycloheteroaryl bromide G afforded the compounds of the invention represented by the structure Z.

Scheme 5

Methods of Use

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

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

Suitably the present invention relates to a method for treating or lessening the severity of skin cancer, including melanoma, including metastatic melanoma.

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

Suitably the present invention relates to a method for treating or lessening the severity of cancers selected from the group consisting of brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer. Suitably the present invention relates to a method for treating or lessening the severity of pre-cancerous syndromes in a mammal, including a human, wherein the precancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplasia syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.

Suitably the present invention relates to a method for treating or lessening the severity of neurodegenerative diseases, such as Alzheimer's disease, stroke, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, and other diseases associated with UPR activation including: diabetes, myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias.

The compounds of this invention inhibit angiogenesis which is implicated in the treatment of ocular diseases. Nature Reviews Drug Discovery 4, 71 1-712 (September 2005). 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 X or a pharmaceutically acceptable salt, thereof to a patient in need thereof.

The invention also provides a compound according to Formula X or a pharmaceutically-acceptable salt thereof for use in medical therapy, and particularly in cancer therapy. Thus, in further aspect, the invention is directed to the use of a compound according to Formula X or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disorder characterized by activation of the UPR, such as cancer.

By the term "treating" and derivatives thereof as used herein, is meant prophylactic and therapeutic therapy. Prophylactic therapy is appropriate, for example, when a subject has a strong family history of cancer or is otherwise considered at high risk for developing cancer, or when a subject has been exposed to a carcinogen.

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

The compounds of Formula X or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. 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 X 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 X and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of cancer or pre-cancerous syndromes.

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 & Wlkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism. Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented PERK inhibiting compounds are chemotherapeutic agents.

Suitably, the pharmaceutically active compounds of the invention are used in combination with a VEGFR inhibitor, suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt thereof, which is disclosed and claimed in in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001 , International Publication Number WO02/0591 10 and an International Publication date of August 1 , 2002, the entire disclosure of which is hereby incorporated by reference, and which is the compound of Example 69. 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide can be prepared as described in International Application No. PCT/U S01/49367.

Suitably, 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide is in the form of a monohydrochloride salt. This salt form can be prepared by one of skill in the art from the description in International Application No. PCT/U S01/49367, having an International filing date of December 19, 2001.

5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide is sold commercially as the monohydrochloride salt and is known by the generic name pazopanib and the trade name Votrient^®.

Pazopanib is implicated in the treatment of cancer and ocular diseases/angiogenesis. Suitably the present invention relates to the treatment of cancer and ocular diseases/angiogenesis, suitably age-related macular degeneration, which method comprises the administration of a compound of Formula (I) alone or in combination with pazopanib.

In one embodiment, the cancer treatment method of the claimed invention includes the co-administration a compound of Formula (X) and/or a pharmaceutically acceptable salt thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.

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 (X) or a pharmaceutically acceptable salt thereof. The compounds of Formula (X) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as PERK inhibitors. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral. 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. Oral administration, which uses lower dosages, is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.

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

The method of this invention of inducing PERK inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective PERK inhibiting amount of a pharmaceutically active compound of the present invention.

The invention also provides for the use of a compound of Formula (X) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as a PERK inhibitor.

The invention also provides for the use of a compound of Formula (X) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in therapy. The invention also provides for the use of a compound of Formula (X) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating neurodegenerative diseases. The invention also provides for the use of a compound of Formula (X) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating cancer.

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

The invention also provides for a pharmaceutical composition for use in the treatment of cancer which comprises a compound of Formula (X) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat cancer, or compounds known to have utility when used in combination with a PERK inhibitor.

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-pyrrolo[2,3-c/]pyrimidin-5-yl)phenyl)-3-phenylpyrroli

one

To a stirred solution of phenylacetic acid (3.0 g, 22.03 mmol) in THF (70 mL) cooled in a dry ice/acetone bath under nitrogen (-60 °C, internal temp) was added 2.5M nBuLi solution (19.4 mL, 48.5 mmol, 2.2 equiv) drop wise over a period of 10 minutes. The first 10 mL was added at -50 to -60 °C. The initial clear solution turned into a white milky mixture. The second 9.4 mL was added at about -60 °C, and the mixture became slightly yellowish and stayed milky. After completion of the nBuLi addition, the cooling bath was removed. The mixture was warmed gradually. After 20 min, the internal temp reached -10 °C and the mixture became a clear and slightly yellow solution. After another 30 min, the temp reached 5 °C and the mixture returned to a milky texture. Allyl bromide (6 mL, 69.3 mmol, 3.2 equiv) was added in one portion. The temp rose to 22 °C and the mixture became a clear solution again. After an additional 30 minutes the mixture became milky. After 16 hours, the milky mixture was diluted with 20 mL of 1 N HCI and extracted with ethyl ether (200 mL, and 100 mL). The combined organic layers were dried over MgS0₄, filtered, and concentrated in vacuo to give 2-pheyl-4-pentenoic acid as a light yellowish oil (3.80 g). LC-MS (ES) m/z = 177 [M+H]⁺, 131 [M-46]⁺. H NMR (400 MHz, CDCI₃) δ ppm 2.50 - 2.61 (m, 1 H), 2.80 - 2.92 (m, 1 H), 3.64 - 3.71 (m, 1 H), 5.04 (dd, J=10.1 , 1.8 Hz, 1 H), 5.07 - 5.16 (m, 1 H), 5.75 (m, 1 H), 7.26 - 7.40 (m, 5 H).

Run 1

To a stirred solution of 2-pheyl-4-pentenoic acid (0.5 g, 2.84 mmol) and 4-bromoaniline (513 mg, 2.98 mmol, 1.05 equiv) in 3 ml of DCM at room temperature was added DIPEA (0.55 mL, 3.12 mmol, 1.1 equiv), followed by HATU (1.19 g, 3.12 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred at room temperature 20 minutes. The suspension was filtered, and the cake was washed with DCM. LCMS showed the desired product was in the filtrate fraction.

Run 2

To a stirred solution of 2-pheyl-4-pentenoic acid (3.62 g, 20.54 mmol) and 4-bromoaniline (3.53 g, 2.0.54 mmol, 1. equiv) in 30 ml of DCM at room temperature was added DIPEA (3.95 mL, 22.6 mmol, 1.1 equiv), followed by HATU (8.59 g, 22.60 mmol, 1.1 equiv) in one portion. The resulting suspension (slightly warm to touch) was stirred at room temperature for 20 minutes. The suspension was filtered, and the cake was washed with DCM. The DCM filtrate (combined with the DCM filtrate from run 1 above, total 150 mL) was washed with 1 N HCI (2x 40 mL), dried over MgS04, filtered, and concentrated in vacuo. The solid residue was triturated in DCM as a suspension, followed by filtration. The cake was washed with DCM (4 mL) and dried under vacuum to give N-(4-bromophenyl)-2-phenyl-4- pentenamide (2.26 g) as off-white solids. LC-MS (ES) m/z = 330.1 , 332.1 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ ppm 2.55 - 2.67 (m, 1 H), 2.96 - 3.07 (m, 1 H), 3.53 - 3.62 (m, 1 H), 5.03 (dd, J=10.1 , 1.8 Hz, 1 H), 5.06 - 5.16 (m, 1 H), 5.77 (m, 1 H), 7.06 (br.s, 1 H), 7.31 - 7.45 (m, 9 H).

The filtrate was absorbed onto a dryload silica gel cartridge. Purification was attempted on an 80 g silica gel cartridge using gradient elution of 1 % EtOAc in hexane to 25% EtOAc in hexane. However, because of precipitation, the instrument's tubing clogged when the product was eluting. Therefore the desired product was only partially recovered. The collected fractions with pure product were combined and concentrated in vacuo. The residue was taken up in DCM and then diluted with hexane to give a suspension, which was filtered. The cake was washed with hexane and dried under vacuum to give N-(4- bromophenyl)-2-phenyl-4-pentenamide (1.55 g) as white solids.

To N-(4-bromophenyl)-2-phenyl-4-pentenamide (1 g, 3.03 mmol) in a mixture of THF (50 mL) and water (10 mL) was added 2.5 wt% osmium tetroxide solution in t-BuOH (3.80 mL, 0.303 mmol) followed by sodium periodate (1.295 g, 6.06 mmol), and the reaction mixture was stirred at room temperature for 3 hours. An aqueous solution of sodium thiosulfate was added, and the resulting mixture was stirred for 10 minutes. The mixture was poured onto EtOAc and saturated aqueous NaHC0₃. The organic layer was separated, washed with brine, dried (MgS0₄), filtered and concentrated to afford a sticky thick oil-foam. LCMS analysis indicated the presence of desired product and the diol intermediate. This material was dissolved in a mixture of THF (50 ml_) and Water (10 ml_) and treated with sodium periodate (1.295 g, 6.06 mmol). The resulting mixture was stirred for 3 hours at room temperature. An aqueous solution of sodium thiosulfate was added, and the resulting mixture was stirred for 10 minutes. The mixture was poured onto EtOAc and saturated aqueous NaHC0₃. The organic layer was separated, washed with brine, dried (MgS0₄), filtered and concentrated to afford the crude product 1-(4-bromophenyl)-5-hydroxy-3- phenyl-2-pyrrolidinone (930 mg) as a white foam as a mixture of stereoisomers. This material was used as such in the next step.

To 1-(4-bromophenyl)-5-hydroxy-3-phenyl-2-pyrrolidinone (930 mg) in dichloromethane (DCM) (30 ml_) was added triethylsilane (1.789 ml_, 11.20 mmol) followed by TFA (4.31 ml_, 56.0 mmol), and the reaction mixture was stirred for 3 hours at room temperature. The reaction was poured onto saturated aqueous NaHC0₃ and EtOAc. The organic layer was separated, washed with brine, dried (MgS0₄), filtered and concentrated to afford the crude desired product as a yellow solid. This material was dissolved in hot EtOAc (~6 ml_) and treated with Hexanes (-12 ml_). A glassy material was observed at the bottom of the flask. A spatula was used to rub the bottom of the flask, and a solid started to form. The mixture was sonicated, and the white precipitate was filtered and washed with hexanes to afford the desired product (375 mg) as a white solid. LCMS (ES) m/z = 316.0, 319.0 [M+H]⁺.

To a mixture of 1-(4-bromophenyl)-3-phenyl-2-pyrrolidinone (100 mg, 0.316 mmol), bis(pinacolato)diboron (80 mg, 0.316 mmol), and potassium acetate (93 mg, 0.949 mmol) was added 1 ,4-dioxane (6 mL), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (12.91 mg, 0.016 mmol) was added, and the reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled down to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (71.8 mg, 0.316 mmol) and saturated aqueous NaHC0₃ (2 ml_) were added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl2(dppf)-CH₂Cl2 adduct (12.91 mg, 0.016 mmol) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The mixture was poured onto water and a precipitate formed. The mixture was filtered, and the solid was taken up into a mixture of 20% CH₃OH/CH2CI2, and injected into a 40 g Si0₂ column, and purified via flash chromatography (gradient: 100% Hexanes to 100% EtOAc to 20% CH₃OH/EtOAc). The fractions containing the desired product were combined and concentrated to afford a yellow solid. This material was dissolved into 2 ml_ of DMSO and purified via HPLC (gradient (0.1 % TFA): 15%CH₃CN/H₂0 to 40%CH₃CN/H₂O). The fractions containing the desired product were combined and concentrated under vacuum to remove most of the CH₃CN. The remaining aqueous solution was freeze dried to afford a TFA salt of the 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3- d]pyrimidin-5-yl)phenyl)-3-phenylpyrrolidin-2-one (17 mg) as a white solid. LCMS (ES) m/z = 384.3 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.14 - 2.30 (m, 1 H), 2.57 - 2.73 (m, 1 H), 3.85 (s, 3 H), 3.93 - 4.07 (m, 3H), 7.23 - 7.44 (m, 5 H), 7.51 (d, J=8.59 Hz, 2 H), 7.60 (s, 1 H), 7.87 (d, J=8.59 Hz, 2 H), 8.43 (s,1 H).

Example 2

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

Method 1 (LHMDS as base)

To a mixture of 1 M LiHMDS in toluene (0.156 ml_, 0.156 mmol) and THF (2 ml_) cooled in a dry-ice acetone bath under nitrogen was added 1-(4-bromophenyl)-3-phenyl-2- pyrrolidinone (38 mg, 0.120 mmol) drop wise. After 30 minutes, iodomethane (9.02 μΙ_, 0.144 mmol) was added and the mixture was allowed to slowly warm to room temperature. After 2hr LCMS showed only product and the reaction was quenched with water and extracted with EtOAc (3 x 5 ml_). The combined organic layers were washed with sat. NaCI solution, dried over MgS0₄, filtered and concentrated. The residue was loaded on to a 10g Biotage SNAp column and purified with 0 to 40% EtOAc in Hexane over 30 min gradient to give 1-(4-bromophenyl)-3-methyl-3-phenyl-2-pyrrolidinone (21 mg, 0.064 mmol, 52.9 % yield) as a clear oil.

Method 2 (LDA as base)

To diisopropylamine (0.022 ml_, 0.152 mmol) in 2 ml_ of THF cooled to -78 °C under nitrogen was slowly added 0.5 M nBuLi in hexanes (0.304 ml_, 0.152 mmol). The solution was allowed to stir for 15 minutes then added by dropwise to a premixed solution of 1-(4- bromophenyl)-3-phenyl-2-pyrrolidinone (40 mg, 0.127 mmol) in 2ml of THF. The base solution turned from clear to light yellowish color. After 15min iodomethane (0.012 ml_, 0.190 mmol) was added in one portion. The solution was allowed to warm to room temperature, and after 1 hour the reaction was checked by LCMS and only product was observed. The reaction was quenched with water then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with sat. NaCI solution, dried over MgS0₄, filtered and concentrated. The residue was loaded onto a 10g Biotage SNAP column and purified with 0 to 45% EtOAc in Hexane over 30 min gradient to isolate 1-(4- bromophenyl)-3-methyl-3-phenyl-2-pyrrolidinone (35 mg) as a clear oil. LCMS (ES) m/z = 330.2, 332.2 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ

1.66 (s, 3 H), 2.31 (dt, J=8.09, 12.88 Hz, 1 H), 2.63 (ddd, J=3.79, 6.82, 12.88 Hz, 1 H), 3.68 - 3.81 (m, 2 H), 7.25 - 7.30 (m, 1 H), 7.33 - 7.39 (m, 2 H), 7.41 - 7.46 (m, 2 H), 7.53 (m, 2 H), 7.60 - 7.65 (m, 2 H),

To 1-(4-bromophenyl)-3-methyl-3-phenyl-2-pyrrolidinone (56 mg, 0.170 mmol) were added bis(pinacolato)diboron (51.7 mg, 0.204 mmol) and ammonium acetate (39.2 mg, 0.509 mmol) into a 5 mL sealable vial then 1 ,4-Dioxane (2 mL) was added. The mixture was then bubbled with N₂ for 5 minutes then PdCl₂(dppf)-CH₂Cl₂ adduct (13.85 mg, 0.017 mmol) was added. The mixture was capped and heated at 85 °C overnight. To the reaction were then added 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (42.4 mg, 0.187 mmol), PdCI₂(dppf)-CH₂Cl₂ adduct (13.85 mg, 0.017 mmol) and 2M K₂C0₃ (1 mL). The reaction was then capped and heated at 100 °C overnight. The reaction was diluted with water (2 mL) and extracted with EtOAc (3x3 mL). The organics were combined, washed with saturated NaCI, and filtered. The mixture was concentrated then dissolved in 3mL of DMSO and then purified on HPLC: (HPLC condition: open-access Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50 ^χ 30.00 mm 5 micron. 7.3-minute run (47ml_/min, 15% ACN/H₂0, 0.1 % TFA to 40% ACN/H₂0, 0.1 % TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the ACN. The remaining aqueous solution was treated with saturated NaHC03 and then extracted with EtOAc (3 x 15ml_). The organic was combined wash with saturated NaCI solution, dried over MgS04, filtered and concentrated. Then residue was dissolved in aqueous acetonitrile and freeze-dried to give 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3- d]pyrimidin-5-yl)phenyl)-3-methyl-3-phenylpyrrolidin-2-one (6 mg). LCMS (ES) m/z = 398.4 [M+H]⁺. H NMR (400 MHz, DMSOc/6) δ

1.55 (s, 3 H), 2.25 - 2.36 (m, 2 H), 2.54 - 2.59 (m, 1 H), 3.75 (s, 3 H), 3.92 (td, J=4.04, 8.97 Hz, 1 H), 6.06 (br s., 2 H), 7.25 - 7.30 (m, 1 H), 7.37 (t, J=7.71 Hz, 2 H), 7.47 (dd, J=8.21 , 10.99 Hz, 4 H), 7.84 (d, J=8.59 Hz, 2 H), 8.16 (s, 1 H).

Example 3

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3- lpyrimidin-5-yl)phenyl)-3-(2,5- difluorophenyl)pyrrolidin-2-one

To a stirred solution of (2,5-difluorophenyl)acetic acid (4.77 g, 27.7 mmol) in THF (100 mL) cooled in a dryice/acetone bath under nitrogen (-60 °C, internal temperature) was added 2.5M nBuLi solution (24.4 mL, 61.0 mmol, 2.2 equiv) portionwise over a period of 10 minutes such that the temperature of the mixture stayed between -50 to -60 °C. After completion of nBuLi addition, the cooling bath was removed. The brownish but clear mixture was warmed gradually. After15 min, the temp reached -10 °C. Allyl bromide (7.67 mL, 89 mmol, 3.2 equiv.) was added in one portion. The internal temperature rose to 10 °C and the mixture became a light yellow but clear solution. After 1 hour at ambient temperature, the mixture was diluted with 40 mL of 1 N HCI and extracted with ethyl ether (200 mL). The organic was dried over MgS0₄, filtered, and concentrated in vacuo to provide 2-(2,5-difluorophenyl)-4-pentenoic acid as a light yellow liquid (5.80 g). LCMS. LC-MS (ES) m/z = 213 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ 2.43 - 2.50 (m, 1 H), 2.72 - 2.79 (m, 1 H), 3.88 (t, J=7.7 Hz, 1 H), 1 H), 4.90 - 5.06 (m, 2 H), 5.64 - 5.74 (m, 1 H),7.09 - 7.31 (m, 3 H), 12.69 (brs., 1 H).

To a stirred solution of 2-(2,5-difluorophenyl)-4-pentenoic acid (5.80 g, 27.3 mmol) and 4- bromoaniline (4.70 g, 27.3 mmol, 1 equiv) in 40 mL of DCM chilled in an ice bath was added DIPEA (5.25 mL, 30.1 mmol, Hequiv), followed by HATU (11.43 g, 30.1 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred when being chilled in the ice bath. After 1 hour, LCMS showed conversion complete. The mixture was filtered. The filtrate was diluted with DCM (up to 150 mL) and washed with 1 N HCI (2 x 30 mL). The organic was dried over MgS0₄, filtered, and concentrated in vacuo. The residue was taken up in DCM and hexane as a bilayer mixture. The top solvent layer was decanted. The bottom layer was triturated in MTBE to give a suspension, which was filtered. The solids were not product by LCMS and discarded. The filtrate, which contained the desired product by LCMS, was concentrated in vacuo and then dissolved in 10 mL of DCM, and stored in a refigerator for 18 hours. Some crystals formed which were collected by filtration and washed with MTBE and dried under vacuum to give A/-(4-bromophenyl)-2- (2,5-difluorophenyl)-3-butenamide (1.81 g) as white chunks. LCMS showed this sample was pure. NMR showed an aromatic impurity present (originated from HATU). This material could be used in the next step. The filtrate was concentrated in vacuo and re- dissolved in DCM and absorbed onto 2 dry load silica gel cartridges. Purification was carried out on a RS-90 g silica gel cartridge using gradient elution of 1 % EtOAc in CHCI₃ to 30% EtOAc in CHCI₃. The desired product eluted near solvent front. The collected fractions were combined and concentrated in vacuo. The solid residue was triturated in DCM and hexane to give a suspension. Filtration and drying under vacuum provided Λ/-(4- bromophenyl)-2-(2,5-difluorophenyl)-3-butenamide (4.04 g) as white solids. LC-MS (ES) m/z = 368 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.45 - 2.56 (m, 1 H), 2.70 - 2.83 (m, 1 H), 4.05 - 4.14 (m, 1 H), 5.01 (dd, J=10.2, 1.9 Hz, 1 H), 5.09 (dd, J=17.1 , 1.9 Hz, 1 H), 5.69 - 5.79 (m, 1 H), 7.12 - 7.21 (m, 1 H), 7.21 - 7.30 (m, 1 H),7.34 (ddd, J=9.4, 5.9, 3.2 Hz, 1 H), 7.48 (d, J=9.1 Hz, 2 H), 7.57 (d, J=8.8 Hz, 2 H), 10.37 (s, 1 H).

To a solution of A/-(4-bromophenyl)-2-(2,5-difluorophenyl)-3-butenamide (5.3 g, 14.47 mmol) in THF (30 mL) and water (6 mL) at room temperature was added potassium osmate dihydrate (267 mg, 0.72 mmol, 0.05 equiv). The mixture was chilled in an ice bath. To this chilled mixture was added Nal0₄ (8.05 g, 37.6 mmol, 2.6 equiv) portionwise over a period of 5 minutes. Since the mixture thickened during the addition, additional THF (20 mL) and water (4 mL) were added to facilitate stirring. Upon completion of Nal0₄ addition, the ice bath was removed. The brownish suspension/paste was stirred at ambient temperature. However, after 15 min, the mixture became warm again. The mixture was re-cooled in the ice bath for another 15 min, and then removed. The mixture (now all white) was stirred for 6 hours. LCMS showed conversion complete, so the mixture was chilled in an ice bath and then 40 mL of 1 N sodium thiosulfate solution was added. After stirring for 10 min, the suspension was filtered. The cake was washed with water (250 mL) and some EtOAc (100 mL). The filtrate was extracted with EtOAc (2 x 200 mL). The organic was dried over Na₂S0₄, filtered, and concentrated in vacuo. The glass-like foamy residue was pumped under vacuum for 1 hour to give 5.68 g of a foam. LCMS showed it was a mixture of of hydroxypyrrolidinone diastereomers in 28:44 ratio by UV. The foam was taken up in 20 mL of DCM and 10 mL of TFA, and then treated with triethylsilane (9.22 mL, 57.9 mmol, 4 equiv). The mixture (pale yellow clear solution) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was dissolved in CHCI₃ and absorbed onto 4 x 90 g dryload silica gel cartridges (equal portions). Purification eluting with 1 % A in hexane to 60% A in hexane (A was a mixture of 2/1 CHCI₃/EtOAc) with flow rate at 50 mL/min. The desired product eluted from 41-48% A. The combined fractions containing pure product were concentrated in vacuo and dried under vacuum to give 1-(4-bromophenyl)-3-(2,5-difluorophenyl)-2-pyrrolidinone (3.18 g) as beige solids. LC-MS (ES) m/z = 354 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ ppm 2.12 - 2.27 (m, 1 H), 2.52 - 2.61 (m, 1 H), 3.83 - 4.01 (m, 2 H), 4.19 (dd, J = 10.7, 9.2 Hz, 1 H), 7.16 - 7.24 (m, 1 H),7.25 - 7.36 (m, 2 H), 7.55 - 7.63 (m, 2 H), 7.65 - 7.75 (m, 2 H).

A mixture of 1-(4-bromophenyl)-3-(2,5-difluorophenyl)-2-pyrrolidinone (1.62 g, 4.60 mmol), bis(pinacolato)diboron (1.40 g, 5.52 mmol, 1.2 equiv), potassium acetate (1.13 g, 11.5 mmol, 2.5 equiv) and PdCl₂(dppf)-CH₂Cl₂ adduct (376 mg, 0.46 mmol, 0.1 equiv) in 20 mL of 1 ,4-dioxane was degassed and backflushed with nitrogen (repeated 4x) and heated in an oil bath at 100 °C. After 18 hours, LCMS showed conversion complete. The mixture was filtered through Celite. The filtrate was concentrated in vacuo. The residue was taken up between EtOAc (100 mL) and brine (30 mL), followed by filtration through Celite again. The filtrate was phase separated. The organic was dried over Na₂S0₄, filtered, and concentrated in vacuo. The residue was dissolved in DCM and absorbed onto a dryload silica gel cartridge. Purification was done on an SF25-40 g silica gel cartridge using gradient elution of 10% A in hexane to 100% A (A was a mixture of 2/1 CHCI₃/EtOAc). The desired product eluted from 44-60% A. The collected fractions with pure product were combined and concentrated in vacuo to afford 3-(2,5-difluorophenyl)-1-[4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-2-pyrrolidinone (1.43 g) as light tan-colored solids. LC-MS (ES) m/z = 400 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 1.30 (s, 12 H), 2.21 (t, J=10.4 Hz, 1 H), 2.47 - 2.62 (m, 1 H), 3.85 - 4.04 (m, 2 H), 4.21 (t, J=10.0 Hz, 1 H), 7.15 - 7.24 (m, 1 H), 7.25 - 7.38 (m, 2 H), 7.64 - 7.82 (m, 4 H).

A mixture of 5-bromo-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-4-amine (0.41 g, 1.80 mmol, 1 equiv), 3-(2,5-difluorophenyl)-1-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-2- pyrrolidinone (0.72 g, 1.80 mmol, 1 equiv), Pd₂(dba)₃ (83 mg, 0.09 mmol, 0.05 equiv) and K₃PC (0.83 g, 3.61 mmol, 2.0 equiv) in 10 mL of dioxane and 3.3 mL of water in a 20 mL microwave vial was bubbled with argon for 10 min, followed by addition of tri-(t- butyl)phosphonium tetrafluoroborate (52 mg, 0.18 mmol, 0.1 equiv). The mixture was capped and heated at 100 °C. After 18 h, LCMS showed conversion complete. The mixture was cooled to room temperature, which became a bilayer. The top organic layer was pipetted off and filtered through a filter paper. The filtrate was concentrated in vacuo. The residue was taken up in water (40 mL) as a suspension, which was filtered. The cake was washed with water and dried under house vacuum at room temperature for 18 hour, and then washed with ether and dried to afford crude product. The solid was dissolved in 30 mL of 10% MeOH in DCM, followed by filtration. The filtrate was absorbed onto a dryload silica gel cartridge. Purification was done on SF40-115 g silica gel cartridge using gradient elution of 1 % A to 60% A in CHCI3 (A was a mixture of 3200/800/80 CHCI₃/MeOH/NH₄OH). The desired product eluted from 25-30% A. The combined fractions with pure product were concentrated in vacuo. The residue was redissolved in 10% MeOH in CHCI₃, followed by filtration. The filtrate was concentrated in vacuo. The residue was taken up in 2 mL of CHCI₃ and 8 mL of MTBE. However, the resulting paste could not be filtered. The mixture was redissolved in 10% MeOH in CHCI₃ (40 mL) and concentrated in vacuo to about 1/4 of the original volume (10 mL). To the suspension was added MTBE (15 mL). The mixture was concentrated in vacuo to about half volume. To the suspension was added another 15 mL of MTBE, followed by filtration. The cake was washed with MTBE (2 x 5 mL) and hexane (2 x 4 mL), and then dried under vacuum at 65 °C for 18 h to afford 1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(2,5- difluorophenyl)pyrrolidin-2-one (500 mg) as beige solids. LC-MS (ES) m/z = 420 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.15 - 2.29 (m, 1 H), 2.54 - 2.64 (m, 1 H), 3.75 (s, 3 H), 3.95 - 4.05 (m, 2 H), 4.21 (t, J=10.0 Hz, 1 H), 5.95 - 6.20 (br s, 1.4 H), 7.15 - 7.26 (m, 1 H), 7.26 - 7.36 (m, 3 H), 7.49 (d, J=8.6 Hz, 2 H), 7.82 (d, J=8.8 Hz, 2 H), 8.16 (s, 1 H).

Example 4

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3- lpyrimidin-5-yl)phenyl)-3-(3- (trifluoromethyl)phenyl)pyrrolidin-2-one

To a stirred solution of [3-(trifluoromethyl)phenyl]acetic acid (5.0 g, 24.49 mmol) in THF (100 mL) cooled in a dryice/acetone bath under nitrogen (-60°C, internal temp) was added 2.5M nBuLi solution (21.6 mL, 53.9 mmol, 2.2 equiv) portionwise over a period of 10 min such that the temp of the mixture stayed around -50 to -60 °C. After completion of nBuLi addition, the cooling bath was removed. The brownish but clear mixture was warmed gradually. After 20 minutes, the temp reached -10 °C. Allyl bromide (6.78 mL, 78 mmol, 3.2 equiv) was added in one portion. The internal temperature rose to 10 °C and the mixture became a light yellow but clear solution. After 30 min, LCMS showed conversion complete. The mixture was mixed with 35 mL of 1 N HCI, and extracted with ethyl ether (200 mL). The organic was dried over MgS0₄, filtered, and concentrated in vacuo to give 2-[3-(trifluoromethyl)phenyl]-4-pentenoic acid as a light yellowish liquid (5.80 g). LC-MS (ES) m/z = 245 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.41 - 2.49 (m, 1 H), 2.65 - 2.83 (m, 1 H), 3.82 (t, J=7.7 Hz, 1 H), 4.91 - 5.1 1 (m, 1 H), 5.65 - 5.75 (m, 1 H), 7.51 -7.72 (m, 4 H), 12.61 (br s, 1 H).

To a stirred solution of 2-[3-(trifluoromethyl)phenyl]-4-pentenoic acid (5.80 g, 23.75 mmol) and 4-bromoaniline (4.09 g, 23.75 mmol, 1. equiv) in 30 ml of DCM chilled in an ice bath was added DIPEA (4.56 mL, 26.1 mmol, 1.1 equiv), followed by HATU (9.93 g, 26.1 mmol, 1.1 equiv) in one portion. The resulting suspension (yellowish mixture, mostly a clear solution with a few solids) was stirred being chilled in the ice bath. After 1 hour, the cold suspension was filtered. The solid, which by LCMS contained no desired product, was discarded. The DCM filtrate was washed with 2 x 30 mL of 1 N HCI. the organic was dried over MgS0₄, filtered, and concentrated in vacuo. The residue was triturated with DCM (5 mL) and hexane (30 mL) to give a suspension, which was filtered. The filtrate was concentrated in vacuo. The residue was dissolved in CHCI₃ and absorbed onto 2 dryload silica gel cartridges (in equal portions). Purification was done on an SF40-80 g silica gel cartridge using gradient elution of 1 % EtOAc in CHCI₃ to 30 % EtOAc in CHCI₃. The product eluted near the solvent front (1 % EtOAc). The pure product fractions were combined and concentrated in vacuo to give A/-(4-bromophenyl)-2-[3- (trifluoromethyl)phenyl]-4-pentenamide (5.54 g) as alight yellowish thick oil/gel, which solidified upon prolonged drying to give a beige solid. LC-MS (ES) m/z = 398, 400 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ 2.45 - 2.54 (m, 1 H), 2.78 - 2.88 (m, 1 H), 3.90 (dd, J=8.6, 6.6 Hz, 1 H), 5.00 (dd, J=10.2, 1.9 Hz, 1 H), 5.09 (dd,J=17.2, 2.0 Hz, 1 H), 5.68 - 5.78 (m, 1 H), 7.45 - 7.50 (m, 2 H), 7.52 - 7.56(m, 2 H), 7.57 - 7.67 (m, 2 H), 7.68 - 7.76 (m, 2 H), 10.35 (s, 1 H). The solidified product was taken up in DCM (5 mL) and hexane (15mL) to give a suspension, which was filtered. The solids were collected and dried under vacuum to give A/-(4-bromophenyl)-2-[3-(trifluoromethyl)phenyl]-4- pentenamide (3.16 g, 57% recovery) as white solids. A second crop was obtained (1.41 g, 25% recovery) as white solids.

To a solution of A/-(4-bromophenyl)-2-[3-(trifluoromethyl)phenyl]-4-pentenamide (4.5 g, 11.30 mmol) in THF (50 mL) and water (10 mL) at room temperature was added potassium osmate dihydrate (208 mg, 0.57 mmol, 0.05 equiv). The mixture was chilled in an ice bath. To this chilled mixture was added Nal0₄ (6.28 g, 29.4mmol, 2.6 equiv) portionwise over a period of 5 minutes .The mixture was stirred in the ice bath, and gradually thickened into a white paste/suspension. The mixture was stirred for 4 hours and then aged in the refigerator for 15 hour, and then warmed up to room temperature for 1 hour. LCMS showed conversion complete. To the mixture was added 40 mL of 1 N sodium thiosulfate solution. After stirring for 10 min, the suspension was filtered. The cake was washed with water (250 mL) and some EtOAc (100mL). The filtrate was extracted with EtOAc (2 x 200 mL). The combined organics was dried over Na₂S0₄, filtered, and concentrated in vacuo. The glass-like foamy residue was pumped under vacuum for 1 hour to give crude hydroxypyrrolidinone intermediate product (5.09g) as a foam. LCMS showed it was a mixture of diastereomers in 23:52 ratio by UV. This material was taken up in 20 mL of DCM and 10 mL of TFA (11.5equiv), and then triethylsilane (7.20 mL, 45.2 mmol, 4 equiv) was added. The mixture (dark brownish) was stirred for 2 hours (LCMS showed conversion complete). The mixture was concentrated in vacuo, and stored at -20 °C freezer for 3 days. The residue was dissolved in CHCI₃ and absorbed onto 4 dryload cartridges (equal portions). Purification was done on an RS-90g silica gel cartridge (repeated 4x) using gradient elution of 1 % A in hexane to 60% A in hexane (A was a mixture of 2/1 CHCI₃/EtOAc) using flow rate of 50 mL/min. The desired product eluted from 41-48% A. The combined fractions containing pure product were concentrated in vacuo and dried under vacuum to give 1-(4-bromophenyl)-3-[3-(trifluoromethyl)phenyl]-2- pyrrolidinone (2.78 g) as pale yellow solids. LC-MS (ES) m/z 384 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.20 - 2.34 (m, 1 H), 2.56 - 2.66 (m, 1 H), 3.87 - 3.96 (m, 2 H), 4.15 (t, J=9.5 Hz, 1 H), 7.54 - 7.75 (m, 8 H).

A mixture of 1-(4-bromophenyl)-3-[3-(trifluoromethyl)phenyl]-2-pyrrolidinone (0.84 g, 2.19 mmol), bis(pinacolato)diboron (0.67 g, 2.62 mmol, 1.2 equiv), potassium acetate (0.54 g, 5.47 mmol, 2.5 equiv) and PdCl₂(dppf)-CH₂Cl₂ adduct (170 mg, 0.22 mmol, 0.1 equiv) in 10 mL of 1 ,4-dioxane in a 20 mL microwave vial was bubbled with argon for 10 min, followed by capping and heating in at 100 °C for 18 hours, LCMS showed conversion complete. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (70 mL) and brine (30 mL), followed by filtration through Celite. The filtrate was phases were separated. The organic was dried over Na₂S0₄, filtered, and concentrated in vacuo. The residue was dissolved in DCM and absorbed onto a dryload silica gel cartridge. Purification was done on an SF25-40g silica gel cartridge using gradient elution of 10% A in hexane to 100%A (A was a mixture of 2/1 CHCI₃/EtOAc). The desired product eluted from 50-70% A. The collected fractions containing pure product were combined and concentrated in vacuo to afford 1-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]- 3-[3-(trifluoromethyl)phenyl]-2-pyrrolidinone (0.59 g) as light yellow solids. LC-MS (ES) m/z = 432 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ 1.30 (s, 12 H), 2.23 - 2.35 (m, 1 H), 2.56 - 2.66 (m, 1 H), 3.91 - 3.98 (m, 2 H), 4.17 (dd, =10.6, 8.8 Hz, 1 H),7.58 - 7.79 (m, 8 H).

A mixture of 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.31 g, 1.37 mmol), 1- [4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-3-[3-(trifluoromethyl)phenyl]-2- pyrrolidinone (0.59 g, 1.37 mmol), Pd₂(dba)₃ (63 mg, 0.07 mmol) and K₃P0₄ (0.63 g, 2.74 mmol) in 10 mL of dioxane and 3.3 mL of water in a 20 mL microwave vial was bubbled with argon for 10 min, and then tri-(t-butyl)phosphonium tetrafluoroborate (40 mg, 0.14 mmol) was added. The mixture was capped and heated in a metal matrix block at 100 °C. After 18 h, LCMS showed conversion complete. The mixture was filtered. The filtrate was concentrated in vacuo. The residue was taken up in water (30 mL) to give a suspension, which was filtered. The solid cake was washed with water and ether. The cake was dried under house vacuum, dissolved in 10% MeOH in DCM. The organic was dried over Na₂S0₄, filtered, and concentrated in vacuo. The residue was dissolved in 10% MeOH in DCM and was absorbed onto a dryload silica gel cartridge. Purification was performed on a 115 g silica gel cartridge using gradient elution of 1 % A to 60% A in CHCI₃ (A was a mixture of 3200/800/80 CHCI₃/MeOH/NH₄OH). The desired product eluted from 25-30% A. The combined fractions containing pure product were concentrated in vacuo. The residue was dissolved in 10% MeOH in CHCI₃ and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in 10% MeOH in DCM (12 mL), to which was added MTBE (15 mL). Solids slowly formed, resulting in a suspension. This mixture was concentrated in vacuo to reduce to half volume, followed by addition of another 15 mL of MTBE. The suspension was filtered. The cake was washed with MTBE (2 x 5 mL) and hexane (2 x 4 mL), dried under vacuum at 65 °C for 20 h to afford 1-4-(4-amino-7-methyl- 7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(2,5-difluorophenyl)pyrrolidin-2-one (449 mg) as an off-white solid. LCMS (ES) m/z = 452 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ ppm 2.22 - 2.35 (m, 1 H), 2.58 - 2.71 (m, 1 H), 3.75 (s, 3 H), 4.00 (dd, J=8.8, 5.3 Hz, 2 H), 4.17 (t, J=9.6 Hz, 1 H), 5.97 - 6.18 (br s, 1.2 H), 7.32 (s, 1 H), 7.49 (d, J=8.6 Hz, 2 H), 7.60 - 7.70 (m, 3 H), 7.73 (s, 1 H), 7.83 (d, J=8.8 Hz, 2 H), 8.16 (s, 1 H).

Example 5

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3- lpyrimidin-5-yl)phenyl)-3-(2- (trifluoromethyl)phenyl)pyrrolidin-2-one

To a stirred solution of [2-(trifluoromethyl)phenyl]acetic acid (5.0 g, 24.49 mmol) in THF (100 mL) cooled in a dryice/acetone bath under nitrogen (-60°C, internal temp) was added 2.5M nBuLi solution (21.6 mL, 53.9 mmol, 2.2 equiv) portionwise over a period of 10 minutes such that the temperature of the mixture stayed around -50 to -60 °C. After completion of the nBuLi addition, the cooling bath was removed. The light brownish but clear mixture was warmed gradually. After 20 minutes, the temp reached -10 °C. Allyl bromide (6.78 mL, 78 mmol, 3.2 equiv) was added in one portion. The internal temp rose to 10 °C and the mixture became a light yellow but clear solution. After 30 minutes, the mixture was mixed with 35 mL of 1 N HCI, and extracted with ethyl ether (200 mL).The organic was dried over MgS0₄, filtered, and concentrated in vacuo to give 2-[2- (trifluoromethyl)phenyl]-4-pentenoic acid as a light brownish liquid (5.80 g). NMR (traces of THF and ether) showed this lot was pure. LC-MS (ES) m/z = 225 [MH-18]⁺. H NMR (400 MHz, DMSOd6) δ 2.41 - 2.50 (m, 1 H), 2.72 - 2.85 (m, 1 H), 3.90 (t, J=7.5 Hz, 1 H), 4.92 - 5.08 (m, 2 H), 5.62 - 5.72 (m, 1 H), 7.44 -7.54 (m, 1 H), 7.60 - 7.77 (m, 3 H), 12.67 (br s, 1 H).

To a stirred solution of 2-[2-(trifluoromethyl)phenyl]-4-pentenoic acid (5.80 g, 23.75 mmol) and 4-bromoaniline (3.2 g, 18.60 mmol, 0.78 equiv) in30 mL of DCM chilled in an ice bath was added DIPEA (4.56 mL, 26.1 mmol, 1.1 equiv), followed by HATU (9.93 g, 26.1 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred while being chilled in the ice bath. After 1 hour, the cold suspension was filtered. The filtrate was washed with 2 x 30 mL of 1 N HCI. The organic was dried over MgS0₄, filtered, and concentrated in vacuo. The residue was dissolved in CHCI₃ and absorbed onto 3 dryload silica gel cartridges (in equal portions). Purification was done on an RS-90 g silica gel cartridge (repeated 3x) using gradient elution of 1 % A in hexane to 100% A in hexane (A was a mixture of 2/1 CHCI₃/EtOAc). The desired product eluted at 41-48% A. The combined fractions containing pure product were concentrated in vacuo and dried under vacuum to afford N- (4-bromophenyl)-2-[2-(trifluoromethyl)phenyl]-4-pentenamide (3.44 g) as a pale yellow thick gel. LC-MS (ES) m/z= 398, 400 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ ppm 2.63 (dt, J=14.5, 7.3 Hz, 1 H), 2.82 (dt, J=14.1 , 7.1 Hz, 1 H), 4.16 (t, J=7.5 Hz, 1 H), 4.98 (dd, J=10.2, 1.9 Hz, 1 H), 5.07 (dd, J=17.2, 2.0 Hz, 1 H), 5.62 - 5.72 (m, 1 H), 7.43 - 7.52 (m, 3 H),7.52 - 7.60 (m, 2 H), 7.66 - 7.74 (m, 2 H), 7.90 (d, J=8.1 Hz, 1 H), 10.27 (s ,1 H).

To a solution of N-(4-bromophenyl)-2-[2-(trifluoromethyl)phenyl]-4-pentenamide (3.44 g, 8.64 mmol) in THF (40 mL) and water (8 mL) at room temperature was added potassium osmate dihydrate (159 mg, 0.43 mmol, 0.05 equiv). The mixture was chilled in an ice bath. To this chilled mixture was added Nal0₄ (4.80 g, 22.46 mmol, 2.6 equiv) portionwise over a period of 5 minutes. The mixture was stirred in the ice bath, and gradually thickened into a white paste/suspension. After 30 minutes, the ice bath was removed. The mixture was stirred at room temperature for 2.5 hours. LCMS showed conversion complete. To the mixture was added 32 mL of 1 N sodium thiosulfate solution. After stirring for 10 minutes, the suspension was filtered. The cake was washed with water (200 mL) and some EtOAc (100 mL). The filtrate was extracted with EtOAc (2 x 100 mL). The combined organics was dried over Na₂S0₄, filtered, and concentrated in vacuo. The glass-like foamy residue was pumped under vacuum for 1 hour to give the intermediate hydroxypyrrolidinone (3.37 g) as a foam. LCMS showed it was a mixture of a pair of diastereomers in 25:48 ratio by UV. This material was taken up in 15 mL of DCM and 7.65 mL of TFA (1 1.5 equiv), and then triethylsilane (5.5 mL, 34.6 mmol, 4 equiv) was added. The mixture (light brownish) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was dissolved in CHCI₃ and absorbed onto 2 dryload silica gel cartridges (equal portions). Purification was done on an RS-90 g silica gel cartridge (repeated 2x) using gradient elution of 1 % A in hexane to 60% A in hexane (A was a mixture of 2/1 CHCI₃/EtOAc) using flow rate at 50 mL/min. The desired product eluted from 32-48% A. The combined fractions containing pure product were concentrated in vacuo and dried under vacuum to give 1-(4-bromophenyl)-3-[2-(trifluoromethyl)phenyl]-2-pyrrolidinone (2.16 g) as white solids. Both NMR and LCMS showed this lot was about 90% pure. This sample was carried on to the next step. LC-MS (ES) m/z 384, 386 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.04 - 2.19 (m, 1 H), 2.55 - 2.65 (m, 1 H), 3.85 - 3.95 (m, 1 H), 4.00 (td, J=9.3, 7.2 Hz, 1 H), 4.25 (t, J=9.6 Hz, 1 H), 7.46 - 7.54 (m, 2 H), 7.58 - 7.64 (m, 2 H), 7.67 - 7.77 (m, 4 H).

A mixture of racemic 1-(4-bromophenyl)-3-[2-(trifluoromethyl)phenyl]-2-pyrrolidinone (0.83 g, 2.16 mmol), bis(pinacolato)diboron (0.66 g,2.59 mmol, 1.2 equiv), potassium acetate (0.53 g, 5.40 mmol, 2.5 equiv)and PdCI₂(dppf)-CH₂CI₂ adduct (176 mg, 0.22 mmol, 0.1 equiv) in 10 mL of 1 ,4-dioxane in a 20 mL microwave vial was bubbled with argon for 10 min, followed by capping and heating in a metal matrix block at 100 °C. After a total of 18 hours, LCMS showed conversion complete. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo. The residue was taken up between EtOAc (70 mL) and brine (30 mL), followed by filtration through Celite. The filtrate was phases were separated. The organic was dried over Na₂S0₄, filtered, and concentrated in vacuo. The residue was dissolved in DCM and absorbed onto a dryload cartridge. Purification was done on an SF25-40 g silica gel cartridge using gradient elution of 10% A in hexane to 100% A (A was a mixture of 2/1 CHCI₃/EtOAc). The desired product eluted from 44-60% A. The collected fractions containing pure product were combined and concentrated in vacuo to afford 1-[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]-2-pyrrolidinone (0.69 g) as light yellow solids. LC-MS (ES) m/z = 432 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 1.30 (s, 12 H), 2.05 - 2.21 (m, 1 H),2.55 - 2.67 (m, 1 H), 3.93 (td, J=9.1 , 2.0 Hz, 1 H), 3.98 - 4.09 (m, 4 1), 4.27 (t, J=9.7 Hz, 1 H), 7.45 - 7.56 (m, 2 H), 7.65 - 7.80 (m, 6 H).

A mixture of 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (363 mg,1.60 mmol, 1 equiv), 1-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-3-[2- (trifluoromethyl)phenyl]-2-pyrrolidinone (690 mg, 1.60 mmol,1 equiv), Pd₂(dba)₃ (73 mg, 0.08 mmol, 0.05 equiv) and K₃P0₄ (737 mg, 3.20mmol, 2.0 equiv) in 10 mL of dioxane and 3.3 mL of water in a 20 mL microwave vial was bubbled with argon for 10 minutes, and then tri-(t-butyl)phosphonium tetrafluoroborate (46 mg, 0.16 mmol, 0.1 equiv) was added. The mixture was capped and heated in a metal matrix block at 100 °C. After 1.5 hours, LCMS showed conversion complete. The mixture was concentrated in vacuo. The residue was taken up in water (30 mL) to give a suspension, which was filtered. The solid cake was washed with water and dried under house vacuum overnight. The cake was then washed with ether, dissolved in 10% MeOH in DCM, and was absorbed onto a dryload cartridge. Purification was done on SF40-115 g silica gel cartridge using gradient elution of 1 % A to 60% A in CHCI₃ (A was a mixture of 3200/800/80 CHCI₃/MeOH/NH₄OH). The desired product eluted from 22-27% A. The combined fractions containing pure product were concentrated in vacuo. The residue was redissolved in 20 mL of 10% MeOH in DCM, followed by filtration. The filtrate was concentrated in vacuo to half volume. The mixture was diluted with MTBE (15 mL). This mixture was concentrated in vacuo to reduce to half volume, followed by addition of another 15 mL of MTBE. The suspension was filtered. The cake was washed with MTBE (2 x 5 mL), and dried under vacuum at 65 °C for 20 h to afford 1-4-(4-amino-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(2-(trifluoromethyl)phenyl)pyrrolidin-2-one (355 mg) as off white solids. LC-MS (ES) m/z = 452 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.08 - 2.18 (m, 1 H), 2.58 - 2.72 (m, 1 H), 3.75 (s, 3 H), 3.92 - 4.13 (m, 2 H), 4.26 (t, J=9.5 Hz, 1 H), 5.95 - 6.23(br s, 1.4 H), 7.33 (s, 1 H), 7.46 - 7.59 (m, 4 H), 7.68 - 7.80 (m, 2 H), 7.84(d, J=8.8 Hz, 2 H), 8.17 (s, 1 H).

Example 6

1-(4-(4-amino-1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-phenylpyrrolidin-

2-one

To a mixture of 1-(4-bromophenyl)-3-phenyl-2-pyrrolidinone (150 mg, 0.474 mmol), bis(pinacolato)diboron (126 mg, 0.498 mmol), and potassium acetate (140 mg, 1.423 mmol) was added 1 ,4-dioxane (6 mL), and the mixture was degassed with N₂ for 10 minutes. PdCl2(dppf)-CH₂Cl2 adduct (19.37 mg, 0.024 mmol) was added, and the reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled down to room temperature. 3-bromo-1-methyl-1 /-/-pyrazolo[3,4-c]pyrimidin-4-amine (108 mg, 0.474 mmol) and sat. aq. NaHC0₃ (2 ml_) were added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl2(dppf)-CH₂Cl2 adduct (19.37 mg, 0.024 mmol) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 C. The mixture was poured onto water and a precipitate was formed. The mixture was filtered, and the solid was taken up into a mixture of 20% CH₃OH/CH2CI2 mixture, and injected into a 90 g silica gel column, and purified via flash chromatography (gradient: 100% Hexanes to 100% EtOAc to 20% CH₃OH/EtOAc). The fractions containing the desired product were combined and concentrated to afford a solid. Trituration with ether afforded the desired product (110 mg) as a tan solid. LC-MS (ES) m/z = 385.3 [M+H]⁺. H NMR (400 MHz, DMSO-d₆) δ 2.16 - 2.30 (m, 1 H), 2.56 - 2.71 (m, 1 H), 3.96 (s, 3 H), 3.97 - 4.05 (m, 3 H), 7.23 - 7.46 (m, 5 H), 7.70 (d, J=8.59 Hz, 2 H), 7.91 (d, J=8.84 Hz, 2 H), 8.27 (s, 1 H).

Example 7

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimiclin-5-yl)-3-fluorophenyl)-3- phenylp

To a stirred solution of 2-pheyl-4-pentenoic acid (1.65 g, 9.375 mmol, 1 equiv) and 4- bromo-3-fluoroaniline (1.87g, 9.843 mmol, 1.05 equiv) in 10 mL of DCM at 0 °C was added DIPEA (1.83 mL, 10.312 mmol, 1.1 equiv), followed by HATU (3.9 g, 10.312 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred at room temperature for 60 minutes. The suspension was diluted with DCM (100 ml_), was washed with 1 N HCI (2 x 50 ml_), and sat NaHC0₃ (2 x 50 ml_), dried over Na₂S0₄, filtered, and concentrated. Purification: 80g silica gel cartridge using elution of DCM only. The collected fractions with pure product were concentrated and washed with n-pentane (3 x 10 ml_), and dried, yield (2.25 g, 69.01 %), white solid. LC-MS (ES) m/z = 348.0, 350.0 [M+H]⁺. H NMR (400 MHz, DMSO-c/6) δ 2.31 - 2.45 (m, 1 H), 2.75 - 2.82 (m, 1 H), 3.71 - 3.75 (m, 1 H), 4.97 (d, J=10.4 Hz, 1 H), 5.07 (d, J=17.2 Hz, 1 H), 5.66 - 5.76 (m, 1 H), 7.22 - 7.26 (m, 2 H), 7.32 (t, J=7.6 Hz, 2 H), 7.36 - 7.38 ( m, 2 H), 7.72 (t, J = 8.4 Hz, 1 H), 7.71 (dd, J=11.6, 2 Hz, 1 H), 10.40 (s, 1 H).

To a stirred solution of A/-(4-bromo-3-fluorophenyl)-2-phenylpent-4-enamide (1 g, 2.873 mmol, 1 equiv) in a mixture of THF (50 ml_) and water (10 ml_) was added 2.5% wt/v osmium tetroxide solution (2.91 ml_, 0.287 mmol, 0.1 equiv) followed by sodium periodate (1.22 g, 5.747 mmol, 2 equiv), and the reaction mixture was stirred at room temperature for 3 hours. An aqueous solution of sodium thiosulfate was added, and the resulting mixture was stirred for 10 minutes. The mixture was extracted into EtOAc (100 ml_) and saturated aqueous NaHC0₃. The organic layer was separated, washed with brine solution (50 ml_), dried over Na₂S0₄, and concentrated. LCMS analysis indicated the presence of desired product and the diol intermediate. This material was dissolved in a mixture of THF (50 ml_) and Water (10 ml_) and treated with sodium periodate (1.22 g, 5.747 mmol, 2 equiv). The resulting mixture was stirred for 3 hours at room temperature. An aqueous solution of sodium thiosulfate was added, and the resulting mixture was stirred for 10 minutes. The mixture was extracted into EtOAc (100 ml_) and saturated aqueous NaHC0₃. The organic layer was separated, washed with brine solution (50 ml_), dried over Na₂S0₄), and concentrated to afford the crude product 1-(4-bromo-3-fluorophenyl)- 5-hydroxy-3-phenylpyrrolidin-2-one (730 mg, 72%) as a off white solid as a mixture of stereoisomers. This material was used as is in the next step. LC-MS (ES) m/z = 350.0, 352.0 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ 2.31 - 2.49 (m, 2 H), 4.17 (t, J =8.8 Hz, 1 H), 5.75 - 5.83 (m, 1 H), 6.57 - 6.63 (m, 1 H), 7.24 - 7.39 (m, 5 H), 7.51 - 7.54 (m, 1 H), 7.72(t, J=.8 Hz, 1 H), 7.75 - 7.79 (m, 1 H).

To a stirred solution of 1-(4-bromo-3-fluorophenyl)-5-hydroxy-3-phenylpyrrolidin-2-one (730 mg, 2.8 mmol, 1 equiv) in dichloromethane (DCM) (20 ml_) was added triethylsilane (1.32 ml_, 8. mmol, 4 equiv) followed by TFA (3.19 ml_, 41.714 mmol, 20 equiv), and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was poured onto saturated aqueous NaHC0₃ and EtOAc (100 ml_). The organic layer was separated, washed with brine solution (30 ml_), dried over Na₂S0₄, filtered and concentrated to afford 1-(4-bromo-3-fluorophenyl)-3-phenylpyrrolidin-2-one (640 mg, 91 %) as a white solid. LCMS (ES) m/z = 334.0, 336.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.13 - 2.23 (m, 1 H), 2.52 - 2.60 (m, 1 H), 3.85 - 3.98 (m, 3 H), 7.25 - 7.36 (m, 5 H), 7.48 - 7.51 (m, 1 H), 7.70 (t, J=8.4 Hz, 1 H), 7.85 ( dd, J=11.6, 2.8 Hz, 1 H).

To a mixture of 1-(4-bromo-3-fluorophenyl)-3-phenylpyrrolidin-2-one (150 mg, 0.449 mmol, 1 equiv), bis(pinacolato)diboron (1 14 mg, 0.449 mmol, 1 equiv), and potassium acetate (132 mg, 1.3 mmol, 3 equiv) was added 1 ,4-dioxane (10 ml_), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (18.32 mg, 0.022 mmol, 0.05 equiv) was added and again degassed with N₂ for 10 minutes. The reaction mixture was stirred for 3h at 100 °C in a sealed vessel. The reaction was cooled down to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (102 mg, 0.449 mmol, 1 equiv) and saturated aqueous NaHC0₃ (3 ml_) was added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (18.32 mg, 0.022 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The mixture was poured onto water and extracted into EtOAc (2 x 30 ml_) dried over Na₂S0₄ and concentrated. Purification: 100 - 200 silicagel, (24 g column) 3% MeOH in DCM mobile phase using CombiFlashORf instrument, yield (34.24 mg) as off white solid. LCMS (ES) m/z = 402.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.18 - 2.31 (m, 1 H), 2.59 (m, 1 H), 3.74 (s, 3 H), 3.93 - 3.98 (m, 3 H), 6.03 (br s, 2 H), 7.28 - 7.38 (m, 6 H), 7.42 (t, J=8.4 Hz, 1 H), 7.58 - 7.60 (m, 1 H), 7.82 - 7.85 (d, J =12.8 Hz, 1 H), 8.15 (s, 1 H). HPLC: 99.23% purity. Example 8 & 9

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimiclin-5-yl)-3-fluorophenyl)-3- phenylpyrrolidin-2-one (Enantiomer I, Example 8 and Enantiomer, II Example

Enantiomer-I Enatiomer-ll

To a mixture of 1-(4-bromo-3-fluorophenyl)-3-phenylpyrrolidin-2-one (1.5 g, 4.5 mmol, 1 equiv), bis(pinacolato)diboron (1.14 g, 4.5 mmol, 1 equiv), and potassium acetate (1.32 g, 13.5 mmol, 3 equiv) was added 1 ,4-dioxane (60 mL), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.183 g, 0.22 mmol, 0.05 equiv) was added and again degassed with N₂ for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7- methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (1.01 g, 4.49 mmol, 1 equiv) and saturated aqueous NaHC0₃ (30 mL) was added, and N₂ gas was bubbled through the reaction mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.183 g, 0.22 mmol, 0.05 eq) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The reaction mixture was cooled and filtered through celite bed, washed with EtOAc (100 mL), the filtrate was dried over Na₂S0₄ and concentrated. Purification: Purified by flash column chromatography using 80 g silica gel column and 2% MeOH in DCM as mobile phase. Finally compound was washed with ether (3 x 10mL) and dried to get desired product as off white solid. Yield (510 mg, 28.33%). LCMS (ES) m/z = 402.2 [M+H]⁺. H NMR (400 MHz, DMSOc/6) δ 2.17 - 2.23 (m, 1 H), 2.55 - 2.63 (m, 1 H), 3.74 (s, 3 H), 3.91 - 4.00 (m, 3H), 5.98 (br s, 2H), 7.25 - 7.38 (m, 6 H), 7.42 (t, J=9.2 Hz, 1 H), 7.58 - 7.60 (d, J=8.4 Hz, 1 H), 7.81 - 7.85 (d, J=1 1.6 Hz, 1 H), 8.14 (s, 1 H). 99.79% of purity by HPLC at 254 nM. Chiral HPLC: (44.50% + 55.34%).

Analytical conditions: Column: Chiralpak IA (250 mm X 4.6 mm X 5 um), Mobile phase: MtBe Methanol with 0.1 %DEA (80:20), Flow rate : 1.0mL/min.

Enantiomer - I (Retention time-17.31 minutes), Enantiomer - II (Retention time-18.89 minutes)

Isomer-I Isomer-ll

Isomers of 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-3-fluorophenyl)-3- phenylpyrrolidin-2-one were separated by chiral HPLC chromatography to obtain pure unknown Isomer I and pure unknown isomer II

Chiral separation:

Chiral Prep HPLC,

Column: Chiral pak IA (250 mm X 4.6 mm X 5 um)

Mobile phase: MTBE: MeOH with 01 % DEA (80:20)

Flow rate: 1.0 ml_/ min

Enantiomer-I (single unknown Enantiomer-I)

Yield (160 mg, 31 %) as a off white solid. LCMS (ES) m/z = 402.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.15 - 2.25 (m, 1 H), 2.55 - 2.66 (m, 1 H), 3.74 (s, 3 H), 3.91 - 4.00 (m, 3 H), 5.98 (br s, 2 H), 7.26 - 7.38 (m, 6 H), 7.42 (t, J=8.8 Hz, 1 H), 7.59 (d, J=10 Hz, 1 H), 7.83 (d, J=12.8 Hz, 1 H), 8.14 (s,1 H). 99.70% of purity by HPLC @ 286 nM. Chiral HPLC: 99.31 % (Enantiomer-I) + 0.69% (Enantiomer-I I).

Enantiomer-ll (single unknown Enantiomer-ll)

Yield (1 10 mg, 21 %) as a off white solid. LCMS (ES) m/z = 402.2 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ 2.18 - 2.25 (m, 1 H), 2.58 - 2.65 (m, 1 H), 3.74 (s, 3 H), 3.91 - 4.00 (m, 3H), 5.98 (br.s., 2H), 7.26 - 7.38 (m, 6 H), 7.42 (t, J=8.4 Hz, 1 H), 7.59 (d, J=8.4 Hz, 1 H), 7.83 (d, J=12 Hz, 1 H), 8.14 (s, 1 H). 99.93% of purity by HPLC @ 286 nM. Chiral HPLC: 1.88% (Enantiomer-I) + 98.12% (Enantiomer-ll).

Example 10 & 11

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimidin-5-yl)phenyl)-3-phenylpyrrolid one (Enantiomer I, Example 10 and Enantiomer II, Example 11)

To a stirred solution of methyl 2-phenylacetate (10 g, 66.66 mmol) in THF (10 mL) was added 2M LDA in THF solution (33 mL, 66.66 mmol, 1 equiv) drop wise at -78 °C, stirred for 30 minutes at -78 °C and 2-bromoacetonitrile (4.64 mL, 66.66 mmol, 1 equiv) was added at same temperature. The reaction mixture was stirred overnight at -78 °C to RT. The reaction mixture was quenched with 1 N HCI (50 mL), and extracted using ethyl acetate (500 mL), dried over Na₂S0₄, and concentrated. Purification: Purified by flash column chromatography using 80g silica gel column with 15% EtOAc in hexane mobile phase to give methyl-3-cyano-2-phenylpropanoate as color less solid, yield (4.5 g, crude with some impurities) H NMR (400 MHz, CDCI₆) δ ppm 2.76 - 2.83 (m, 1 H), 2.99 - 3.05 (m, 1 H), 3.71 (s, 3 H), 3.93 (t, J=7.2 Hz, 1 H), 7.27 (m, 2 H), 7.31 - 7.39 (m, 3 H).

To a solution of methyl-3-cyano-2-phenylpropanoate (4.5 g, 23.8 mmol, 1 equiv) in EtOH (150 mL) was added Raney Ni (4.5 g) and aq NH₄OH (50 mL). The reaction mixture was kept in parr shaker vessel at 60 psi (RT) for 2 days. Then the reaction mixture was filtered through celite bed, the filtrate was concentrated. The crude was diluted with DCM (100 mL), washed with 2N aq HCI (2 x 50 mL), dried over Na₂S0₄ and concentrated to get desired product as light yellow solid. Yield (2.46 g, 64%). LC-MS (ES) m/z = 162.1 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ 2.01 - 2.10 (m, 1 H), 2.45 - 2.46 (m, 1 H), 3.23 - 3.28 (m, 2 H), 3.50 (t, J=8.8 Hz, 1 H), 7.21 - 7.23 (m, 3 H), 7.28 - 7.32 (m, 2 H), 7.77 (br s, 1 H).

To a stirred solution of 3-phenylpyrrolidin-2-one (2.46 g, 15.3 mmol, 1 equiv) and 1- bromo-4-iodobenzene (5.18 g, 18.3 mmol, 1.2 equiv) in EtOAc (30 mL) was added cesium fluoride (5.8 g, 38.2 mmol, 2.5 equiv), Λ/,Λ/'-dimethylethylenediamine (0.165 mL, 1.5 mmol, 0.1 equiv) and Cul (0.145 g, 0.763 mmol, 0.05 equiv) at RT. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (200 mL), washed with water 100 mL), saturated aqueous NaHC0₃ (100 mL) and brine solution (100 mL) finally, dried over Na₂S0₄ and concentrated. Purification: Purified by flash column chromatography using 80 g silica gel column and 10% EtOAc in hexane as mobile phase to get desired product as off white solid. Yield (3.75 g, 78%). LC-MS (ES) m/z = 316.0, 318.1 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ 2.26 - 2.35 (m, 1 H), 2.61 - 2.69 (m, 1 H), 3.85 - 3.91 (m, 3 H), 7.28 - 7.31 (m, 3 H), 7.35 - 7.38 (m, 2 H), 7.48 (d, J=8.8 Hz, 2 H), 7.60 (d, J 8.8 Hz, 2 H).

To a mixture of 1-(4-bromophenyl)-3-phenylpyrrolidin-2-one (2.5 g, 7.9 mmol, 1 equiv), bis(pinacolato)diboron (2 g, 7.9 mmol, 1 equiv), and potassium acetate (2.3 g, 23.7 mmol, 3 equiv) was added 1 ,4-dioxane (100 mL), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.32 g, 0.395 mmol, 0.05 equiv) was added and again degassed with N₂ for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7- methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (1.79 g, 7.911 mmol, 1 equiv) and saturated aqueous NaHC0₃ (30 mL) was added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.32 g, 0.395 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The reaction mixture was cooled and filtered through celite bed, washed with EtOAc (100 mL), the filtrate was dried over Na₂S0₄ and concentrated. Purification: Purified by flash column chromatography using 80 g silica gel column and 2.5 % MeOH in DCM as mobile phase. Repurified using reverse phase column 24 g silica (C18) by flash column chromatography using 30 % water (0.01 % NH₄OH) in ACN as mobile phase. [compound loading 0.5g crude] and obtained desired product as off white solid. Yield (0.77 g, 25%). LCMS (ES) m/z = 384.2 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ 2.17 - 2.22 (m, 1 H), 2.55 - 2.60 (m, 1 H), 3.73 (s, 3 H), 3.93 - 3.97 (m, 3H), 6.03 (br s, 2 H), 7.27 - 7.38 (m, 6 H), 7.46 (d, J=8 Hz, 2 H), 7.81 (d, J=8.4 Hz, 2 H), 8.15 (s, 1 H). 99.90% of purity by HPLC @ 284 nM. Chiral HPLC: 49.69%( Enantiomer-I at 25.19 minutes retention time)+50.31 %( Enantiomer-ll at 30.41 minutes retention time).

Analytical conditions: Column: chiralpak IA (250 mm X 4.6mm X 5 urn), Mobile phase: MtBe:Ethanol w ith 0.1 %DEA(80:20), Flow rate : 1.0mL/min: (Enantiomer-I at 25.19 minutes retention time) and ( Enantiomer-ll at 30.41 minutes retention time).

Enantiomer-I Enantiomer-ll

Isomers of 1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3- phenylpyrrolidin-2-one were separated by chiral HPLC chromatography to obtain pure unknown Isomer I and pure unknown isomer II

Chiral separation:

Chiral Prep HPLC,

Column: Chiral pak IA (250 mm X 4.6 mm X 5 urn)

Mobile phase: MTBE: MeOH with 01 % DEA (80:20)

Flow rate: 1.0 ml_/ min

Enantiomer-I (single unknown enantiomer-l)

Yield (150 mg, 30%) as off white solid. LCMS (ES) m/z = 384.2 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ 2.17 - 2.24 (m, 1 H), 2.56 - 2.66 (m, 1 H), 3.73 (s, 3 H), 3.93 - 3.97 (m, 3 H), 6.03 (br s, 2 H), 7.27 - 7.38 (m, 6 H), 7.46(d, J=8 Hz, 2 H), 7.81 (d, J=8.4 Hz, 2 H), 8.14 (s, 1 H). 99.77% of purity by HPLC @ 289 nM. Chiral HPLC: 99.15%. (Retention time of Enantiomer-I at 22.2 minutes) Enantiomer-ll (single unknown enantiomer-ll)

Yield (130 mg, 26%) as off white solid. LCMS (ES) m/z = 384.2 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ 2.15 - 2.24 (m, 1 H), 2.58 - 2.66 (m, 1 H), 3.73 (s, 3 H), 3.93 - 3.97 (m, 3 H), 6.03 (br s., 2H), 7.27 - 7.38 (m, 6 H), 7.46(d, J=8 Hz, 2 H), 7.81 (d, J=8.4 Hz, 2 H), 8.14 (s, 1 H). 99.93% of purity by HPLC @ 288 nM. Chiral HPLC: 98.87%. (Retention time of Enantiomer-ll at 24.6 minutes)

Example 12 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3- lpyrimidin-5-yl)phenyl)-3-(3,5- dimethylphenyl)pyrrolidin-2-one

A solution of 2-(3,5-dimethylphenyl)acetic acid (0.5 g, 30.450 mmol, 1.0 equiv) in 20 mL THF was cooled to -78°C and added 1.2M nBuLi in Hexane solution (5.84 mL, 7.00 mmol, 2.3 equiv) drop wise, the reaction mixture became clear and turned yellow opaque solution/suspension after some time. After completion of the addition, the cooling bath was removed, the reaction mixturewas allowed to room temperature gradually. After 50 min, 3-bromoprop-1-ene (0.84 mL, 9.75 mmol, 3.2 equiv) was added in one portion at 0°C, reaction was allowed to stirr at room temperature for 16h. After completion of the starting material (by TLC), the reaction mixture was quenched with 1 N HCI, extracted with Ethyl Acetate (2 x 100mL). The organic layers were combined and dried over Na₂S0₄, filtered and evaporated to afford the desired product 2-(3,5-dimethylphenyl)pent-4-enoic acid as a Yellow solid (0.48 g, crude) and proceeded further without any purification. H NMR (400 MHz, CDCI₃) δ 2.30 (s, 6 H), 2.48 - 2.51 (m, 1 H), 2.80 - 2.99 (m, 1 H), 3.56 - 3.59 (m, 1 H), 4.09 - 4.13 (m, 1 H), 5.01 (d, J=8.0 Hz, 1 H), 5.09 (d, J=8.0 Hz, 1 H), 5.65 - 5.78 (m, 1 H), 6.88 - 6.92 (m, 3 H).

To a stirred solution of 2-(3,5-dimethylphenyl)pent-4-enoic acid (0.48 g, 2.4 mmol, 1.0 equiv) and 4-bromoaniline (0.364 g, 2.1 mmol, 0.9 equiv) in 15 mL of DCM at room temperature was added DIPEA (0.45 mL, 2.58 mmol, 1.1 equiv) followed by addition of HATU (0.983 g, 2.6 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 30 min. After completion of the starting material, the reaction mixture was washed with 1 N HCI (30 mL), saturated aqueous NaHC0₃ (30 mL), water and brine successively. The mixed organic layers were dried over Na₂S0₄, filtered, evaporated. The crude compound was triturated using n-pentane to afford the desired product as a pale yellow solid (0.648 g, Crude). LC-MS (ES) m/z= 358, 360 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 6 H), 2.35 - 2.44 (m, 1 H), 2.72 - 2.79 (m, 1 H), 3.63 (s, 1 H), 4.96 (d, J=8.0 Hz, 1 H), 5.06 (d, J=20.0 Hz, 1 H), 5.64 - 5.76 (m, 1 H), 6.86 (s, 1 H), 6.97 (s, 2 H), 7.43 (d, J=8.0 Hz, 2 H), 7.53 (d, J=8.0 Hz, 2 H), 10.14 (s, 1 H).

To a stirred solution of A/-(4-bromophenyl)-2-(3,5-dimethylphenyl)pent-4-enamide (0.645 g, 1.80 mmol, 1.0 equiv), in THF (30 mL), water (6 mL) at RT was added 2.5% wt/v Osmium tetraoxide solution (1.84 mL, 0.18 mmol, 0.1 equiv) drop wise and the resulting solution was stirred for 20-30 min. followed by the addition of Sodium periodate (1.54 g, 7.20 mmol, 4.0 equiv) and stirred for 4h at room temperature. The reaction mixture was quenched with saturated aqueous Sodium thiosulphate (25 ml). The reaction mixture completely turned to reddish brown via formation and dissolution of a precipitate, followed by the addition of saturated aqueous NaHC0₃. The reaction mixture was extracted with EtOAc. The mixed organic layers were washed with brine, dried over Na₂S0₄ and evaporated to afford pale yellow semi solid, which was proceeded further without purification (0.542 g, Crude). The compound was about 80% pure by LCMS. LC-MS (ES) m/z = 360, 362 [M+H]⁺.

To a stirred solution of 1-(4-bromophenyl)-3-(3,5-dimethylphenyl)-5-hydroxypyrrolidin-2- one (0.539 g, 1.5 mmol, 1.0 equiv) in 25 mL DCM was added Triethylsilane (0.96 mL, 6 mmol, 4.0 equiv) followed by Trifluoroaceticacid (1.95 mL, 30 mmol, 20 equiv). The resulting solution was stirred at room temperature for 3h. After completion of the starting material, the reaction mixture was quenched with saturated aqueous NaHC0₃, extracted with DCM. The combined organic layers were washed with brine, dried over Na₂S0₄, filtered, organic solvent was evaporated and purified by Silica gel flash chromatography. Using 10 -11 % EtOAc in Hexane. The combined fractions were concentrated in vacuo to afford the desired product 1-(4-bromophenyl)-3-(3,5-dimethylphenyl)pyrrolidin-2-one as white solid (yield: 0.327 g, 63.5%). LC-MS (ES) m/z = 344, 346 [M+H]⁺. H NMR (400 MHz, CDCIs) δ 2.24 - 2.28 (m, 1 H), 2.31 (s, 6 H), 2.61 - 2.62 (m, 1 H), 3.79 (t, J=8.0 Hz, 1 H), 3.89 - 3.91 (m, 2 H), 6.90 - 6.92 (m, 3 H), 7.48 (d, J=12.0 Hz, 2 H), 7.61 (d, J=8.0 Hz, 2 H).

To a degassed solution of 1-(4-bromophenyl)-3-(3,5-dimethylphenyl)pyrrolidin-2-one (0.20 g, 0.5 mmol, 1.0 equiv), Bis(pinacolato)diboron (0.148 g, 0.5 mmol, 1.0 equiv), and potassium acetate (0.171 g, 1.74 mmol, 3.0 equiv) in 1 ,4-Dioxane (20 ml_) was added Pd(dppf)CI₂.DCM complex (0.024 g, 0.029 mmol, 0.05 equiv) and heated in a sealed vessel for 3 hours at 100°C. The reaction mixture was forwarded to next step without any workup. The reaction mixture was cooled to room temperature, 5-bromo-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-4-amine (0.145 g, 0.639 mmol, 1.1 equiv) and saturated aqueous NaHC0₃ (10 ml_) were added to that, degassed thoroughly and added with Pd(dppf)CI₂.DCM complex (0.048 g, 0.06 mmol, 0.1 equiv) the vessel was sealed, and the reaction mixture was heated to 100°C for overnight. After completion of the starting material, the reaction mixture was partitioned between EtOAc and water. The two layers were separated. Organic phase was washed with brine, dried over Na₂S0₄ and the crude material was purified by flash chromatography. The desired product was eluted about 2.0 - 2.5% MeOH in DCM. The combined fractions were concentrated in vacuo to afford the desired product with 89% purity by HPLC. It was repurified by prep HPLC using analytical conditions: Column: Zorbax XDB C18 (150 mm x 4.6 mm x 3.5 μηι). Mobile phase A: 0.01 % Ammonia in water, Mobile phase B: ACN, Flow rate: 1.0 mL/min.). The pure fractions were concentrated to afford the required product 1-(4-(4-amino-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(3,5-dimethyl phenyl)pyrrolidin-2-one as a white solid (0.301 g, 12%). LC-MS (ES) m/z = 412.3 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ ppm 2.14 - 2.16 (m, 1 H), 2.23 (s, 6 H), 2.54 - 2.59 (m, 1 H), 3.73 (s, 3 H), 3.84 (t, J=8.0 Hz, 1 H), 3.94 (t, J=8.0 Hz, 2 H), 6.03 (br s, 2 H), 6.93 (s, 3 H), 7.29 (s, 1 H), 7.46 (d, J=8.0 Hz, 2 H), 7.80 (d, J=8.0 Hz, 2 H), 8.14 (s, 1 H).

Example 13

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

To a stirred solution of 2-(3,5-dimethylphenyl)pent-4-enoic acid (1.20 g, 2.6 mmol, 5.9 equiv) and 4-bromo-3-fluoroaniline (1.01 g, 5.3 mmol, 0.9 equiv) in 25 ml_ of DCM at room temperature was added DIPEA (0.835 g, 6.5 mmol, 1.1 equiv) followed by addition of HATU (2.458 g, 6.5 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 30 min. After completion of the starting material, the reaction mixture was washed with 1 N HCI (30 ml_), saturated aqueous NaHC0₃ (30 ml_), water and brine successively. The combined organic layers were dried over Na₂S0₄, filtered, evaporated. The crude material was triturated using n-pentane thoroughly to afford the desired product A/-(4-bromo-3-fluorophenyl)-2-(3,5-dimethylphenyl)pent-4-enamide as pale yellow solid (2.190 g, Crude). LC-MS (ES) m/z = 375.0, 377.0 [M+H]⁺.

To a stirred solution of A/-(4-bromo-3-fluorophenyl)-2-(3,5-dimethylphenyl)pent-4-enamide (2.190 g, 5.8 mmol, 1.0 equiv), in THF (100 ml_), water (20 ml_) at room temperature was added 2.5 wt% osmium tetraoxide solution (5.92 ml_, 0.6 mmol, 0.1 equiv) drop wise and the resulting solution was stirred for 10 - 20 minutes followed by the addition of Sodium periodate (4.987 g, 23.3 mmol, 4.0 equiv) and stirred for 4h at room temperature. The reaction mixture was quenched with saturated aqueous Sodium thiosulphate, followed by the addition of saturated aqueous NaHC0₃. The reaction mixture extracted with EtOAc. The organic layer was washed with brine, dried over Na₂S0₄ and evaporated to afford the desired compound 1-(4-bromo-3-fluorophenyl)-3-(3,5-dimethylphenyl)-5-hydroxypyrrolidin- 2-one as a brown semi solid (1.780 g, Crude) which was proceeded to next step without purification. LC-MS (ES) m/z = 378.0, 380.0 [M+H]⁺.

To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(3,5-dimethylphenyl)-5-hydroxypyrro lidin-2-one (1.780 g, 4.7 mmol, 1.0 equiv) in 50 ml_ DCM was added with Triethylsilane (3.0 ml_, 18.8 mmol, 4.0 equiv) followed by Trifluoroaceticacid (6.20 ml_, 94.1 mmol, 20 equiv). The resulting solution was stirred at room temperature for 2h. After completion of the starting material, the reaction mixture was quenched with saturated aqueous NaHC0₃, extracted with DCM. The combined organic layers was washed with brine, dried over Na₂S0₄, filtered, evaporated and purified by Silica gel flash chromatography using solid loading cartridge. The desired product was eluted at 9% EtOAc in Hexane. The combined fractions were concentrated in vacuum to afford the desired product 1-(4-bromo-3- fluorophenyl)-3-(3,5-dimethylphenyl)pyrrolidin-2-one as a white solid (0.370 g, 21.7 %). LC-MS (ES) m/z = 362.0, 364.0 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ ppm 2.31 (s, 6 H), 2.32 - 2.33 (m, 1 H), 2.61 - 2.63 (m, 1 H), 3.83 (t, J=8.0 Hz, 1 H), 3.87 - 3.90 (m, 2 H), 6.89 (s, 2 H), 6.93 (s, 1 H), 7.34 - 7.36 (m, 1 H), 7.54 (t, =8.0 Hz, 1 H), 7.70 - 7.73 (m, 1 H).

To a degassed solution of 1-(4-bromo-3-fluorophenyl)-3-(3,5-dimethylphenyl)pyrrolidin-2- one (0.360 g, 1.0 mmol, 1.0 equiv), Bis(pinacolato)diboron (0.253 g, 1.0 mmol, 1.0 equiv), and potassium acetate (0.293 g, 3.0 mmol, 3.0 equiv) in 20 mL of 1 ,4-Dioxane was added Pd(dppf)CI₂.DCM complex (0.024 g, 0.03 mmol, 0.05 equiv) and heated in a sealed vessel for 3 hours at 100°C. The reaction mixture was cooled to room temperature, 5-bromo-7- methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.282 g, 1.2 mmol, 1.25 equiv) and saturated aqueous NaHC0₃ (13 mL) were added to that, degassed thoroughly and added with Pd(dppf)CI₂.DCM complex (0.081 g, 0.1 mmol, 0.1 equiv) the vessel was sealed, and the reaction mixture was heated to 100°C for overnight. After completion of the starting material (by TLC monitoring), the reaction mixture was partitioned between EtOAc and water. The organic phase was separated and washed with brine, dried over Na₂S0₄ and the crude was purified by flash chromatography using 2.9 to 3.0 % MeOH in DCM as eluent. The combined fractions were concentrated in vacuo to afford an off white solid which was washed with pentane, acetonitrile (0.5 mL) and finally with ether (2 x 1.5 mL) and dried to afford the desired product 1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin- 5-yl)-3-fluorophenyl)-3-(3,5-dimethylphenyl)pyrrolidin-2-one as off white solid (0.101 g, 24%). LC-MS (ES) m/z = 430.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.10 - 2.21 (m, 1 H), 2.26 (s, 6 H), 2.54 - 2.64 (m, 1 H), 3.74 (s, 3 H), 3.84 - 4.06 (m, 3 H), 5.98 (br s, 2 H), 6.90 (s, 3 H), 7.42 (t, J=8.0 Hz, 1 H), 7.59 (d, J=8.0 Hz, 1 H), 7.83 (d, J=12.0 Hz, 1 H), 8.14 (s, 1 H).

Example 14

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

Run 1

To a stirred solution of 2-(m-tolyl)acetic acid (0.3 g, 1.2 mmol, 1.0 equiv) in THF (15 mL) was added 1.2 M nBuLi solution (3.66 mL, 4.4 mmol, 2.2 equiv) drop wise over a period of 10 minutes at -78 °C. Cooling bath was removed, the mixture was warmed gradually. After stirring for 60 minutes, allyl bromide (0.553 mL, 6.4 mmol, 3.2 equiv) was added in one portion at 0°C and the reaction mixture was allowed to stir at room temperature for 8 h. After completion of SM, reaction mixture was quenched with 10 mL of 1 N HCI and extracted with ethyl acetate and the organic layers were combined and washed with brine and dried over Na₂S0₄, filtered and concentrated in vacuo to give 2-(m-tolyl)pent-4-enoic acid as yellow color oil (0.41 g). LC-MS (ES) m/z = 190.1 [M+H]⁺ . H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3 H), 2.33 - 2.43 (m, 1 H), 2.64 - 2.7 (m, 1 H), 3.51 - 3.59 (m, 1 H), 4.90 - 5.05 (m, 2 H), 5.63 - 5.73 (m, 1 H), 7.06 - 7.23 (m, 4 H), 12.31 (s, 1 H).

Run 2

To a stirred solution of 2-(m-tolyl) acetic acid (2.0 g, 13.3 mmol, 1.0 equiv) in THF (60 mL) was added 1.2M nBuLi solution (25 mL, 29.3 mmol, 2.2 equiv) drop wise over a period of 10 minutes at -78 °C. Cooling bath was removed, the mixture was warmed gradually. After stirring for 60 minutes, allyl bromide (3.68 mL, 42.62 mmol, 3.2 equiv) was added in one portion at 0 °C allowed reaction mixture to stir at room temperature for 8 h. After completion of SM, reaction mixture was quenched with 30 mL of 1 N HCI and extracted with ethyl acetate and the organics were combined and washed with brine and dried over Na₂S0₄, filtered and concentrated in vacuo to give 2-(m-tolyl)pent-4-enoic acid as yellow color oil (3.21 g). LC-MS (ES) m/z = 190.1 [M+H]⁺ . H NMR (400 MHz, DMSOd6) δ ppm 2.27 (s, 3 H), 2.33 - 2.43 (m, 1 H), 2.64 - 2.7 (m, 1 H), 3.51 - 3.59 (m, 1 H),4.90 - 5.05 (m, 2 H), 5.63 - 5.73 (m, 1 H), 7.06 7.23 (m, 4 H), 12.31 (s, 1 H).

To a stirred solution of 2-(m-tolyl)pent-4-enoic acid (3.61 g, 19.0 mmol, 1.0 equiv) in DCM (80 mL) was added 4-bromo-3-fluoroaniline (3.24 g, 17.1 mmol, 0.9 equiv) and DIPEA (3.64 mL, 20.9 mmol, 1.1 equiv), followed by HATU (7.95 g, 20.9 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred at room temperature for 2 h. After consumption of SM, quenched the reaction mixture with 35 mL of H₂0, and extracted with EtOAc (2 x 50 mL)and was washed with 1 N HCI (1 x 50 mL), and sat NaHC0₃ (2 X 50mL), dried over Na₂S04, filtered, and concentrated in vacuo to get N-(4-bromo-3- fluorophenyl)-2-(m-tolyl)pent-4-enamide as brown color oil (6.1 g). LC-MS (ES) m/z = 362.0, 364.1 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.27 (s, 3 H), 2.34 - 2.44 (m, 1 H), 2.72 - 2.84 (m, 1 H), 3.67 - 3.71 (m, 1 H), 4.96 (d, J=10.0 Hz, 1 H), 5.07 (d, J=17.2 Hz, 1 H), 5.65 - 5.74 (m, 1 H), 7.04 (d, J=7.20 Hz, 1 H), 7.15 - 7.22 (m, 3 H), 7.26 ( d, J=8.4 Hz, 1 H), 7.57 (t, J=8.4 Hz, 1 H), 7.72 - 7.75 (m, 1 H), 10.39 (s, 1 H).

To a stirred solution of A/,A/-(4-bromo-3-fluorophenyl)-2-(m-tolyl)pent-4-enamide (6.1 g, 16.8 mmol, 1.0 equiv) in THF (90 mL) and water (20 mL) was added 2.5 wt% osmium tetroxide solution in t-BuOH (17.12 mL, 1.7 mmol, 0.1 equiv) followed by sodium periodate (14.35 g, 67.4 mmol, 4.0 equiv), and the reaction mixture was stirred at room temperature for 5 hours. After consumption of SM, reaction mixture was quenched with 30 mL of aqueous solution of sodium thiosulfate, and the resulting mixture was stirred for 10 minutes. The mixture was extracted with EtOAc (2 x 50 mL), and sat. aqueous NaHC0₃ (35 mL). The organic layer was separated, washed with brine solution (50 mL), dried over Na₂S0₄, and concentrated to afford the crude product as 1-(4-bromo-3-fluorophenyl)-5- hydroxy-3-(m-tolyl) pyrrolidin-2-one (5.98 g) as black color semi solid. LC-MS (ES) m/z = 364.0, 366.0 [M+H]⁺.

To a stirred solution of 11-(4-bromo-3-fluorophenyl)-5-hydroxy-3-(m-tolyl) pyrrolidin-2-one (5.98 g, 16.4 mmol, 1.0 equiv) in DCM (90 mL) was added triethylsilane (10.49 mL, 65.7 mmol, 4.0 equiv) followed by TFA (20.1 1 mL, 263.0 mmol, 20.0 equiv), and the reaction mixture was stirred for 3 hours at room temperature. After consumption of SM, the reaction mixture was concentrated and added saturated aqueous NaHC0₃ and extracted with DCM (2 x 70 mL). The organic layer was separated, washed with brine solution (50 mL), dried over Na₂S0₄, filtered and concentrated. Purification: Purified by flash column chromatography using silica gel column using 10-12 % EtOAc in Hexane as eluent desired product 1-(4-bromo-3-fluorophenyl)-3-(m-tolyl) pyrrolidin-2-one was obtained as off white solid (yield: 1.7 g, 29.7%). LCMS (ES) m/z = 348.0, 350.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.12 - 2.21 (m, 1 H), 2.29 (s, 3 H), 2.53 - 2.54 (m, 1 H), 3.84 - 3.93 (m, 3 H), 7.08 (t, J=7.60 Hz, 3 H), 7.22 (t, J=7.6 Hz, 1 H), 7.49 (d, J=8.8 Hz, 1 H), 7.70 (t, J=8.4 Hz, 1 H), 7.85(d, J=1 1.6 Hz, 1 H).

To a stirred solution of mixture of 1-(4-bromo-3-fluorophenyl)-3-(m-tolyl)pyrrolidin-2-one (0.5 g, 1.4 mmol, 1.0 equiv), was added bis(pinacolato)diboron (0.365 g, 1.4 mmol, 1.0 equiv), and potassium acetate (0.422 g, 4.3 mmol, 1.0 equiv), and the mixture was degassed with Argon for 10 minutes then PdCl₂(dppf)-CH₂Cl₂ adduct (0.05 g, 0.072 mmol, 0.05 equiv) was added and again degassed with Argon for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.326 g, 1.436 mmol, 1.0 equiv) and saturated aqueous NaHC0₃ (6 mL) was added, and Argon gas was bubbled through the reaction mixture for 10 minutes and PdCl₂(dppf)-CH₂Cl₂ adduct (0.05 g, 0.072 mmol, 0.05 equiv) was added. The vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The crude mixture was filtered through celite and the filtrate was extracted with EtOAc and dried over Na₂S0₄ and concentrated. Purification: Purified by flash column chromatography using silica gel column, using 3 to 4 % MeOH in DCM as eluent to get desired product as white color solid. Yield: (0.055 g, 9.23%); LCMS (ES) m/z = 416.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.16 - 2.23 (m, 1 H), 2.30 (s, 3 H), 2.57 - 2.65 (m, 1 H), 3.74 (s, 3 H), 3.91 - 4.01 (m, 3 H), 5.98 (br s, 2 H), 7.10 (t, J=6.8 Hz, 3 H), 7.23 (t, J=6.80 Hz, 1 H), 7.30 (s, 1 H), 7.42 (t, J=8.4 Hz, 1 H), 7.59 (d, J=7.60 Hz, 1 H), 7.83 (d, J=12.8 Hz, 1 H), 8.14 (s, 1 H).

Example 15 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3- lpyrimidin-5-yl)-3-fluoroph

fluorophenyl)

Run 1

To a stirred solution of 2-(3-fluorophenyl)acetic acid (0.3 g, 1.950 mmol, 1.0 equiv) in THF (20 mL) was added 1.0 M LHMDS solution (4.28 mL, 4.282 mmol, 2.2 equiv) drop wise over a period of 10 minutes at -78 °C. After consumption of the LHMDS addition, the cooling bath was removed, the reaction mixture was warmed gradually. After 60 minutes, allyl bromide (0.54 mL, 6.23 mmol, 3.2 equiv) was added in one portion at 0°C and the reaction mixture was allowed to stir at room temperature for 6 h. After consumption of SM, the reaction mixture was quenched with 15 mL of 1 N HCI and extracted with ethyl acetate and the organics were combined and washed with brine and dried over Na₂S0₄, filtered and concentrated in vacuo to obtain 2-(3-fluorophenyl)pent-4-enoic acid as yellow color oil (0.5 g, crude). LC-MS (ES) m/z = 193.0 [M-H]⁺ .

Run 2

To a stirred solution of 2-(3-fluorophenyl)acetic acid (1.7 g, 11.0 mmol, 1.0 equiv) in THF (60 mL) was added 1.0 M LHMDS solution (24.26 mL, 24.3 mmol, 2.2 equiv) drop wise over a period of 10 minutes at -78 °C. After completion of the LHMDS addition, the cooling bath was removed, the mixture was warmed gradually. After 60 minutes, allyl bromide (0.54 mL, 6.2 mmol, 3.2 equiv) was added in one portion at 0°C and the reaction mixture was allowed to stir at room temperature for 6 h. After consumption of SM the reaction mixture was quenched with 40 mL of 1 N HCI and extracted with ethyl acetate (2x 50 mL)and the organics were combined and washed with brine and dried over Na₂S0₄, filtered and concentrated in vacuum to get 2-(3-fluorophenyl)pent-4-enoic acid as yellow color oil (2.2 g, crude). LC-MS (ES) m/z = 193.0 [M-H]⁺. H NMR (400 MHz, DMSOd6) δ ppm 2.38 -2.45 (m, 1 H), 2.65 - 2.72 (m, 1 H), 3.66 (t, =7.60 Hz, 1 H), 4.94 - 5.05 (m, 2 H),

5.63 - 5.73 (m, 1 H), 6.99 - 7.14 (m, 3 H), 7.32 - 7.40 (m, 1 H), 12.48 (s, 1 H).

To a stirred solution of 2-(3-fluorophenyl)pent-4-enoic acid (2.70 g, 13.9 mmol, 1.0 equiv) in DCM (80 mL) was added 4-bromo-3-fluoroaniline (2.37 g, 12.5 mmol, 0.9 equiv) and then added DIPEA (2.66 mL, 15.3 mmol, 1.1 equiv), followed by HATU (5.81 g, 15.3 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred at room temperature for 2 h. After consumption of SM, the reaction mixture was quenched with 35 mL of H₂0, and extracted with EtOAc, (2 x 50 mL). The organic layer was washed with 1 N HCI (1 x 50 mL), and sat NaHC0₃ (2 X 50mL), dried over Na₂S04, filtered, and concentrated. Purification: Purified by flash column chromatography using silica gel column, compound was eluted at 12-15% EtOAc in Hexane. A/-(4-bromo-3-fluorophenyl)-2-(3- fluorophenyl)pent-4-enamide as off white solid (2.60 g, 51.1 %). LC-MS (ES) m/z = 366.0, 368.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.42 - 2.49 (m, 1 H), 2.74 - 2.81 (m, 1 H), 3.78 (t, J=7.60 Hz, 1 H), 4.97 - 5.09 (m, 2 H), 5.66 - 5.76 (m, 1 H), 7.08 (t, J=7.60 Hz, 1 H), 7.19 (t, J=8.40 Hz, 2 H), 7.25 (d, J=19.60 Hz, 1 H), 7.34 - 7.39 (m, 1 H), 7.59 (t, J=8.40 Hz, 1 H), 7.70 - 7.73 (m, 1 H), 10.44 (s, 1 H).

To a stirred solution of A/-(4-bromo-3-fluorophenyl)-2-(3-fluorophenyl)pent-4-enamide (1.5 g, 4.1 mmol, 1.0 equiv) in THF (60 mL) and water (12 mL) was added 2.5 wt% osmium tetroxide solution in t-BuOH (4.20 mL, 0.409 mmol, 0.1 equiv) followed by sodium periodate (3.59 g, 16.4 mmol, 4.0 equiv), and the reaction mixture was stirred at room temperature for 8 hours. After consumption of starting material, reaction mixture was quenched with 30 mL of aqueous solution of sodium thiosulfate, and the resulting mixture was stirred for 10 minutes. The mixture was extracted into EtOAc (2 x 50 mL), and saturated aqueous NaHC0₃. The organic layer was separated, washed with brine solution (50 mL), dried over Na₂S0₄, and concentrated to afford the crude product as 1-(4-bromo- 3-fluorophenyl)-3-(3-fluorophenyl)-5-hydroxypyrrolidin-2-one (1.60 g, crude) as black color semi solid. LC-MS (ES) m/z = 368.0, 370.0 [M+H]⁺.

To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(3-fluorophenyl)-5-hydroxypyrrolidin- 2-one (1.60 g, 4.3 mmol,1.0 equiv) in DCM (50 ml_) was added triethylsilane (2.77 ml_, 17.4 mmol, 4.0 equiv) followed by TFA (6.66 ml_, 86.9 mmol, 20.0 equiv), and the reaction mixture was stirred for 3h at room temperature. After consumption of SM, the reaction mixture was concentrated. To the residue obtained was added saturated aqueous NaHC0₃ and extracted with DCM (2 x 50 ml_). The organic layer was separated, washed with brine solution (50 ml_), dried over Na₂S0₄, filtered and concentrated. Purification: Purified by flash column chromatography using silica gel column, compound was eluted at 15-20% EtOAc in Hexane. 1-(4-bromo-3-fluorophenyl)-3-(3-fluorophenyl)pyrrolidin-2-one (0.920 g, 60.1 %) as light brown color solid. LCMS (ES) m/z = 352.0, 354.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.16 - 2.26 (m, 1 H), 2.53 - 2.59 (m, 1 H), 3.85 - 3.95 (m, 2 H), 4.03 (t, J=9.20 Hz, 1 H), 7.10 (t, J=7.20 Hz, 1 H), 7.15 - 7.17 (m, 2 H), 7.29 - 7.42 (m, 1 H), 7.49 (d, J=8.80 Hz, 1 H), 7.71 (t, J=8.40 Hz, 1 H), 7.83 - 7.86 (m, 1 H).

To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(3-fluorophenyl)pyrrolidin-2-one (0.6 g, 1.4 mmol, 1.0 equiv), in 1 ,4-dioxane (15 ml_) was added bis(pinacolato)diboron (0.361 g, 1.4 mmol, 1.0 equiv), and potassium acetate (0.417 g, 4.3 mmol, 3.0 equiv), and the mixture was degassed with Argon for 10 minutes then PdCl₂(dppf)-CH₂Cl₂ adduct (0.058 g, 0.07 mmol, 0.05 equiv) was added and again degassed with Argon for 10 minutes. The reaction mixture was stirred for 4 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-4-amine (0.322 g, 1.4 mmol, 1.0 equiv) and saturated aqueous NaHC0₃ (5 ml_) was added, and Argon gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.071 g, 0.09 mmol.O. 05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The crude mixture was filtered through celite and the filtrate was dried over Na₂S0₄ and concentrated. Purification: Purified by flash column chromatography using silica gel column, compound was eluted at 3-4 % MeOH in DCM. Yield: (0.05 g, 8.4 %) as off white solid. LCMS (ES) m/z = 420.2 [M+H]⁺. H NMR (400 MHz, CDCIs) δ 2.18 - 2.28 (m, 1 H), 2.56 - 2.66 (m, 1 H), 3.74 (s, 3 H), 3.91 - 3.99 (m, 2 H), 4.05 (t, J=9.60 Hz, 1 H), 5.98 (br s, 2 H), 7.11 (t, J=8.40 Hz, 1 H), 7.19 (t, J=6.00 Hz, 2 H), 7.30 (s, 1 H), 7.38 - 7.44 (m, 2 H), 7.59 (d, J=8.40 Hz, 1 H), 7.82 (d, J=12.80 Hz, 1 H), 8.14 (s, 1 H). Example 16

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimidin-5-yl)phenyl)-3-(3,5-difluoro phenyl)pyrrolidin-2-one

To a stirred solution of 2-(3,5-difluorophenyl)acetic acid (3 g, 17.441 mmol, 1 equiv) in THF (40 mL) was added LHMDS (1 M in THF) (40 mL, 40.1 16 mmol, 2.3 equiv) drop wise at -78°C. The reaction mixture was cooled to 5 °C and stirred for 1 h, allyl bromide (4.9 mL, 56.686, 3.25 equiv) was added to the reaction mixture at 0°C and allowed for 16 h stirring at RT. After completion of the reaction, reaction mixture was quenched with 1 N HCI and extracted with ethyl acetate, dried over Na₂S0₄, and evaporated under vacuum to get 2-(3,5-difluorophenyl)pent-4-enoic acid as brown liquid .(3.6 g, crude) as crude product, and was forwarded for next stage.

LC-MS (ES) m/z = 212.2 [M+H]⁺ .

To a stirred solution of 2-(3,5-difluorophenyl)pent-4-enoic acid (1.50 g, 7.1 mmol, 1.0 equiv) in DCM (15 mL) was added 4-bromoaniline (1.20 g, 7.1 mmol, 1.0 equiv) and DIPEA (1.38 mL, 7.8 mmol, 1.1 equiv), followed by HATU (2.13 g, 6.2 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred at room temperature for 1 h. After consumption of SM, reaction mixture was diluted with DCM (100 mL), Organic layer was washed with 1 N HCI (2 x 50 mL) and saturated NaHC0₃ (2 X 50mL), dried over Na₂S04, filtered, and concentrated and the crude product was purified by flash chromatography. The product was eluted in DCM. The collected fractions with pure product were concentrated and washed with n-pentane (3 x 10 mL) and dried to afford the desired product A/-(4-bromophenyl)-2-(3,5-difluorophenyl)pent-4-enamide as white solid (1.08 g, 42%). LC-MS (ES) m/z = 366.0, 368.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.31 - 2.45 (m, 1 H), 2.75 - 2.82 (m, 1 H), 3.71 - 3.75 (m, 1 H), 4.97 (d, J=10.4 Hz, 1 H), 5.07 (d, J=17.2 Hz, 1 H), 5.66 - 5.76 (m, 1 H), 7.22 - 7.26 (m, 2 H), 7.32 (t, J=7.6 Hz, 2 H), 7.37 (d, J=7.6 Hz, 2 H), 7.58 (t, J=8.4 Hz, 1 H), 7.71 - 7.74 (m, 1 H), 10.40 (s, 1 H).

To a stirred solution of A/-(4-bromophenyl)-2-(3,5-difluorophenyl)pent-4-enamide (1.08 g, 2.6 mmol, 1.0 equiv) in THF (50 mL) and water (10 mL) was added 2.5 wt % osmium tetroxide solution (2.99 mL, 0.3 mmol, 0.1 equiv) followed by sodium periodate (1.260 g, 5.9 mmol, 2.0 equiv), and the reaction mixture was stirred at room temperature for 3 hours. Sodium periodate (1.260 g, 5.9 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for 3 hours. After consumption of SM, reaction mixture was quenched with aqueous solution of sodium thiosulfate, and stirred for 10 minutes. The mixture was extracted into EtOAc (2 x 50 mL), and saturated aqueous NaHC0₃. The organic layer was separated, washed with brine solution (50 mL), dried over Na₂S0₄), and concentrated to afford the crude product 1-(4-bromophenyl)-3-(3,5- difluorophenyl)-5-hydroxypyrrolidin-2-one (1.32 g, crude) as off white color oil.

To a stirred solution of 1-(4-bromophenyl)-3-(3,5-difluorophenyl)-5-hydroxypyrrolidin-2- one (1.32 g, 3.6 mmol, 1.0 equiv) in DCM (50 mL) was added triethylsilane (2.29 mL, 14.4 mmol, 4.0 equiv) followed by TFA (5.49 mL, 71.7 mmol, 20.0 equiv), and the reaction mixture was stirred for 3h at room temperature. After consumption of starting material, the reaction mixture was quenched with saturated aqueous NaHC0₃ and extracted with EtOAc. The organic layer was separated, washed with brine solution, dried over Na₂S0₄, filtered and concentrated. Purification: Crude was purified by flash column chromatography using 2-4% methanol in DCM as an eluent to afford 1-(4-bromophenyl)- 3-(3,5-difluorophenyl)pyrrolidin-2-one (yield: 0.710 g, 56.3%) as light brown solid. LCMS (ES) m/z = 352.0, 354.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.18 - 2.31 (m, 1 H), 2.51 - 2.59 (m, 1 H), 3.87 - 3.90 (m, 2 H), 4.03 (t, J=9.20 Hz, 1 H), 7.09 - 7.15 (m, 3 H), 7.58 (t, J=8.80 Hz, 2 H), 7.67 (d, J=8.80 Hz, 2 H).

To a mixture of 1-(4-bromophenyl)-3-(3,5-difluorophenyl)pyrrolidin-2-one (0.3 g, 0.9 mmol, 1.0 equiv), bis(pinacolato)diboron (0.216 g, 0.9 mmol, 1.0 equiv), and potassium acetate (0.251 g, 2.6 mmol, 3.0 equiv), was added 1 ,4-dioxane (15 mL) and the mixture was degassed with N₂ for 10 minutes then PdCl₂(dppf)-CH₂Cl₂ adduct (0.04 g, 0.04 mmol, 0.05 equiv) was added and the reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled down to room temperature. 5-bromo-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-4-amine (0.205 g, 0.9 mmol, 1.0 equiv) and saturated aqueous NaHC0₃ (6 mL) was added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.04 g, 0.043 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The crude mixture was filtered through celite and the filtrate was extracted with EtOAc and dried over Na₂S0₄ and concentrated. Purification: Crude was purified by Flash column chromatography to obtain desired product as light brown color solid. Yield: (0.02 g, 5.71 %). LCMS (ES) m/z = 420.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.23 - 2.31 (m, 1 H), 2.59 (s, 1 H), 3.73 (s, 3 H), 3.97 (d, J=7.60 Hz, 2 H), 4.06 (t, J=9.60 Hz, 1 H), 6.03 (br s, 2 H), 7.12 (d, J=6.80 Hz, 3 H), 7.30 (s, 1 H), 7.47 (d, J=8.0 Hz, 2 H), 7.80 (d, J=7.60 Hz, 2 H), 8.15 (s,1 H). Example 17

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimiclin-5-yl)-3-fluorophenyl)-3-(3,5- difluorophenyl)pyrrolidin-2-one

To a stirred solution of 2-(3,5-difluorophenyl)pent-4-enoic acid (1.5 g, 7.075 mmol, 1 equiv) and 4-bromo-3-fluoroaniline (1.33 g, 7.074 mmol, 1 equiv) in 10 ml of DCM at 0 °C was added DIPEA (1.38 mL, 7.783 mmol, 1.1 equiv), followed by HATU (2.95 g, 7.783 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred at room temperature for 60 minutes. The suspension was diluted with DCM (100ml_), and washed with 1 N HCI (2 x 50 mL), followed by sat NaHC0₃ (2 X 50 mL), dried over Na₂S04, filtered, and concentrated. Purification: Purified by CombiFlashORfby eluting 8% EtOAc in hexane as mobile phase to get desired product as light red color liquid. Yield (1.5g, crude), LC-MS (ES) m/z = 384.0, 386.0 [M+H]⁺.

To a stirred solution of Ay-(4-bromo-3-fluorophenyl)-2-(3,5-difluorophenyl)pent-4-enamide (1.5 g, 3.9 mmol, 1 equiv) in THF (75 mL) and water (15 mL) was added 2.5 wt% osmium tetroxide solution in t-BuOH (3.96 mL, 0.4 mmol, 0.1 equiv) followed by sodium periodate (1.66 g, 7.8 mmol, 2 equiv), and the reaction mixture was stirred at room temperature for 3 hours. Sodium periodate (1.66 g, 7.812 mmol, 2 equiv) was added at RT, and stirred for another 3h at RT. An aqueous solution of sodium thiosulfate was added to the reaction mixture, and stirred for 10 minutes. The mixture was extracted with EtOAc (100 mL) and saturated aqueous NaHC0₃ (50 mL). The organic layer was separated, washed with brine solution (30 mL), dried over Na₂S0₄, and concentrated to get desired product as gummy light brown solid. The crude product was used for next step without any purification, yield (1.5 g, crude). LC-MS (ES) m/z = 386.0, 388.0 [M+H]⁺.

To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(3,5-difluorophenyl)-5- hydroxypyrrolidin-2-one (1.5 g, 3.9 mmol, 1 equiv) in DCM(30 mL) was added triethylsilane (2.47 mL, 15.5 mmol, 4 equiv) followed by TFA (5.95 mL, 77.7 mmol, 20 equiv), and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was poured onto saturated aqueous NaHC0₃ and EtOAc (100 mL). The organic layer was separated, washed with brine solution (30 mL), dried over Na₂S0₄, filtered and concentrated. Purification: Purified by CombiFlashORfusing 20% EtOAc in hexane as mobile phase to afford the desired product (0.83 g, 58.04%) as a white solid. LCMS (ES) m/z = 372.0, 374.0 [M+H]⁺. H NMR (400 MHz, CDCI3) δ ppm 2.24 - 2.34 (m, 1 H), 2.64 - 2.72 (m, 1 H), 3.85 - 3.91 (m, 3 H), 6.75 (t, J=8.8 Hz, 1 H), 6.88 (d, J=6.4 Hz, 2 H), 7.32 (d, J=8.8 Hz, 1 H), 7.53 (t, J=8.4 Hz, 1 H), 7.68 (d, J=10.8 Hz, 1 H).

To a mixture of 1-(4-bromo-3-fluorophenyl)-3-(3,5-difluorophenyl)pyrrolidin-2-one (300 mg, 0.8 mmol, 1 equiv), bis(pinacolato)diboron (206 mg, 0.8 mmol, 1 equiv), and potassium acetate (238 mg, 2.4 mmol, 3 equiv) was added 1 ,4-dioxane (15 mL), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (33 mg, 0.04 mmol, 0.05 equiv) was added and again degassed with N₂ for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (195 mg, 0.8 mmol, 1 equiv) and saturated aqueous NaHC0₃ (5 mL) was added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (33 mg, 0.040 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The mixture was poured onto water and extracted into EtOAc (2 x 30 mL) dried over Na₂S0₄ and concentrated. Purification: Purified by CombiFlashORf, using 0 to 3% MeOH in DCM mobile phase. After purification compound was washed with n- pentane (2 x 3 mL), and Acetonitrile (2 x 3 mL) and dried to get desired product as light pink color solid. Yield (31 mg, 8.75%). LCMS (ES) m/z = 438.3 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.21 - 2.31 (m, 1 H), 2.56 - 2.66 (m, 1 H), 3.74 (s, 3 H), 3.90 - 4.01 (m, 2 H), 4.09 (t, J=9.2 Hz, 1 H), 5.97 (br s, 2 H), 7.10 - 7.17 (m, 3 H), 7.31 (s, 1 H), 7.42 (t, J=8.4 Hz, 1 H), 7.59 (d, J=8.4 Hz, 1 H), 7.83 (d, J=12.8 Hz, 1 H), 8.14 (s, 1 H). 99.04% purity by HPLC @ 254 nM.

Example 18

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimidin-5-yl)phenyl)-3-(2,3-clifluoro phenyl)pyrrolidin-2-one

To a stirred solution of 2-(2,3-difluorophenyl)acetic acid (3.0 g, 17.4 mmol, 1.0 equiv) inTHF (70 mL) at -78°C was added 2.2 M LHMDS solution (38.3 mL, 38.4 mmol, 2.2 equiv) drop wise over a period of 10 minutes. After completion of addition, the cooling bath was removed and after 50 min, 3-bromoprop-1-ene (4.75 mL, 55.8 mmol, 3.2 equiv) was added in one portion at 0°C. The reaction mixture was stirred for 16h at room temperature. The reaction mixture was quenched with 1 N HCI (30 mL) and extracted with EtOAc (2 x 100 mL). The organics were combined and dried over Na₂S0₄, filtered and concentrated to afford the desired product 2-(2,3-difluorophenyl)pent-4-enoic acid as light red color oil (3.10 g, crude). LC-MS (ES) m/z = 21 1.1 [M-H]⁺. H NMR (400 MHz, CDCI₃) δ 2.51 - 2.59 (m, 1 H), 2.81 - 2.88 (m, 1 H), 4.05 (t, J=7.6 Hz, 1 H), 5.01 - 5.09 (m, 2 H),

To a stirred solution of 2-(2,3-difluorophenyl)pent-4-enoic acid (1.55 g, 7.3 mmol, 1.0 equiv) and 4-bromoaniline (1.131 g, 6.6 mmol, 0.9 equiv) in 30 mL of DCM at room temperature was added DIPEA (1.4 mL, 8.035 mmol, 1.1 equiv) followed by addition of HATU (3.05 g, 8.0 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 30 min. After consumption of the starting material, the reaction mixture was washed with 1 N HCI (30 mL), saturated aqueous NaHC0₃ (30 mL), water and brine successively. The combined organic layers were dried over Na₂S0₄, filtered & evaporated. The crude product was washed in n-pentane to afford the desired product A/-(4-bromophenyl)-2-(2,3- difluorophenyl)pent-4-enamide as a brown semi solid (2.709 g, crude) which has a purity of 79% as evidenced by LCMS and proceeded further without purification. H NMR (400 MHz, DMSOd6) δ 2.89 (s, 1 H), 4.1 1 (t, J=8.0 Hz, 1 H), 4.97 - 5.07 (m, 2 H), 5.68 - 5.78 (m, 1 H), 7.15 - 7.22 (m, 1 H), 7.28 - 7.34 (m, 2 H), 7.45 (d, J=12.0 Hz, 2 H), 7.54 (d, J=12.0 Hz, 2 H), 10.31 (s, 1 H).

To a stirred solution of A/-(4-bromophenyl)-2-(2,3-difluorophenyl)pent-4-enamide (2.144g, 5.9 mmol, 1 equiv), in THF (100 mL), water (20 mL) at room temperature was added 2.5 wt% osmium tetroxide solution in t-BuOH (6 mL, 0.585 mmol, 0.1 equiv) followed by sodium periodate (5.02 g, 23.4 mmol, 4 equiv) and the resulting solution was stirred for 4h at room temperature. The reaction mixture was quenched with saturated aqueous sodium thiosulphate and stirred for 10 minutes. The mixed organic layers were washed with saturated aqueous NaHC0₃ followed by brine, dried over Na₂S0₄, filtered and evaporated to afford the desired product 1-(4-bromophenyl)-3-(2,3-difluorophenyl)-5-hydroxy pyrrolidin-2-one as brown oil (3.420 g, crude) and proceeded further without purification. LC-MS (ES) m/z = 368.0, 370.0 [M+H]⁺, H NMR (400 MHz, DMSOd6) δ ppm 2.34 - 2.37 (m, 1 H), 2.68 - 2.70 (m, 1 H), 4.44 (t, J=8.0 Hz, 1 H), 5.71 - 5.81 (m, 1 H), 6.58 (d, J=8.0

To a stirred solution of 1-(4-bromophenyl)-3-(2,3-difluorophenyl)-5-hydroxypyrrolidin -2- one (2.156 g, 5.9 mmol, 1 equiv) in DCM (80 mL) was added with Triethylsilane (3.80 mL, 23.4 mmol, 4 equiv) followed by Trifluoroaceticacid (7.63 mL, 1 17.1 mmol, 20 equiv). The resulting solution was stirred at room temperature for 3h. After consumption of the starting material, the reaction mixture was quenched with saturated aqueous NaHC0₃, extracted with DCM. The mixed organic layers was washed with brine, dried over Na₂S0₄, filtered, evaporated and purified by silica gel flash chromatography using 1 1 % EtOAc in Hexane as mobile phase. The combined fractions were concentrated in vacuo to afford the desired product 1-(4-bromophenyl)-3-(2, 3-difluorophenyl)pyrrolidin-2-one as off white solid (1.681 g, 81.6%). LC-MS (ES) m/z = 352.0, 354.0 [M+H]⁺, H NMR (400 MHz, CDCIs) δ 2.22 - 2.30 (m, 1 H), 2.63 - 2.71 (m, 1 H), 3.88 - 3.95 (m, 2 H), 4.13 (t, J=8.0 Hz, 1 H), 7.02 - 7.14 (m, 3 H), 7.50 (d, J=8.0 Hz, 2 H), 7.59 (d, J=8.0 Hz, 2 H).

Run1 :

To a stirred and degassed solution of 1-(4-bromophenyl)-3-(2,3-difluorophenyl)pyrrolidin- 2-one (0.050 g, 0.141 mmol, 1.0 equiv), bis(pinacolato)diboron (0.180 g, 0.142 mmol, 1.0 equiv), and potassium acetate (0.209 g, 0.425 mmol, 3.0 equiv) in 1 ,4-dioxane (3 ml_) was added Pd(dppf)CI₂.DCM complex (0.006 g, 0.007 mmol, 0.05 equiv) and heated in a sealed vessel for 4 hours at 100 °C. After consumption of the starting material, the reaction mixture was cooled to room temperature and taken to LCMS. The LCMS analysis showed the formation of the desired product and was combined with run 2

Run2:

To a stirred and degassed solution of 1-(4-bromophenyl)-3-(2,3-difluorophenyl) pyrrolidin- 2-one (0.250 g, 0.8 mmol, 1.0 equiv), Bis(pinacolato)diboron (0.180 g, 0.8 mmol, 1.0 equiv), and potassium acetate (0.209 g, 2.1 mmol, 3.0 equiv) in 1 ,4-Dioxane (15 ml_) was added Pd(dppf)CI₂.DCM complex (0.029g, 0.04 mmol, 0.05 equiv) and heated in a sealed vessel for 4 hours at 100°C. After consumption of the starting material, the reaction mixture was cooled to room temperature and was combined with the reaction mixture from run 1 to afford a total 18 ml_. The combined reaction mixture waspartitioned between water and EtOAc. The two layers were separated and the combined organic layers were washed with brine, dried over Na₂S0₄, evaporated and the crude product was purified via silica gel flash chromatography. The desired product was eluted over a solvent gradient of 19 - 20% EtOAC: Hexanes. The fractions containing the desired product was concentrated to afford 3-(2,3-difluorophenyl)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)pyrrolidin-2-one as off white solid (0.168 g, 48%). LC-MS (ES) m/z = 400.2 [M+H]⁺, H NMR (400 MHCDCI₃) δ 1.34 (s, 12 H), 2.23 - 2.33 (m, 1 H), 2.56 - 2.65 (m, 1 H), 3.95 - 3.97 (m, 2 H), 4.15 (m, 1 H), 7.07 - 7.13 (m, 3 H), 7.70 (d, J=8.0 Hz, 2 H), 7.84

Run1 :

To a stirred and degassed solution of 3-(2,3-difluorophenyl)-1-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (0.025 g, 0.06 mmol, 1.0 equiv) in 1 ml_ 1 ,4-dioxane and 0.25 ml_ water was added 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin- 4-amine (0.018 g, 0.08 mmol, 1.25 equiv), K₃P0₄ (0.027 g, 0.6 mmol, 10 equiv) and tri-(t- butyl)phosphonium tetrafluoroborate ( 0.0018 g, 0.006 mmol, , 0.1 equiv), Pd₂(dba)₃ (0.003 g, 0.003 mmol, 0.05 equiv) and the vessel is closed and heated to 100°C for 3 hours. After consumption of the starting material, the reaction mixture was partitioned between EtOAc and water, the two layers were separated. The combined organic phase was washed with brine, dried over Na₂S0₄, filtered and evaporated, the crude material was combined with run 2. LC-MS (ES) m/z = 420.1 [M+H]⁺ Run2:

To a stirred and degassed solution of 3-(2,3-difluorophenyl)-1-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (0.1 15 g, 0.3 mmol, 1.0 equiv) in 14 mL 1 ,4-dioxane and 3.4 mL water was added 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4- amine (0.0.72 g, 0.3 mmol, 1.12 equiv), K₃P0₄ (0.122 g, 0.6 mmol, 2 equiv), and tri-(t- butyl)phosphonium tetrafluoroborate (0.0084 g, 0.03 mmol, 0.1 equiv) followed by Pd₂(dba)₃ (0.013g, 0.0144 mmol, 0.05 equiv) and the vessel is closed and heated to 100°C for 3 hours. After consumption of the starting material, the reaction mixture was cooled to room temperature and combined with the reaction mixture from Run1 , (total 18.65 mL) was partitioned between EtOAc and water, the two layers were separated. The combined organic phase was washed with brine, dried over Na₂S0₄, filtered and evaporated. The crude product was purified by flash chromatography using solvent gradient of 2% MeOH:DCM. The isolated product has 80% HPLC purity and further it was repurified by prep HPLC. Analytical conditions: Column: Zorbax XDB C18 (150 mm x 4.6 mm x 3.5 μηι). Mobile phase A: 0.01 % Ammonia in water, Mobile phase B: ACN, Flow rate: 1.0 mL/min. The pure fractions were concentrated to afford the desired product 1-(4- (4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(2,3-difluorophenyl)pyrrolidin- 2-one as off white solid (0.08 g, 47%). LC-MS (ES) m/z = 420.1 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.21 (t, J=12.0 Hz, 1 H), 2.59 (t, J=4.0Hz, 1 H), 3.73 (s, 3 H), 3.97 - 4.01 (m, 2 H), 4.25 (t, J=8.0 Hz, 1 H), 6.03 (br s, 2 H), 7.22 - 7.30 (m, 2 H), 7.29 (s, 1 H), 7.33 - 7.40 (m, 1 H), 7.47 (d, J=8.0 Hz, 2 H), 7.80 (d, J=8.0 Hz, 2 H), 8.14 (s, 1 H).

Example 19

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimiclin-5-yl)-3-fluorophenyl)-3-(2,3- difluorophenyl)pyrrolidin-2-one:

To a stirred solution of 2-(2,3-difluorophenyl)pent-4-enoic acid (1.55 g, 7.30 mmol, 1.0 equiv) and 4-bromo-3-fluoroaniline (1.250 g, 6.6 mmol, 0.9 equiv) in 30 mL of DCM at room temperature was added W./V-diisopropylethylamine (1.039 g, 8.0 mmol, 1.1 equiv) followed by addition of HATU (3.05 g, 8.0 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 30 min, after consumption of the starting material, the reaction mixture was washed with 1 N HCI (30 mL), saturated aqueous NaHC0₃ (30 mL), water and brine successively. The mixed organic layer was dried over Na₂S0₄, filtered and evaporated. The crude material was washed in n-pentane to afford the desired product as brown oil (2.897 g, crude), crude product was preceded to next step without purification. H NMR (400 MHz, DMSOd6) δ 2.45 - 2.49 (m, 1 H), 2.73 - 2.85 (m, 1 H), 4.11 (t, J=8.0 Hz, 1 H), 4.98 - 5.07 (m, 2 H), 5.68 - 5.78 (m, 1 H), 7.14 - 7.22 (m, 1 H), 7.24 - 7.35 (m, 3 H), 7.60 (t, J=8.0 Hz, 1 H), 7.71 - 7.75 (m, 1 H), 10.51 (s, 1 H).

To a stirred solution of Ay-(4-bromo-3-fluorophenyl)-2-(2,3-difluorophenyl)pent-4-enamide (1.970 g, 5.128 mmol, 1 equiv), in THF (100 mL) and water (20 mL) at room temperature was added 2.5 wt% osmium tetroxide solution in t-BuOH (0.131 g, 0.513 mmol, 0.1 equiv) followed by sodium periodate (4.387 g, 20.511 mmol, 4 equiv) and the resulting solution was stirred for 4h at room temperature. The reaction mixture was quenched with saturated sodium thiosulphate solution and stirred for 10 minutes. The combined organic layers were washed with saturated aqueous NaHC0₃ solution and brine solution, dried over Na₂S0₄, filtered and evaporated to afford the desired product 1-(4-bromo-3- fluorophenyl)-3-(2,3-difluorophenyl)-5-hydroxy pyrrolidin-2-one as brown viscous liquid (3.00 g, crude) and proceeded further without purification. LC-MS (ES) m/z = 386.0, 388.0 [M+H]⁺, H NMR (400 MHz, DMSOd6) δ ppm 2.34 - 2.37 (m, 1 H), 2.68 (s, 1 H), 4.45 (t, J=8.00 Hz, 1 H), 5.73 - 5.83 (m, 1 H), 6.68 (d, J=4.0 Hz, 1 H), 7.21 - 7.26 (m, 2 H), 7.35 - 7.42 (m,

To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(2,3-difluorophenyl)-5-hydroxy pyrrolidin-2-one (1.980 g, 5.13 mmol, 1.0 equiv) in 60 mL of DCM was added triethylsilane (3.30 mL, 2.051 mmol, 4.0 equiv) followed by trifluoro acetic acid (TFA) (6.7 mL, 102.6 mmol, 20.0 equiv). The resulting solution was stirred at room temperature for 2h. After consumption of the starting material, the reaction mixture was quenched with saturated aqueous NaHC0₃, & extracted with DCM. The mixed organic layers was washed with brine, dried over Na₂S0₄, filtered, & evaporated. The crude product was purified by silica gel flash chromatography. The desired product eluted in 10% EtOAc:Hex. The combined fractions were concentrated in vacuo to afford the desired product 1-(4-bromo-3-fluorophenyl)-3-(2,3-difluorophenyl)pyrrolidin-2-one as a pale yellow solid (1.30 g, 68.7%). LC-MS (ES) m/z = 370.0, 372.0 [M+H]⁺, H NMR (400 MHz, DMSOd6) δ ppm 2.22 - 2.32 (m, 1 H), 2.64 - 2.72 (m, 1 H), 3.89 - 3.93 (m, 2 H), 4.13 (t, J=12.0 Hz, 1 H), 6.99 - 7.06 (m, 1 H), 7.07 - 7.16 (m, 2 H), 7.33 (dd, J=2.0, 8.80 Hz, 1 H),

Run 1 :

To a stirred and degassed solution of 1-(4-bromo-3-fluorophenyl)-3-(2,3-difluorophenyl) pyrrolidin-2-one (0.10 g, 0.3 mmol, 1.0 equiv), bis(pinacolato)diboron (0.072 g, 0.28 mmol, 1.05 equiv), and potassium acetate (0.080 g, 0.810 mmol, 3.0 equiv) in 1 ,4-dioxane (7 mL) was added Pd(dppf)CI₂.DCM complex (0.01 1 g, 0.0135 mmol, 0.05 equiv) and heated in a sealed vessel for 3 hours at 100°C. Reaction monitoring by LCMS showed consumption of starting material and it was used along with run 2 for next step. Run2:

To a stirred and degassed solution of 1-(4-bromo-3-fluorophenyl)-3-(2,3-difluoro phenyl)pyrrolidin-2-one (0.300 g, 0.8 mmol, 1.0 equiv), bis(pinacolato)diboron (0.216 g, 0.85 mmol, 1.05 equiv), and potassium acetate (0.239 g, 22.4 mmol, 3.0 equiv) in 20 mL 1 ,4-dioxane was added Pd(dppf)CI₂.DCM complex (0.033g, 0.040 mmol, 0.05 equiv) and heated in a sealed vessel for 3 hours at 100°C. The reaction mixture was cooled to room temperature (combined with the reaction mixture from run1), 5-bromo-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-4-amine (0.224 g, 1.0 mmol, 1.3 equiv) and sat. NaHC0₃ (11 mL) were added and degassed thoroughly. Pd(dppf)CI₂.DCM complex (0.062 g, 0.076 mmol, 0.1 equiv) was added and the vessel was sealed, and the reaction mixture was heated to 100°C and stirred overnight. After consumption of the starting material, the reaction mixture was partitioned between water (35 mL) and EtOAc (200 mL). The two layers were separated and the combined organic layers were washed with brine, dried over Na₂S0₄, evaporated and the crude product was purified by flash chromatography. The desired product was eluted over 24 g column using 2.5% MeOH:DCM as eluent. The pure fractions were concentrated to afford the required product 1-4-(4-amino-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(3,5-dimethyl phenyl) pyrrolidin-2-one as beige solid (0.094 g, 28.4%). LC-MS (ES) m/z = 438.1 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.19 - 2.27 (m, 1 H), 2.59 - 2.66 (m, 1 H), 3.74 (s, 3 H), 3.97 - 4.01 (m, 2 H), 4.29 (t, J=8.0 Hz, 1 H), 5.99 (br s, 2 H), 7.22 (s, 2 H), 7.31 (s, 1 H), 7.34 - 7.45 (m, 2 H), 7.59 (d, J=8.0 Hz, 1 H), 7.81 (d, J=12.0 Hz, 1 H), 8.14 (s, 1 H).

Example 20 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimiclin-5-yl)-3-fluorophenyl)-3-(3,4- difluorophenyl)pyrrolidin-2-one

To a stirred solution of 2-(3,4-difluorophenyl)acetic acid (3.0 g, 17.4 mmol, 1.0 equiv) in THF (40 mL) was added 1.0 M LHMDS solution (40.1 mL, 38.4 mmol, 2.2 equiv) drop wise over a period of 10 minutes at -78°C. After completion of LHMDS addition, the cooling bath was removed, the mixture was warmed to 0°C gradually. After stirring for 1 hour, allyl bromide (4.9 mL, 56.676 mmol, 3.25 equiv) was added in one portion at 0°C. The temperature rose to 22 °C and the mixture became a clear solution again. After an additional 30 minutes the mixture became milky. The reaction mixture was stirred for 16h, the reaction mixture was diluted with 1 N HCI (30 mL) and extracted with ethyl acetate (2 X 100 mL). The organics were combined and washed with saturated aqueous NaHC0₃ (2 X 50 mL), brine solution (60 mL) and dried over Na₂S0₄, filtered, and evaporated to afford the crude product 2-(3,4-difluorophenyl)pent-4-enoic acid as brown liquid (3.01 g). LC-MS (ES) m/z = 21 1.1 [M-H]⁺.

To a stirred solution of 2-(3,4-difluorophenyl)pent-4-enoic acid (1.5 g, 7.1 mmol, 1.0 equiv ) and 4-bromoaniline (1.0 g, 6.4 mmol, 0.9 equiv) in 30 ml of DCM at room temperature was added DIPEA (1.35 mL, 7.78 mmol, 1.1 equiv), followed by HATU (2.95 g, 7.78 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred at room temperature for 60 minutes. After completion of the reaction, the suspension was diluted with DCM (100mL), was washed with 1 N HCI (2 x 50 mL), saturated aqueous NaHC0₃ (2 x 50mL), brine solution (60 mL) and dried over Na₂S0₄, filtered, and evaporated to afford the crude product N-(4-bromophenyl)-2-(3,4-difluorophenyl)pent-4-enamide as brown liquid (2.1 g). LC-M

To a stirred solution of A/-(4-bromophenyl)-2-(3,4-difluorophenyl)pent-4-enamide (1.1 g, 3.0 mmol) in a mixture of THF (55 mL) and water (12 mL) was added osmium tetroxide solution (2.5 wt% in t-BuOH) (3.0 mL, 0.3 mmol, 0.1 equiv), followed by sodium periodate (1.28 g, 6.0 mmol, 2.0 equiv), and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, an aqueous solution of sodium thiosulfate was added, and the resulting mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate (2 x 80 mL) and the combined organic layers were washed with aqueous NaHC0₃ and brine solution (60 mL), dried over Na₂S0₄, and evaporated the solvent under reduced pressure. LCMS analysis indicated the presence of desired product and the diol intermediate. This material was dissolved in a mixture of THF (55 mL) and Water (12 mL) and treated with sodium periodate (1.28 g, 6.1 mmol, 2 equiv). The resulting mixture was stirred for 3 hours at room temperature. After completion of the reaction, an aqueous solution of sodium thiosulfate was added, and the resulting mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate (2 x 80 mL) and the combined organic layers were washed with aqueous NaHC0₃ and brine solution (60 mL), dried over Na₂S0₄, and evaporated to afford crude product 1-(4-bromophenyl)-3- (3,4-difluorophenyl)-5-hydroxypyrrolidin-2-one (1.1 g) as brown solid. LC-MS (ES) m/z = 367.0, 369.0 [M+H]⁺.

To a stirred solution of 1-(4-bromophenyl)-3-(3,4-difluorophenyl)-5-hydroxypyrrolidin-2- one (1.1 g, 3.0 mmol) in DCM (20 mL) was added triethylsilane (1.91 mL, 12 mmol, 4.0 equiv), followed by TFA (3.9 mL, 59.945 mmol, 20.0 equiv), and the reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was poured onto saturated aqueous NaHC0₃ and ethyl acetate (100 mL). The organic layer was separated and washed with brine solution (30 mL), dried over Na₂S0₄, filtered and evaporated the solvent under reduced pressure to afford the crude product. Purification: The crude product was purified by using flash chromatography with 100 - 200 silica gel (24 g column) using 6% EtOAc in n-Hexane as mobile phase to afford the titled product 1-(4-bromophenyl)-3-(3,4-difluorophenyl)pyrrolidin-2-one (0.57 g, 57%) as white solid. LCMS (ES) m/z = 352.0, 354.0 [M+H]⁺. ]⁺. H NMR (400 MHz, DMSO d6) δ 2.18 - 2.23 (m, 1 H), 2.53 - 2.57 (m, 1 H), 3.87 - 3.90 (m, 2 H), 3.99 (t, J=9.2 Hz, 1 H, 7.18 (br s., 1 H), 7.36 - 7.45 (m, 2 H), 7.56 (d, J=8.8 Hz, 2 H), 7.67 (d, J=8.8 Hz, 2 H).

To a mixture of 1-(4-bromophenyl)-3-(3,4-difluorophenyl)pyrrolidin-2-one (270 mg, 0.8 mmol), bis(pinacolato)diboron (190 mg, 0.8 mmol, 1.0 equiv), and potassium carbonate (310 mg, 3.2 mmol, 3.0 equiv) was added 1 ,4-dioxane (5 mL), and the mixture was degassed with argon gas for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (31.0 mg, 0.04 mmol, 0.05 equiv) was added and again degassed with argon gas for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. After completion of the reaction, the reaction was cooled to room temperature. 5-bromo-7-methyl-7H-pyrrolo[2,3- d]pyrimidin-4-amine (140 mg, 0.769 mmol, 1.0 equiv) and saturated aqueous NaHC0₃ (5 mL) was added, and argon gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (31.0 mg, 0.038 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100°C. After completion of the reaction, the mixture was poured onto water and extracted with ethyl acetate (2 x 30 mL) and the combined organic layers were washed with brine solution (30 mL), dried over Na₂S0₄ and evaporated the to afford the crude product. Purification : The crude product was purified by using flash chromatography with 100 - 200 silica gel (24g column) and eluted with 3% MeOH in DCM mobile phase to afford the titled product 1-(4-(4-amino-7- methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3,4-difluorophenyl)pyrrolidin-2-one (0.03 g, 10%) as a white solid. LCMS (ES) m/z = 420.1 [M+H]⁺. H NMR (400 MHz, DMSO d6) δ ppm

2.17 - 2.27 (m, 1 H), 2.55 - 2.61 (m, 1 H), 3.73 (s, 3 H), 3.73 - 3.97 (m, 2 H), 4.02 (t, J=9.6 Hz, 1 H), 6.03 (br s, 2 H), 7.20 (br s., 1 H), 7.29 (s, 1 H), 7.38 - 7.48 (m, 4 H), 7.80 (d, J=8.8 Hz, 2 H), 8.15 (s, 1 H). Example 21

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimiclin-5-yl)-3-fluorophenyl)-3-(3,4- difluorophenyl)pyrrolidin-2-one

To a stirred solution of 2-(3,4-difluorophenyl)pent-4-enoic acid (2.5 g, 11.8 mmol, 1.0 equiv) and 4-bromo-3-fluoroaniline (2.0 g, 10.6 mmol, 0.9 equiv) in 50 ml of DCM at room temperature was added DIPEA (2.2 mL, 12.96 mmol, 1.1 equiv), followed by HATU (4.9 g, 12.968 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred at room temperature for 60 minutes. After completion of the reaction, the suspension was diluted with DCM (100mL), washed with 1 N HCI (2 x 40 mL), followed by saturated aqueous NaHC0₃ (2 x 40 mL) and brine solution (50 mL), organic layers were combined and dried over Na₂S04, filtered, and evaporated the solvent to afford the crude product A/-(4-bromo- 3-fluorophenyl)-2-(3,4-difluorophenyl)pent-4-enamide as brown liquid (2.55 g). LC-MS (ES) m/z = 384.0, 386.0 [M+H]⁺.

To a stirred solution of A/-(4-bromo-3-fluorophenyl)-2-(3,4-difluorophenyl)pent-4-enamide (2.55 g, 6.6 mmol, 1 ,0 equiv) in THF (70 mL) and water (20 mL) was added osmium tetroxide solution (2.5 wt% in V-BuOH (6.7 mL, 0.7 mmol, 0.1 equiv), followed by sodium periodate (2.84 g, 13.3 mmol, 2.0 equiv), and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, an aqueous solution of sodium thiosulfate was added, and the resulting mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were washed with aqueous NaHC0₃, brine solution (50 mL), dried over Na₂S0₄), and evaporated the solvent under reduced pressure to afford the crude product. LCMS analysis indicated the presence of desired product and the diol intermediate. This material was dissolved in a mixture of THF (70 mL) and Water (20 mL) and treated with sodium periodate (2.84 g, 13.3 mmol, 2.0 equiv). The resulting mixture was stirred for 3 hours at room temperature. After completion of the reaction, an aqueous solution of sodium thiosulfate was added, and the resulting mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were washed with aqueous NaHC0₃, brine solution (50 mL), dried over Na₂S0₄ and evaporated the solvent under reduced pressure to afford the crude product 1-(4-bromo-3- fluorophenyl)-3-(3,4-difluorophenyl)-5-hydroxypyrrolidin-2-one (2.5 g) as brown solid. LC- MS (ES) m/z = 385.0, 387.0 [M+H]⁺.

To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(3,4-difluorophenyl)-5- hydroxypyrrolidin-2-one (2.5 g, 6.5 mmol, 1.0 equiv) inDCM (50 mL) was added triethylsilane (4.1 mL, 26.0 mmol, 4.0 equiv), followed by TFA (8.4 mL, 130.0 mmol, 20.0 equiv), and the reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was poured onto saturated aqueous NaHC0₃ and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, washed with brine solution (50 mL), dried over Na₂S0₄, filtered and evaporated the solvent under reduced pressure to afford the crude product. Purification: The crude product was purified by using flash chromatography with 100 - 200 silica gel (24 g column) and eluted using 5% EtOAc in n-Hexane as mobile phase to afford the desired product, 1-(4-bromo-3-fluorophenyl)-3-(3,4-difluorophenyl)pyrrolidin-2-one (1.0 g, 43.4%) as white solid. LCMS (ES) m/z = 369.0, 371.0 [M+H]⁺.. H NMR (400 MHz, DMSOd6) δ 2.15 - 2.25 (m, 1 H), 2.52 - 2.55 (m, 1 H), 3.84 - 3.93 (m, 2 H), 4.05 (t, J=9.6 Hz, 1 H), 7.18 (br s., 1 H), 7.36 - 7.43 (m, 2 H), 7.45 - 7.50 (m, 1 H), 7.70 (t, J=8.8 Hz, 1 H), 7.82 - 7.86 (m, 1 H).

To a mixture of 1-(4-bromo-3-fluorophenyl)-3-(3,4-difluorophenyl)pyrrolidin-2-one (0.5 g, 2.7 mmol, 1.0 equiv), bis(pinacolato)diboron (0.34 g, 2.7 mmol, 1.0 equiv), and potassium carbonate (0.56 g, 8.1 mmol, 3.0 equiv) was added 1 ,4-dioxane (10 mL), and the mixture was degassed with Argon gas for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.05 g, 0.135 mmol, 0.05 equiv) was added and again degassed with argon gas for 10 minutes. The reaction mixture was stirred for 3 hours at 100°C in a sealed vessel. After completion of the reaction, the reaction was cooled down to room temperature. 5-bromo-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-4-amine (0.35 g, 2.710 mmol, 1.0 equiv) and saturated aqueous NaHC0₃ (5 mL) was added, and purged argon gas through the reaction mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.05 g, 0.135 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100°C. After completion of the reaction, the reaction mixture was poured onto water and extracted with ethyl acetate (2 x 40 mL) and the combined organic layers were washed with brine solution (30 mL), dried over Na₂S0₄ and evaporated the solvent under reduced pressure to afford the crude product. Purification: The crude product was purified by using flash chromatography with 100 - 200 silica gel (24 g column) and eluted using 2.5% MeOH in DCM mobile phase to afford the desired product, 1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3- d]pyrimidin-5-yl)-3-fluorophenyl)-3-(3,4-difluorophenyl)pyrrolidin-2-one (0.045 g, 9%) as off white solid. LCMS (ES) m/z = 438.1 [M+H]⁺. H NMR (400 MHz, DMSO cB) δ ppm

2.20 - 2.31 (m, 1 H), 2.57 - 2.66 (m, 1 H), 3.74 (s, 3 H), 3.90 - 3.98 (m, 2 H), 4.00 - 4.07 (m, 2 H), 5.97 (br s., 2 H), 7.20 (br s., 1 H), 7.30 (s, 1 H), 7.38 - 7.46 (m, 3 H), 7.58 (d, J=7.2 Hz, 1 H), 7.82 (d, J=12.8 Hz, 1 H), 8.14 (s, 1 H). Example 22

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimiclin-5-yl)-3-fluorophenyl)-3-(2,5- difluorophenyl)pyrrolidin-2-one

To a stirred solution of 2-(2,5-difluorophenyl)pent-4-enoic acid (1.2 g, 5.6 mmol, 1.0 equiv) and 4-bromo-3-fluoroaniline (1.27 g, 6.7 mmol, 1.2 equiv) in 50 ml of DCM at room temperature was added DIPEA (2.9 mL, 16.8 mmol, 3 equiv), after 10 min followed by HATU (3.2 g, 8.4 mmol, 1.5 equiv) in one portion. The resulting suspension was stirred at room temperature 16 h. The reaction mixture was concentrated in vacuo to give crude compound. The crude compound was purified with CombiFlashORf, Si0₂ column and compound was eluted at 13% ethyl acetate in n-hexane. The collected fractions with pure product were concentrated to give A/-(4-bromo-3-fluorophenyl)-2-(2,5-difluorophenyl)pent- 4-enamide(1.2 g, 57%). LC-MS (ES) m/z = 384.0, 386.0 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ ppm 2.71 - 2.78 (m, 1 H), 4.02 - 4.09 (m, 1 H), 4.97 - 5.00 (m, 1 H), 5.04 - 5.09 (m, 1 H), 5.67 - 5.77 (m, 1 H), 7.06 - 7.13 (m, 1 H), 7.15 - 7.33 (m, 3 H), 7.59 (t, J=8.4 Hz, 1 H), 7.71- 7.74 (m, 1 H), 10.52 (s, 1 H).

To a stirred solution of N-(4-bromo-3-fluorophenyl)-2-(2,5-difluorophenyl)pent-4-enamide (1.2 g, 3.1 mmol) in THF (60 mL) and water (10 mL) was added 2.5 wt% osmium tetroxide solution in t-BuOH (4.1 mL, 0.3 mmol, 0.1 equiv) followed by sodium periodate (2.6 g, 13.0 mmol, 4.0 equiv), and the reaction mixture was stirred at room temperature for 3 hours. An aqueous solution of sodium thiosulfate (60 mL) and sodium bicarbonate solution (60 mL) was added, and extracted with EtOAc (2 x 60 mL). The organics were combined and dried over Na₂S0₄, filtered, and concentrated in vacuo to give 1-(4-bromo- 3-fluorophenyl)-3-(2,5-difluorophenyl)-5-hydroxypyrrolidin-2-one as black color oil (1. 0 g, crude). This material was used without purification in the next step. LC-MS (ES) m/z = 386.0,

To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(2,5-difluorophenyl)-5- hydroxypyrrolidin-2-one (1 g, 2.5 mmol) in dichloromethane (40 mL) was added triethylsilane (1.6 mL, 10.0 mmol, 4.0 equiv) followed by TFA (3.4 mL, 4.6 mmol, 1.5 equiv), and the reaction mixture was stirred for 3 hours at room temperature. The reaction was poured onto saturated aqueous NaHC0₃ and extracted with EtOAc (2 x 60 mL). The organic layer was separated, washed with brine, dried (Na₂S0₄), filtered and concentrated to afford 1-(4-bromo-3-fluorophenyl)-3-(2,5-difluorophenyl)pyrrolidin-2-one (0.4 g, 43%). LCMS (ES) m/z = 370.0, 372.0 [M+H]⁺. δ 2.15 - 2.21 (m, 1 H), 2.49 - 2.53 (m, 1 H), 3.91 - 3.94 (m, 2 H), 4.20 (t, J=10.0 Hz, 1 H), 7.16 - 7.29 (m, 3 H), 7.49 (d, J=7.6 Hz, 1 H), 7.71 (t, J= 8.4 Hz, 1 H), 7.82 - 7.85 (m, 1 H).

To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(2,5-difluorophenyl)pyrrolidin-2-one (0.3 g, 0.8 mmol, 1.0 equiv ) in 1 ,4-dioxane (20 mL) was added bis(pinacolato)diboron (0.24 g, 1.0 mmol, 1.2 equiv) and potassium carbonate (0.33 g, 2.4 mmol, 3.0 equiv). The reaction mixture was degassed with N₂ for 15 minutes, PdCl₂(dppf)-CH₂Cl₂ adduct (0.033 g, 0.04 mmol, 0.05 equiv) was added and the reaction mixture was stirred for 3 hours at 100 °C in a sealed tube. The reaction was cooled to room temperature, 5-bromo-7- methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.27 g, 1.2 mmol, 1.5 equiv) and saturated aqueous NaHC0₃ (10 mL) were added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.033 g, 0.040 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organics were combined and dried over Na₂S0₄, filtered, and concentrated in vacuo to get crude compound. Crude product was purified by flash chromatography on silica gel and compound was eluted with 3% MeOH/DCM. The fractions containing the desired product were combined and concentrated to afford 1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3- d]pyrimidin-5-yl)-3-fluorophenyl)-3-(2,5-difluorophenyl)pyrrolidin-2-one (20 mg, 5.6 %) as off white solid. LCMS (ES) m/z = 438.3 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ ppm 2.21 - 2.31 (m, 2 H), 3.74 (s, 3 H), 3.97 (t, J=7.6 Hz, 2 H), 4.20 - 4.30 (m, 1 H), 5.98 (br s,2 H), 7.18 - 7.22 (m, 1 H), 7.27 - 7.31 (m, 3 H), 7.39 - 7.45 (m, 1 H), 7.59 (d, J=8.4 Hz, 1 H), 7.81 (d, J=11.6 Hz, 1 H), 8.14 (s, 1 H).

Example 23

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimiclin-5-yl)-2-fluorophenyl)-3-(3,5- difluorophenyl)pyrrolidin-2-one

To a stirred solution of 2-(3,5-difluorophenyl)pent-4-enoic acid (2 g, 9.4 mmol, 1 equiv) and 4-bromo-2-fluoroaniline (1.79 g, 9.4 mmol, 1 equiv) in 30 ml of DCM at 0 °C was added DIPEA (2.5 ml_, 14.2 mmol, 1.5 equiv), followed by HATU (3.94 g, 10.4 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred at room temperature for 3h. The suspension was diluted with DCM washed with 1 N HCI (50 ml_), and sat NaHC0₃ (50 ml_), dried over Na₂S0₄, filtered and concentrated. Purification: purified by flash column chromatography (40g column), using 5% ethyl acetate in hexane as mobile phase to get desired product as off white solid. Yield (1.8g, 50%). LC-MS (ES) m/z = 384.0, 386.0 [M+H]⁺. H NMR (400 MHz, DMSOc/6) δ 2.43 - 2.49 (m, 1 H), 2.71 - 2.79 (m, 1 H), 4.02 (t, J=7.6 Hz, 1 H), 5.00 (d, J=10 Hz, 1 H), 5.10 (d, J=17.2 Hz, 1 H), 5.66 - 5.76 (m, 1 H), 7.08 - 7.13 (m, 3 H), 7.34 (d, J=8.8 Hz, 1 H), 7.56 (d, J=8.8 Hz, 1 H), 7.78 (t, J=8.8, 2 Hz, 1 H), 10.05

To a stirred solution of A/-(4-bromo-2-fluorophenyl)-2-(3,5-difluorophenyl)pent-4-enamide (1.8 g, 4.7 mmol, 1 equiv) in a mixture of THF (75 ml_) and water (15 ml_) was added 2.5 wt% osmium tetroxide solution in t-BuOH (4.76 ml_, 0.5 mmol, 0.1 equiv) and sodium periodate (3.9 g, 18.8 mmol, 4 equiv ), the reaction mixture was stirred at room temperature for overnight. Aqueous solution of sodium thiosulfate was added, and stirred for 10 minutes. The mixture was extracted into EtOAc and saturated aqueous NaHC0₃ (100 ml_). The organic layer was separated, washed with brine solution, dried over Na₂S0₄, and concentrated to afford the crude product (2 g, crude) as brown liquid. This material was used for next step without purification. LC-MS (ES) m/z = 386.0, 388.0 [M+H]⁺.

To a stirred solution of 1-(4-bromo-2-fluorophenyl)-3-(3,5-difluorophenyl)-5- hydroxypyrrolidin-2-one (2 g, 5.2 mmol, 1 equiv) in dichloromethane (20 mL) was added tnethylsilane (3.3 mL, 20.7 mmol, 4 equiv) and TFA (7.9 mL, 10.6 mmol, 20 equiv), the reaction mixture was stirred for overnight at room temperature. The reaction mixture was poured onto saturated aqueous NaHC0₃ and EtOAc. The organic layer was separated, washed with brine solution, dried over Na₂S0₄ and concentrated. Purification: Purified by flash column chromatography (80g silica gel column) using 10% EtOAc in hexane as mobile phase to afford 1-(4-bromo-2-fluorophenyl)-3-phenylpyrrolidin-2-one (0.8 g, 42%) as brown color liquid. LCMS (ES) m/z = 370.0, 372.0 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ 2.26 - 2.35 (m, 1 H), 2.65 - 2.73 (m, 1 H), 3.81 - 3.86 (m, 2 H), 3.88 - 3.95 (m, 1 H), 6.71 - 6.77 (m, 1 H), 6.87 - 6.92 (m, 2 H), 7.31 - 7.38 (m, 3 H).

To a mixture of 1-(4-bromo-2-fluorophenyl)-3-phenylpyrrolidin-2-one (500 mg, 1.35 mmol, 1.0 equiv), bis(pinacolato)diboron (343 mg, 1.35 mmol, 1.0 equiv ), and potassium acetate (397 mg, 4.05 mmol, 3.0 equiv ) was added 1 ,4-dioxane (23 mL), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (55 mg, 0.067 mmol, 0.05 equiv) was added and again degassed with N₂ for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (306 mg, 1.35 mmol, 1.0 equiv) and saturated aqueous NaHC0₃ (7 mL) was added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (55 mg, 0.067 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The reaction mixture was cooled and filtered through celite bed, washed with EtOAc (100 mL), the filtrate was dried over Na₂S0₄ and concentrated. The crude was purified by flash column chromatography with 24 g silica gel column and 3% MeOH in DCM as mobile phase. Finally compound was washed with acetonitrile (3 x 3 mL) and dried to get desired product as off white solid. Yield (90 mg, 15%). LCMS (ES) m/z = 438.22 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ 2.25 - 2.33 (m, 1 H), 2.60 - 2.68 (m, 1 H), 3.73 (s, 3 H), 3.80 - 3.84 (m, 1 H), 3.88 - 3.94 (m, 1 H), 4.02 (t, J=9.2 Hz, 1 H), 6.17 (br s, 2 H), 7.10 - 7.17 (m, 3 H), 7.31 - 7.38 (m, 2 H), 7.41 (s, 1 H), 7.58 (t, J=8 Hz, 1 H), 8.16(s, 1 H). 99.36% of purity by HPLC@ 290 nM.

Example 24

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3- lpyrimidin-5-yl)-3-fluoroph

(trifluoromethyl)phenyl)pyrrolidin-2-one

To a stirred solution of 2-(3-(trifluoromethyl)phenyl)pent-4-enoic acid (3.60 g, 14.7 mmol, 1.0 equiv) and 4-bromo-3-fluoroaniline (2.521 g, 13.3 mmol, 0.9 equiv) in 60 mL of DCM at room temperature was added A/./V-Diisopropylethylamine (DIPEA) (2.83 mL, 16.2 mmol, 1.1 equiv) followed by HATU (6.165 g, 16.2 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 1 hour. After consumption of the starting material, the reaction mixture was washed with 1 N HCI followed by saturated aqueous NaHC0₃ and brine solution successively and dried over Na₂S0₄, filtered, & evaporated to get desired product A/-(4-bromo-3-fluorophenyl)-2-(3-(trifluoromethyl) phenyl)pent-4-enamide as yellow oil (8.012 g, crude) which has a purity of 79% as evidenced by LCMS and proceeded to next step without purification. LC-MS (ES) m/z = 416.0, 418.0 [M-H]⁺ H NMR (400 MHz, DMSO-d6) δ ppm 2.72 - 2.84 (m, 1 H), 3.03 (br s, 1 H), 3.52 - 3.59 (br. s., 1 H), 3.89 (t, =8.0 Hz, 1 H), 4.97 - 4.99 (m, 1 H), 5.04 - 5.09 (m, 1 H), 5.65 - 5.76 (m, 1 H), 7.24 - 7.27 (m, 1 H), 7.54 - 7.63 (m, 3 H), 7.67 - 7.74 (m, 2 H), 10.54 (s, 1 H).

To a stirred solution of A/-(4-bromo-3-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)pent-4- enamide (2.14g, 5.9 mmol, 1.0 equiv), in THF (100 ml_), and water (20 ml_) at room temperature was added 2.5 wt% osmium tetroxide solution in t-BuOH (6 ml_, 0.585 mmol, 0.1 equiv) and stirred for 20 minutes. Sodium periodate (5.02 g, 23.4 mmol, 4 equiv) was added and the resulting solution was stirred for overnight at room temperature. After consumption of the starting material, the reaction mixture was quenched with saturated Sodium thiosulphate solution and the two layers were separated. The combined organic layers were washed with saturated aqueous NaHC0₃ followed by brine, dried over Na₂S0₄, filtered and evaporated to afford the desired product 1-(4-bromo-3-fluorophenyl)- 5-hydroxy-3-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one as dark brown semi solid (6.864 g, crude [M+H]⁺.

To a stirred solution of 1-(4-bromo-3-fluorophenyl)-5-hydroxy-3-(3-(trifluoromethyl)phenyl) pyrrolidin-2-one (5.150 g, 12.3 mmol, 1 equiv) in 40 ml_ DCM was added with triethylsilane (7.90 ml_, 49.3 mmol, 4 equiv) followed by TFA (16 ml_, 246.3 mmol, 20 equiv). The resulting solution was stirred at room temperature for overnight. After consumption of the starting material, the reaction mixture was evaporated and the crude reaction mixture was quenched with saturated aqueous NaHC0₃, extracted with DCM. The combined organic phase was washed with brine, dried over Na₂S0₄, filtered, evaporated to get crude material. The crude product was purified by ilica gel flash chromatography using a gradient 8 - 9% EtOAc in Hexane as eluent. The combined fractions were concentrated in vacuo to afford the desired product 1-(4-bromo-3- fluorophenyl)-3-(3-(trifluoromethyl) phenyl)pyrrolidin-2-one as pale yellow solid (1.41 g, 28%). LC-MS (ES) m/z = 404.0 [M+H]⁺, H NMR (400 MHz, CDCI₃) δ 2.29 - 2.39 (m, 1 H), 2.67 - 2.75 (m, 1 H), 3.90 - 3.98 (m, 3 H), 7.33 (d, J=4.0 Hz, 1 H), 7.50 - 7.53 (m, 3 H), 7.57 (s, 2 H), 7.68 - 7.71 (m, 1 H).

To a stirred and degassed solution of 1-(4-bromo-3-fluorophenyl)-3-(3-(trifluoromethyl) phenyl)pyrrolidin-2-one (0.350 g, 0.9 mmol, 1.0 equiv), bis(pinacolato)diboron (0.221 g, 0.9 mmol, 1.0 equiv), and potassium acetate (0.256 g, 2.6 mmol, 3.0 equiv) in 20 ml_ 1 ,4- dioxane was added Pd(dppf)CI₂.DCM complex (0.036 g, 0.04 mmol, 0.05 equiv) and heated in a sealed vessel for 4 hours at 100 °C. After consumption of the starting material, the reaction mixture was proceeded for Suzuki coupling without any work-up. The reaction mixture was cooled to room temperature, 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4- amine (0.257 g, 1.131 mmol, 1.3 equiv) and sat. NaHC0₃ (6 ml_) were added, degassed under Argon and added Pd(dppf)CI₂.DCM complex (0.070 g, 0.087 mmol, 0.1 equiv). The vessel was sealed and the reaction mixture was heated to 100°C for overnight. After consumption of the starting material, the reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The two layers were separated and the combined organic phase was washed with brine, dried over Na₂S0₄, filtered and evaporated. The crude product was purified by flash chromatography using solid loading cartridge. The product was eluted over a solvent gradient of 2.8 - 3.5% MeOH:DCM. The isolated product was re-purified by Prep HPLC. Analytical conditions: Column: Inertsil ODS 3V (250 mm x 4.6 mm x 5 mic). Mobile phase A: 0.01 % Ammonia in water, Mobile phase B: ACN, Flow rate: 1.0 mL/min) to afford desired product 1-(4-(4-amino-7-methyl- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-3-(3-(trifluoromethyl) phenyl)pyrrolidin-2- one as white solid (0.062 g, 15%). LC-MS (ES) m/z = 470.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ ppm 2.25 - 2.31 (m, 1 H), 2.60 - 2.65 (m, 1 H), 3.74 (s, 3 H), 3.92 - 4.03 (m, 2 H), 4.18 (t, J=8.0 Hz, 1 H), 5.97 (br s, 2 H), 7.31 (s, 1 H), 7.43 (t, J=8.0 Hz, 1 H), 7.59 - 7.67 (m, 4 H), 7.17 (s, 1 H), 7.82 - 7.85 (m, 1 H), 8.14 (s, 1 H).

Example 25

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimidin-5-yl)phenyl)-3-(3,5-dimethoxy phenyl)pyrrolidin-2-one

To a stirred solution of 2-(3,5-dimethoxyphenyl)acetic acid (2 g, 10.2 mmol, 1 equiv) in MeOH (20 mL) was added 2 drops of con. H₂S0₄ and heated to 80 °C for 1 h. MeOH was removed under vacuum, reaction mixture was dissolved in EtOAc, and organic layer was washed with saturated NaHC0₃, dried over Na₂S0₄ and concentrated to afford the desired product as pale yellow liquid (2.14 g, 93%). LC-MS (ES) m/z = 21 1 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ 3.51 (s, 2 H), 3.69 (s, 3 H), 3.78 (s, 6 H), 6.37 - 6.38 (m, 1 H), 6.43 (d, J=4.0

To a stirred solution of methyl 2-(3,5-dimethoxyphenyl)acetate (2.14 g, 10.9 mmol, 1 equiv) in THF (30 mL) was added 2M LDA solution (7.6 mL, 25.5 mmol, 1.5 equiv) at -78 °C and stirred at RT for 30 minutes. To the above reaction mixture was added allyl bromide (0.78 mL, 9.2 mmol, 0.9 equiv) at -78 °C and stirred at RT for 1.5h. Reaction mixture was quenched with saturated NH₄CI solution (50 mL) and extracted to ethyl acetate (2 x 50 mL) and dried over Na₂S0₄ and concentrated. Purification: Column chromatography by 20% EtOAc in hexane as eluent as brown color liquid (1.4 g, 56%). LC-MS (ES) m/z = 251 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ 2.46 - 2.52 (m, 1 H), 2.75 - 2.82 (m, 1 H), 3.54 - 3.58 (t, J=16 Hz, 1 H), 3.78 (s, 6 H), 5.00 (d, J=8 Hz, 1 H), 5.07 (d, J =20 Hz, 1 H), 5.67 - 5.77 (m, 1 H), 6.36 (s, 1 H), 6.46 (s, 2 H).

To a solution of methyl 2-(3,5-dimethoxyphenyl)pent-4-enoate (1.4 g, 5.6 mmol, 1 equiv) in MeOH (20 mL) and water was added LiOH.H₂0 (0.7g, 16.8 mmol, 3 equiv) and stirred at RT for 16 h. MeOH was removed under vacuo. Reaction mixture was acidified (~pH = 6) with citric acid and extracted to EtOAc (2 x 50 mL) and dried over Na₂S0₄ and concentrated to obtain 2-(3,5-dimethoxyphenyl)pent-4-enoic acid (1.4 g, crude). LC-MS (ES) m/z = 237.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.34 - 2.39 (m, 1 H), 2.61-2.68 (m, 1 H), 3.71 ( s, 6 H), 3.49 - 3.53 (t, J=8 Hz, 1 H), 4.95 (d, J=12 Hz, 1 H), 5.03 (d, J=20 Hz, 1 H), 5.64 - 5.74 (m, 1 H), 6.37 (s, 1 H), 6.43 (s, 2H), 12.32 (s, 1 H).

To a stirred solution of 2-(3,5-dimethoxyphenyl)pent-4-enoic acid (1.4 g, 5.9 mmol, 1 equiv) and 4-bromoaniline (1.01 g, 5.9 mmol, 1 equiv) in 30 ml of DCM at RT was added HATU (5.6 g, 14.8 mmol, 2.5 equiv) and DIPEA (3.09 mL, 17.7 mmol, 3 equiv) and stirred at room temperature for 2h. Reaction mixture was washed with sat NaHC0₃ and extracted with DCM (2 x 25 mL), organic layer was dried over Na₂S04 and concentrated. Purification: Purified by flash column chromatography by using 20% EtOAc in hexane as eluent to afford the desired product as colorless liquid (1 g, 43%). LC-MS (ES) m/z = 390.0, 392.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.38 - 2.43 (m, 1 H), 2.71 - 2.79 (m,

1 H), 3.64 - 3.65 (m, 1 H), 3.71 ( s, 6 H), 4.97 (d, J= 8 Hz, 1 H), 5.07 (d, J=20 Hz, 1 H), 5.66 - 5.76 (m, 1 H), 6.37 (s, 1 H), 6.52 (s, 2 H), 7.44 (d, J=8 Hz, 2 H), 7.53 (d, J=8.0 Hz,

2 H), 10.15 (s, 1 H).

To a stirred solution of Ay-(4-bromophenyl)-2-(3,5-dimethoxyphenyl)pent-4-enamide (1 g, 2.6 mmol, 1 equiv) in THF (40 mL) and water (10 mL) was added 2.5 wt% osmium tetroxide solution in t-BuOH (2.6 mL, 0.3 mmol, 0.1 equiv) followed by sodium periodate (2.19 g, 10.2 mmol, 4 equiv), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with aqueous solution of sodium thiosulfate and saturated aqueous NaHC0₃, and extracted with EtOAc. Combined organic layer was dried over Na₂S0₄, and concentrated. The crude product was used for next reaction with

To a stirred solution of 1-(4-bromophenyl)-3-(3,5-dimethoxyphenyl)-5-hydroxypyrrolidin-2- one (1 g, 2.6 mmol, 1 equiv) in dichloromethane (30 mL) was added triethylsilane (1.64 mL, 10.2 mmol, 4 equiv) followed by TFA (3.29 mL, 51.0 mmol, 20 equiv), and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was poured onto saturated aqueous NaHC0₃ and EtOAc (100 mL). The organic layer was separated, washed with brine solution, dried over Na₂S0₄, filtered and concentrated. Purification: Purified by flash column chromatography using 15 - 20% EtOAc in hexane as eluent to afford the desired product (0.3 g, 31 %) as yellow solid. LCMS (ES) m/z = 376.0, 378.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 1.97 (m, 1 H), 2.50 (m, 1 H), 3.72 (s, 6 H), 3.85 - 3.88 (m, 3 H), 6.40 (s, 1 H), 6.45 (s, 2 H), 7.56 (d, J=8.0 Hz, 2 H), 7.67 (d, J=8.0

Run-1

To a mixture of 1-(4-bromophenyl)-3-(3,5-dimethoxyphenyl)pyrrolidin-2-one (50 mg, 0.13 mmol, 1 equiv), bis(pinacolato)diboron (33 mg, 0.13 mmol, 1 equiv), and potassium acetate (38 mg, 0.39 mmol, 3 equiv) was added 1 ,4-dioxane (4 mL), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (5.3 mg, 0.007 mmol, 0.05 equiv) was added and again degassed with N₂ for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature, 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (29 mg, 0.13 mmol, 1 equiv) and saturated aqueous NaHC0₃ (1 mL) were added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCI₂(dppf)-CH₂CI₂ adduct (5.3 mg, 0.0065 mmol, 0. 05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The mixture was poured onto water and extracted into EtOAc (2 x 30 mL) dried over Na₂S0₄ and concentrated. (80 mg, crude). Crude product was mixed with Run-2 and purified. Run-2

To a mixture of 1-(4-bromophenyl)-3-(3,5-dimethoxyphenyl)pyrrolidin-2-one (250 mg, 0.7 mmol, 1 equiv), bis(pinacolato)diboron (168 mg, 0.7 mmol, 1 equiv), and potassium acetate (195 mg, 2.0 mmol, 3 equiv) was added 1 ,4-dioxane (12 ml_), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (27 mg, 0.03 mmol, 0.05 equiv) was added and again degassed with N₂ for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-Bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (150 mg, 0.664 mmol,

1 equiv) and saturated aqueous NaHC0₃ (4 ml_) were added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (27 mg, 0.033 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The mixture was poured onto water and extracted into EtOAc (2 x 30 ml_) dried over Na₂S0₄ and concentrated.

Purification (1): Run-1 and Run-2 were mixed and purified using 100 - 200 silica gel, 24g column in Rf-cobiflash, eluted with 5% MeOH in DCM as mobile phase.

Purification (2): Prep HPLC, Zorbax.XDBC18 (150 mm X 4.6 mm X 3.5 uM), mobile phase(A): 0.01 % Ammonia in water, (B): ACN. Flow rate: 1.0 mLJ min, T/%B, 0/20, 10/70, 25/70, 27/20, 30/20.Yield (18 mg, 5.09%, combined yield of Run-1 and Run-2) as off white solid. LCMS (ES) m/z = 444.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.14 - 2.26 (m, 1 H), 2.52 - 2.60 (m, 1 H), 3.73 (s, 9 H), 3.84 - 3.90 (m, 1 H), 3. 90 - 4.00 (m, 2 H), 6.02 (brs,

2 H), 6.41 (s, 1 H), 6.45 (s, 2 H), 7.28 (s, 1 H), 7.46 (d, J=8.4 Hz, 2 H), 7.80 (d, J=8.8 Hz, 2 H), 8.14 (s, 1 H). 98.62% purity by HPLC @ 250 nM.

To a stirred solution of 2-(2-bromophenyl)acetic acid (3.0 g, 14.0 mmol, 1.0 equiv) in MeOH (40 ml_) was added slowly drop wise H₂S0₄ (0.8 ml_, catalytic amount) at 0 °C and gradually allowed to warm to room temperature. Then the reaction mixture was heated to 60 °C for 6 hours. After consumption of the SM, the reaction mixture was cooled then poured into ice water (100 ml_) and extracted with ethyl acetate and the organic layers were combined and washed with brine and dried over Na₂S0₄, filtered and concentrated to obtain as color less liquid of methyl 2-(2-bromophenyl)acetate (3.10 g, crude) LC-MS (ES) m/z = 229.0, 231.0 [M+H]⁺.

To a stirred solution of Methyl 2-(2-bromophenyl)acetate (2.50 g, 10.9 mmol, 1.0 equiv), in toluene (100 ml_) and water (7 ml_) was added cyclopropylboronic acid (1.221 g, 14.2 mmol, 1.3 equiv), KH₂P0₄ (4.45 g, 32.8 mmol, 3.0 equiv), (Cy)₃P (0.61 1 g, 2.2 mmol, 0.2 equiv), and stirred for 5 minutes at room temperature. The reaction mixture was degassed with argon for 10 minutes, Pd(OAc)₂ (0.245 g, 1.1 mmol, 0.1 equiv) was added and the reaction mixture was stirred for 8 hours at 105 °C. After consumption of the SM, the reaction mixture was quenched with 0.5 N HCI solution and extracted with ethyl acetate and the organic layers were combined and washed with brine and dried over Na₂S0₄, filtered and concentrated. Purification: Crude material was purified by flash column chromatography to get methyl 2-(2-cyclopropylphenyl)acetate as pale yellow color liquid, yield: (1.9 g, 76.2 %). LCMS (ES) m/z = 191.1 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 0.56 (t, J=5.60 Hz, 2 H), 0.83 - 0.88 (m, 2 H), 1.83 - 1.87 (m, 1 H), 3.60 (s, 3 H), 3.83 (s, 2

To a stirred solution of Methyl 2-(2-cyclopropylphenyl)acetate (1.9 g, 1.0 mmol, 1.0 equiv) in THF (80 ml_) was added LiOH solution (0.84 g, 20.00 mmol, 20.0 equiv) at room temperature. The reaction mixture was stirred for 16 hours at room temperature. After consumption of the SM, the reaction mixture was concentrated then the aqueous phase pH adjusted to 1 with 1 N HCI then the aqueous phase was stirred for 10 minutes at room temperature then extracted with ethyl acetate and the organic layers were combined and washed with brine and dried over Na₂S0₄, filtered and concentrated to obtained as brown color liquid. 2-(2-cyclopropylphenyl) acetic acid (2.1 g, crude). LC-MS (ES) m/z = 177.1 [M+H]⁺ . H NMR (400 MHz, DMSOd6) δ 0.60 - 0.68 (m, 2 H), 0.89 - 0.94 (m, 2 H), 1.84 - 1.90 (m, 1 H), 3.60 (d, J=3.20 Hz, 5 H), 6.93 (d, J=8.0 Hz, 1 H), 6.96 (s, 1 H), 6.99 (d, J=7.60

To a stirred solution of 2-(2-cyclopropylphenyl)acetic acid (2.1 g, 1 1.9 mmol, 1.0 equiv) in THF (50 mL) was added 1.0 M LHMDS solution (26.22 mL, 26.2 mmol, 2.2 equiv) drop wise over a period of 10 minutes at -78 °C. After completion of the LHMDS addition, cooling bath was removed, the mixture was warmed gradually and stirred for about 50 minutes, allyl bromide (4.62 mL, 38.1 mmol, 3.2 equiv) was added in one portion at 0°C and the reaction mixture was allowed to stir at RT for 16 h. After consumption of SM, reaction mixture was quenched with 25 mL of 1 N HCI and extracted with ethyl acetate and the organics were combined and washed with brine and dried over Na₂S0₄, filtered and concentrated in vacuo to give 2-(2-cyclopropylphenyl)pent-4-enoic acid as pale yellow liquid (2.5 g, crude). LC-MS (ES) m/z = 193.0 [M-H]⁺ . H NMR (400 MHz, DMSOd6) δ 0.53 - 0.68 (m, 2 H), 0.72 - 0.95 (m, 2 H), 1.88 - 2.03 (m, 1 H), 2.31 - 2.49 (m, 1 H), 2.68 - 2.75 (m, 1 H), 4.23 (t, J=7.20 Hz, 1 H), 4.93 - 5.05 (m, 2 H), 5.65 - 5.77 (m, 1 H), 6.98 - 7.03 (m, 1 H), 7.08 - 7.21 (m, 2 H), 7.25 (t, J=6.80 Hz, 1 H), 12.31 (s, 1 H).

To a stirred solution of 2-(2-cyclopropylphenyl)pent-4-enoic acid (2.50 g, 5.6 mmol, 1.0 equiv) in DCM (50 mL) was added 4-bromoaniline (1.790 g, 10.4 mmol, 0.9 equiv) and DIPEA (0.796 mL, 6.2 mmol, 1.1 equiv), followed by HATU (2.13 g, 6.2 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred at room temperature for 2 h. After consumption of SM, reaction mixture was quenched with 35 mL of H₂0, and extracted with EtOAc, organics were washed with 1 N HCI (1 x 50 mL), and sat NaHC0₃ (2 x 50mL), dried over Na₂S0₄, filtered, and concentrated to get A/-(4-bromophenyl)-2-(2- cyclopropylphenyl)pent-4-enamide as pale yellow solid (1.320 g, crude). LC-MS (ES) m/z = 370.1 , 372.0 [M+H]⁺.

To a stirred solution of A/-(4-bromophenyl)-2-(2-cyclopropylphenyl)pent-4-enamide (1.32 g, 3.6 mmol, 1.0 equiv) in THF (50 mL) and water (10 mL) was added 2.5 wt% osmium tetroxide (3.62 mL, 0.4 mmol, 0.1 equiv) followed by sodium periodate (3.04 g, 14.3 mmol, 4.0 equiv), and the reaction mixture was stirred at room temperature for 6 hours. After consumption of SM, reaction mixture was quenched with 30 mL of aqueous solution of sodium thiosulfate and the resulting mixture was stirred for 10 minutes. The reaction mixture was extracted with EtOAc (2 x 50 mL), organic layer was washed with saturated aqueous NaHC0₃, brine solution (50 mL), and dried over Na₂S0₄), and concentrated to afford the crude product 1-(4-bromophenyl)-3-(2-cyclopropylphenyl)-5-hydroxypyrrolidin-2- one (1.530 g, crude) as pale yellow semi solid. LC-MS (ES) m/z = 372.0, 374.0 [M+H]⁺.

To a stirred solution of 1-(4-bromophenyl)-3-(2-cyclopropylphenyl)-5-hydroxypyrrolidin-2- one (1.53 g, 4.1 mmol, 1.0 equiv) in DCM (50 mL) was added Triethylsilane (2.63 mL, 16.4 mmol, 4.0 equiv) followed by TFA (6.30 mL, 82.2 mmol, 20.0 equiv), and the reaction mixture was stirred for 3 hours at room temperature. After consumption of SM, the reaction mixture was concentrated and added saturated aqueous NaHC0₃ to the residue and extracted with EtOAc (2 x 50 mL). The organic layer was washed with brine solution (50 mL), dried over Na₂S0₄, filtered and concentrated. Purification: Crude was purified by flash column chromatography to get 1-(4-bromophenyl)-3-(2-cyclopropylphenyl)pyrrolidin- 2-one as yellow solid (0.740 g, 51.0%). LCMS (ES) m/z = 356.0, 358.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ ppm 0.61 - 0.75 (m, 2 H), 0.82 - 0.95 (m, 2 H), 1.97 - 2.06 (m, 1 H), 2.08 - 2.15 (m, 1 H), 2.55 - 2.64 (m, 1 H), 3.85 - 3.99 (m, 2 H), 4.48 (t, J=9.20 Hz, 1 H), 7.03 (t, J=5.60 Hz, 1 H), 7.11 - 7.17 (m, 2 H), 7.32 - 7.40 (m, 1 H), 7.57 (d, J=7.20 Hz, 2

To a stirred solution of 1-(4-bromophenyl)-3-(2-cyclopropylphenyl)pyrrolidin-2-one (0.5 g, 1.4 mmol, 1.0 equiv) in 1 ,4-dioxane (15 mL) was added bis(pinacolato)diboron (0.356 g, 1.4 mmol, 1 equiv), and potassium acetate (0.413 g, 4.2 mmol, 3 equiv).The reaction mixture was degassed with Argon for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.1 15 g, 0.14 mmol, 0.1 equiv) was added and degassed with Argon for further 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. Reaction mixture was cooled to RT and filtered over celite. The filtrate was concentrated and purified over silica gel flash column chromatography. 3-(2-cyclopropylphenyl)-1-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (0.250 g, 45.0%) as white solid. LCMS (ES) m/z = 404.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 0.61 - 0.66 (m, 2 H), 0.90 - 0.92 (m, 2 H), 1.28 (s, 12 H), 2.00 - 2.03 (m, 1 H), 2.09 - 2.14 (m, 1 H), 3.91 - 3.97 (m, 2 H), 4.50 (t, J=9.20 Hz, 1 H), 7.03 (t, J=4.40 Hz, 1 H), 7.14 - 7.17 (m, 3 H), 7.68 (d, J=8.40 Hz, 2 H), 7.74 (d J=8.40 Hz, 2 H).

Run 1

To a stirred solution of 3-(2-cyclopropylphenyl)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (0.05 g, 0.1 mmol, 1.0 equiv), 5-bromo-7- methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.03 g, 0.1 mmol, 1.0 equiv) and potassium phosphate (0.053 g, 0.2 mmol, 2 equiv) in 1 ,4-dioxane: water (3 ml_: 1 ml_) was added Pd₂(dba)₃ (0.006 g, 0.006 mmol, 0.05 equiv). The reaction mixture was degassed with N₂ for 5 minutes then Tri-tert-butylphosphonium tetrafluoroborate (0.004 mg, 0.01 mmol, 0.1 equiv) was added and the reaction mixture was further degassed for 5 minutes. The vial was sealed and the reaction mixture was heated to 100 °C for overnight. The reaction mixture was filtered through celite and the filtrate was concentrated to obtain crude compound. Yield: (0.06 g, crude) LCMS (ES) m/z = 424.2 [M+H]⁺.

Run 2

To a stirred solution of 3-(2-cyclopropylphenyl)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (0.175 g, 0.4 mmol, 1.0 equiv), 5-bromo-7- methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.098 g, 0.4 mmol, 1.0 equiv) and potassium phosphate (0.184 g, 0.9 mmol, 2 equiv) in 1 ,4-dioxane: water (8 ml_: 2.5 ml_). Pd₂(dba)₃ (0.02 g, 0.02 mmol, 0.05 equiv) was added and the reaction mixture was degassed with N₂ for 5 minutes, tri-tert-butylphosphonium tetrafluoroborate ( 0.013 g, 0.043 mmol, 0.1 equiv) was added and the reaction mixture was further degassed for 5 minutes. The vial was sealed and the reaction mixture was heated to 100 °C for overnight. The reaction mixture was filtered through celite and the filtrate was concentrated to obtain crude compound. Purification: Crude (Run-1 & Run 2) was purified by flash column chromatography to get 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3- (2-cyclopropylphenyl)pyrrolidin-2-one as off white solid (0.095 g, 40.2 %). LCMS (ES) m/z = 424.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 0.63 - 0.67 (m, 2 H), 0.93 (d, J=8.40 Hz, 2 H), 1.97 - 2.05 (m, 1 H), 2.01 - 2.18 (m, 1 H), 2.66 (s, 1 H), 3.73 (s, 3 H), 3.99 (t, J=8.00 Hz, 2 H), 4.49 (t, J=9.20 Hz, 1 H), 6.03 (br s, 2 H), 7.04 (d, J=4.40 Hz, 1 H), 7.17 (d, J=9.60 Hz, 3 H), 7.29 (s, 1 H), 7.47 (d, J=8.40 Hz, 2 H), 7.82 (d, J=8.40 Hz, 2 H), 8.14 (s, 1 H).

Example 27

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3- lpyrimidin-5-yl)-3-fluoroph

cyclopropylpheny

Run 1

Acetyl chloride (0.08 mL, 1.2 mmol, 0.5 equiv), and 2-(3-bromophenyl)acetic acid (0.5 g, 2.3 mmol, 1.0 equiv) were added to MeOH (10 mL) and the reaction mixture was refluxed for 2 h. After consumption of starting material, the reaction mixture was concentrated and extracted with DCM. The organics were combined and washed with brine and dried over Na₂S0₄, filtered and concentrated in vacuum to give methyl 2-(3-bromophenyl)acetate as colorless oil (0.525 g, 98.7%). LC-MS (ES) m/z = 229.0, 231.0 [M+H]⁺ . H NMR (400 MHz, DMSOd6) δ 3.61 (s, 3 H), 3.70 (s, 2 H), 7.26 - 7.30 (m, 2 H), 7.43 - 7.46 (m, 1 H), 7.48 (s, 1 H). Run 2

Acetyl chloride (0.6 mL, 9.3 mmol, 0.5 equiv), and 2-(3-bromophenyl)acetic acid (4.0 g, 18.6 mmol, 1.0 equiv) were added to MeOH (50 mL) and the reaction mixture was refluxed for 2 h. After consumption of SM, the reaction mixture was concentrated and extracted with DCM. The organics were combined and washed with brine and dried over Na₂S0₄, filtered and concentrated in vacuum to give methyl 2-(3-bromophenyl)acetate as colorless oil (4.1 g, 96.2 %). LC-MS (ES) m/z = 229.0, 231.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 3.61 (s, 3 H), 3.70 (s, 2 H), 7.26 - 7.30 (m, 2 H), 7.43 - 7.46 (m, 1 H), 7.48 (s, 1

Run 1

To a stirred solution of methyl 2-(3-bromophenyl)acetate (0.5 g, 2.2 mmol, 1.0 equiv) in Toluene (15 mL) was added cyclopropylboronic acid (0.204 g, 2.4 mmol, 1.1 equiv ) and K₃PO4 (1.85 g, 8.7 mmol, 4.0 equiv) at room temperature. The reaction mixture was stirred for 5 minutes under N₂ atmosphere. Pd(PPh₃)₄ (0.126 g, 0.1 mmol, 0.05 equiv) was added and the reaction mixture was stirred for 16 h at 110 °C. After consumption of the SM the reaction mixture was filtered through celite and concentrated. Purification: Purified by flash column chromatography using silica gel column, compound was eluted at 4-6% EtOAc: Hexane. The pure fractions were evaporated to obtain methyl 2-(3- cyclopropylphenyl)acetate as color less oil (0.180 g, 43.4 %). LC-MS (ES) m/z = 191.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ ppm 0.60 - 0.68 (m, 2 H), 0.89 - 0.94 (m, 2 H), 1.84 - 1.90 (m, 1 H), 3.60 (d, J=3.20 Hz, 5 H), 6.93 (d, J=8.0 Hz, 1 H), 6.96 (s, 1 H), 6.99 (d, J=7.60 Hz, 1 H), 7.17 (t, J=7.60 Hz, 1 H).

Run 2

To a stirred solution of methyl 2-(3-bromophenyl)acetate (4.1 g, 17.9 mmol, 1.0 equiv) in toluene (75 mL) was added cyclopropylboronic acid (1.675 g, 19.7 mmol, 1.1 equiv ) and K₃PC (15.20 g, 71.6 mmol, 4.0 equiv) at room temperature. The reaction mixture was stirred for 5 minutes under N₂ atmosphere. Pd(PPh₃)₄ (1.03 g, 0.9 mmol, 0.05 equiv) was added and the reaction mixture was stirred for 16 h at 110°C. After consumption of the SM the reaction mixture was filtered through celite and concentrated. Purification: Flash column chromatography using silica gel column, compound was eluted at 4 - 6% EtOAc: Hexane. The pure fractions were evaporated to obtain methyl 2-(3- cyclopropylphenyl)acetate as color less oil (1.62 g, 47.6 %). LC-MS (ES) m/z = 191.1 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 0.61 - 0.64 (m, 2 H), 0.89 - 0.94 (m, 2 H), 1.85 - 1.89 (m, 1 H), 3.59 - 3.61 (m, 5 H), 6.93 (d, J=8.0 Hz, 1 H), 6.96 (s, 1 H), 6.99 (d, J=7.60 Hz, 1 H), 7.17 (t, J=7.60 Hz, 1 H).

To a stirred solution of methyl 2-(3-cyclopropylphenyl)acetate (1.3 g, 6.8 mmol, 1.0 equiv) in THF (50 mL) was added 2M LDA in THF solution (3.42 mL, 6.8 mmol, 1.0 equiv) drop wise at -78 °C, then stirred for 30 minutes at -78 °C and 2-bromoacetonitrile (0.5 mL, 6.8 mmol, 1.0 equiv) was added at same temperature. The reaction mixture was stirred for 4 h at - 78 °C to RT. The reaction mixture was quenched with 1 N HCI (20 mL ), extracted into ethyl acetate (2 x 25 mL), and the organic layers were combined and washed with brine and dried over Na₂S0₄, filtered and concentrated. Purification: Purified by flash column chromatography using silica gel column, compound was eluted at 10-12 % EtOAc: Hexane. The pure fractions were evaporated to obtain methyl 3-cyano-2-(3- cyclopropylphenyl)propanoate as light yellow oil Yield (0.990 g, 63.2%). H NMR (400 MHz, DMSOd6) δ 0.64 (s, 2 H), 0.94 (t, J=1.6 Hz, 2 H), 1.86 - 1.92 (m, 1 H), 2.97 - 3.03 (m, 1 H), 3.07 - 3.15 (m, 1 H), 3.63 (s, 3 H), 4.10 (t, J=7.60 Hz, 1 H), 6.99 (d, J=7.60 Hz, 1 H), 7.05 (d, J=9.20 Hz, 2 H), 7.22 (t, J=7.60 Hz, 1 H).

To a stirred solution of methyl 3-cyano-2-(3-cyclopropylphenyl)propanoate (0.99 g, 4.3 mmol, 1.0 equiv) in EtOH (25 mL) was added Raney Ni (0.99 g) and aq NH₄OH (10 mL). The reaction mixture was kept in parr shaker vessel at 60 psi (RT) for 24h. Then the reaction mixture was filtered through celite bed, the filtrate was concentrated. The crude was diluted with DCM (30 mL), washed with 1 N aq HCI (2 x 20 mL), dried over Na₂S0₄ and concentrated to obtain desired product as colorless liquid. Yield (0.760 g, crude). LC- MS (ES) m/z = 202.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 0.64 (s, 2 H), 0.93 (s, 2 H), 1.24 (s, 1 H), 1.89 (s, 1 H), 2.05 (s, 1 H), 3.18 - 3.46 (m, 3 H), 6.91 - 6.96 (m, 2 H), 7.18 (s, 2 H), 7.75 (s, 1 H).

To a stirred solution of CsF (1.43 g, 9.5 mmol, 2.5 equiv) in EtOAc (40 mL) was added 3- (3-cyclopropylphenyl)pyrrolidin-2-one (0.760 g, 4.0 mmol, 1.0 equiv), 1-bromo-2-fluoro-4- iodobenzene (1.14 g, 4.0 mmol, 1.0 equiv), DMEDA (0.04 mL, 0.4 mmol, 0.1 equiv), Cul (0.04 g, 0.2 mmol, 0.05 equiv). The reaction mixture was stirred at RT for 24 h. After consumption of the SM, the reaction mixture was filtered through celite and washed with H₂0 (2 x 30 mL) and brine (30 mL) and the organics were combined and dried over Na₂S0₄, filtered, and concentrated. Purification: Purified by flash column chromatography using silica gel column, using 9 - 12 % EtOAc in Hexane as mobile phase the desired product 1-(4-bromo-3-fluorophenyl)-3-(3-cyclopropylphenyl)pyrrolidin-2-one was obtained as light yellow solid (0.190 g, 13.5%). LC-MS (ES) m/z = 374.0, 376.1 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 0.65 (d, J=4.4 Hz, 2 H), 0.93 (d, J=3.36 Hz, 2 H), 1.86 - 1.93 (m, 1 H), 2.12 - 2.20 (m, 1 H), 2.49 (s, 1 H), 3.83 - 3.93 (m, 3 H), 6.93 (d, J=7.6 Hz, 1 H), 7.03 (d, J=8.8 Hz, 2 H), 7.20 (t, J=7.60 Hz, 1 H), 7.50 (d, J=8.8 Hz, 1 H), 7.70 (t, J=8.8 Hz, 1 H), 7.85 (d, J=1 1.6 Hz, 1 H).

To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-(3-cyclopropylphenyl)pyrrolidin-2-one (0.190 g, 0.5 mmol, 1.0 equiv), was added bis(pinacolato)diboron (0.130 g, 0.5 mmol, 1.0 equiv), and potassium acetate (0.150 g, 1.5 mmol, 3.0 equiv), and the mixture was degassed with Argon for 10 minutes then PdCl₂(dppf)-CH₂Cl₂ adduct (0.021 g, 0.003 mmol, 0.05 equiv) was added and again degassed with Argon for 10 minutes. The reaction mixture was stirred for 8 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.120 g, 0.5 mmol, 1.0 equiv) and saturated aqueous NaHC0₃ (2.5 mL) were added, and Argon gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.021 g, 0.003 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 RT, filtered through celite and the filtrate was dried over Na₂S0₄ and concentrated. Purification: Purified by flash column chromatography using silica gel column, compound was eluted at 3 - 4 % MeOH in DCM. The compound was re-purified by Prep HPLC. Analytical Conditions: Inertsil ODS 3V (250 mm x 4.6 mm x 5 μηι), Mobile phase A: 0.01 %Ammonia in H₂0, Mobile phase B: ACN, Flow rate: 1.0 mL / min. to get desired product as off white solid Yield: (0.02 g, 9.0 %). LCMS (ES) m/z = 442.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 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=8.8 Hz, 1 H), 7.59 (d, J=8.4 Hz, 1 H), 7.83 (d, J 11.6 Hz, 1 H), 8.14 (s, 1 H).

Example 28 1 -4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-3-(2-methyl-

1 H-indol-3-yl)pyrrolidin-2-one

To a stirred solution of 2-(2-methyl-1 /-/-indol-3-yl)acetic acid (2 g, 10.6 mmol, 1 equiv) in MeOH (30 mL) was added con. HCI (3 mL) at RT, reaction mixture was refluxed for overnight. The reaction mixture was concentrated and diluted with EtOAc (100 mL), washed with saturated NaHC0₃ (50 mL), water (50 mL) and brine solution (50 mL). The organic layer was dried over Na₂S0₄ and concentrated to afford the desired product as dark liquid (2.2 g, crude). LC-MS (ES) m/z = 204.1 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.31 (s, 3 H), 3.56 (s, 3 H), 3.65 (s, 2 H), 6.92 (t, J=7.6 Hz, 1 H), 6.98 (t, J=7.2 Hz, 1 H), 7.23 (d, J=8 Hz, 1 H), 7.35 (d, J=7.6 Hz, 1 H), 10.82 (s, 1 H).

To a stirred solution of methyl 2-(2-methyl-1 /-/-indol-3-yl)acetate (2.2 g, 10.8 mmol, 1 equiv) in DCM (20 mL) was added triethylamine (2.2 mL, 16.3 mmol, 1.5 equiv), DMAP (0.26 g, 2.2 mmol, 0.2 equiv) and (Boc)₂0 (3.5 g, 16.3 mmol, 1.5 equiv) at room temperature, stirred for 2h at room temperature. Then reaction mixture was concentrated and purified by flash column chromatography using silica column and 20 % EtOAc in hexane as mobile phase to get desired product as colorless solid. Yield (3.1 g, 96%). LC- MS (ES) m/z = 204.1 [M+H-0₂COtBu]. H NMR (400 MHz, DMSOd6) δ 1.62 (s, 9 H), 2.48 (s, 3 H), 3.58 (s, 3 H), 3.75 (s, 2 H), 7.17 - 7.25 (m, 2 H), 7.44 (d, J=7.6 Hz, 1 H), 8.01 (d, J=8 Hz, 1 H).

To a stirred solution of tert-butyl 3-(2-methoxy-2-oxoethyl)-2-methyl-1 H-indole-1- carboxylate (2.5 g, 8.3 mmol, 1 equiv) in DMF (30 mL) was added 60% NaH (0.33g, 8.3 mmol, 1 equiv) at 0 °C and stirred for 30 minutes at 0 °C. Allyl bromide (1.07 mL, 12.376 mmol, 1.5 equiv) was added at 0 °C and stirred at room temperature for 3h. The reaction mixture was quenched with ice water, extracted in to ethyl acetate, dried over Na₂S0₄ and concentrated. Purification: Purified by flash column chromatography with silica column and 10% EtOAc in hexane as mobile phase to get desired product as colorless liquid. Yield (1.98 g, 70%). LC-MS (ES) m/z = 244.2 [M+H-0₂COtBu].. H NMR (400 MHz, CDCIs) δ 1.68 (s, 9 H), 2.57 (s, 3 H), 2.59 - 2.67 (m, 1 H), 2.95 - 3.02 (m, 1 H), 3.63 (s, 3 H), 3.86 - 3.90 (m, 1 H), 4.94 - 5.05 (m, 2 H), 5.64 - 5.75 (m, 1 H), 7.16 - 7.24 (m, 2 H), 7.56 (d, J=7.2 Hz, 1 H), 8.10 (d, J=8 Hz, 1 H).

To a solution of tert-butyl 3-(1-methoxy-1-oxopent-4-en-2-yl)-2-methyl-1 H-indole-1- carboxylate (1.98 g, 5.8 mmol, 1 equiv) in MeOH (10 mL), THF ( 10 mL) and water (10 mL) was added LiOH.H₂0 (1.21 g, 28.9 mmol, 5 equiv) and heated at 70 °C and stirred for 2h. The reaction mixture was cooled and concentrated excess of MeOH and THF. The crude was diluted with water acidified with aqueous citric acid solution, extracted with DCM. The DCM layer was dried and concentrated to obtain desirted product as colorless liquid. Yield (1.7 g, crude). LC-MS (ES) m/z = 230.1 [M+H-0₂COtBu].

To a stirred solution of 2-(1-(tert-butoxycarbonyl)-2-methyl-1 H-indol-3-yl)pent-4-enoic acid (1.7 g, 5.167 mmol, 1 equiv) and 4-bromo-3-fluoroaniline (0.98 g, 5.167 mmol, 1 equiv) in 20 ml of DMF at room temperature was added DIPEA (0.99 g, 7.8 mmol, 1.5 equiv), followed by HATU (2.15 g, 5.7 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred at room temperature for 2h. The reaction mixture was diluted with ice water, extracted into EtOAc, washed with saturated aqueous NaHC0₃, water, brine, and dried over Na₂S0₄ and concentrated. Purification: Purified by flash column chromatography using silica gel column and 10 to 20% EtOAc in hexane as mobile phase to get desired product as off white solid. Yield (1 g, crude). LCMS (ES) m/z =, 403.1 [M+H-0₂COtBu]. H NMR (400 MHz, DMSOd6) δ 1.62 (s, 9 H), 2.54 (m, 1 H), 2.59 (s, 3 H), 2.89 - 2.96 ( m, 1 H), 4.01 (t, J=7.2 Hz, 1 H), 4.90 - 4.93 (d, J=10 Hz, 1 H), 4.97 - 5.01 (d, J=17.2 Hz, 1 H), 5.65 - 5.74 (m, 2 H), 7.13 - 7.21 (m, 2 H), 7.26 (d, J=8.8 Hz, 1 H), 7.56 (t, J =8.4 Hz, 1 H), 7.70 (d, J=11.2 Hz, 1 H), 7.77 (d, J=7.6 Hz, 1 H), 8.00 (d, J=8 Hz, 1 H), 10.01 (s, 1 H).

To a stirred solution of tert- butyl 3-(1-((4-bromo-3-fluorophenyl)amino)-1-oxopent-4-en-2- yl)-2-methyl-1/-/-indole-1-carboxylate (1 g, 2.0 mmol, 1 equiv) in a mixture of THF (50 mL) and water (10 mL) was added 2.5 wt% osmium tetroxide solution in t-BuOH (2 mL, 0.199 mmol, 0.1 equiv) followed by sodium periodate (1.7 g, 7.984 mmol, 4 equiv), and the reaction mixture was stirred for overnight at room temperature. Then reaction was quenched with aqueous solution of sodium thiosulfate and stirred for 10 minutes, and then extracted into EtOAc (100 mL) washed with saturated aqueous NaHC0₃ dried and concentrated. The crude product was used for next reaction without any purification. Yield (1.1 g, crude). LC-MS (ES) m/z = 403.0, 405.0 [M+H-0₂COtBu].

To a stirred solution of tert-butyl 3-(1-(4-bromo-3-fluorophenyl)-5-hydroxy-2-oxopyrrolidin- 3-yl)-2-methyl-1 H-indole-1-carboxylate (1.1 g, 2.2 mmol, 1 equiv) in DCM (10 mL) was added triethylsilane (1.39 mL, 8.7 mmol, 4 equiv) and TFA (3.3 mL, 43.7 mmol, 20 equiv) at RT. The reaction mixture was stirred for overnight at room temperature. The reaction mixture was concentrated, diluted with DCM (100 mL), washed with saturated aqueous NaHC0₃ ( 100 mL), water ( 50 mL) and brine solution ( 50 mL). The DCM layer was dried over Na₂S0₄ and concentrated. Purification: Purified by flash column chromatography using silica column and 30% EtOAc in hexane as mobile phase to get desired product as light brown liquid. Yield (0.24 g, crude). LCMS (ES) m/z = 387.1 , 389.1 [M+H]⁺.

To a mixture of 1-(4-bromo-3-fluorophenyl)-3-(2-methyl-1 H-indol-3-yl)pyrrolidin-2-one (240, 0.6 mmol, 1 equiv), bis(pinacolato)diboron (157 mg, 0.6 mmol, 1 equiv), and potassium acetate (182 mg, 1.9 mmol, 3 equiv) was added 1 ,4-dioxane (15 mL), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (25 mg, 0.031 mmol, 0.05 equiv) was added and again degassed with N₂ for 10 minutes. The reaction mixture was stirred for 4 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (140 mg, 0.620 mmol, 1 equiv) and saturated aqueous NaHC0₃ (5 mL) was added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (25 mg, 0.031 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The reaction mixture was filtered through celite bed, washed with 5% MeOH in DCM, the filtrate was dried over Na₂S0₄ and concentrated. Purification: (i) Purified by flash column chromatography with silica column and 3% MeOH in DCM as mobile phase, (ii) re-purified by prep HPLC using Inertsil ODS3V( 250 mm x 4.6 mm x 5 mic), mobile phase (A): 0.01 % ammonia in water, (B): ACN. Flow rate 1.0 mL / min.T/%B: 0/10, 10/70, 25/70, 27/10, 30/10. To get desired product. Yield (15 mg, 5.3%). LCMS (ES) m/z = 455.5 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.23 (t, J=10.8 Hz, 1 H), 2.34 (s, 3 H), 3.75 (s, 3 H), 3.96 - 4.01 (m, 1 H), 4.01 - 4.05 (m, 1 H), 4.18 (t, J=10.4 Hz, 1 H), 6.00 (br.s., 2 H), 6.89 (t, J=7.2 Hz, 1 H), 6.98 (t, J=7.6 Hz, 1 H), 7.24 - 7.27 (m, 2 H), 7.31 (s, 1 H), 7.44 (t, J=8.4 Hz, 1 H), 7.63 (d, J=8 Hz, 1 H), 7.87 (d, J=12.4 Hz, 1 H), 8.15 (s, 1 H), 10.84 (s, 1 H). 98.25% purity by HPLC @ 284 nM.

Example 29

1-f4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-3-(3,5- difluorophenyl)pyrrolidin-2-one

To a mixture of 1-(4-bromo-3-fluorophenyl)-3-(3,5-difluorophenyl)pyrrolidin-2-one (400 mg, 1.1 mmol) in 1 ,4-dioxane was added bis(pinacolato)diboron (280 mg, 1.1 mmol, 1 equiv), and potassium acetate (320 mg, 3.2 mmol, 1 equiv). The reaction mixture was degassed with N₂ for 5 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (45 mg, 0.05 mmol, 0.05 equiv) was added and degassed with N₂ for further 5 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7-isopropyl-7/-/-cyclopenta[d]pyrimidin-4-amine (280 mg, 1.1 mmol, 1.0 equiv), saturated aqueous NaHC0₃ (6 ml_), PdCl₂(dppf)-CH₂Cl₂ adduct (45 mg, 0.054 mmol, 0.05 equiv) were added and the reaction mixture was degassed with N₂ for 5 minutes. The vessel was sealed and the reaction mixture was stirred for 16 hours at 100 °C. The crude was filtered through celite and the filtrate was extracted in ethyl acetate. The organic layer was dried over Na₂S0₄ and concentrated to obtain dark oily compound. The crude was purified over silica gel flash column chromatography. The compound eluted out as a mixture in 2% MeOH:DCM. The fractions were evaporated to obtain crude which was further purified over preparative HPLC instrument. Analytical conditions: Column: Inertsil ODS 3V (250 mm x 4.6 mm x 5 mic), Mobile Phase A/B : 0.01 % Ammonia in water/ Acetonitrile, Flow rate: 1 mL/min. The pure fractions were evaporated to obtain 1-4-(4-amino-7-isopropyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-3-fluorophenyl)-3-(3,5- difluorophenyl)pyrrolidin-2-one (20 mg, 4%) as off white solid. LCMS (ES) m/z = 466.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ ppm 1.46 (d, J=6.8 Hz,6 H), 2.23 - 2.31 (m, 1 H), 2.58 - 2.66 (m, 1 H),3.90 - 4.01 (m, 2 H), 4.07 - 4.1 1 (m, 1 H),4.93 - 5.0(m, 1 H), 5.96 (br s, 2 H), 7.11 - 7.17 (m, 3 H), 7.42 - 7.46 (m, 2 H), 7.57 - 7.59 (m, 1 H), 7.80 - 7.83 (m, 1 H), 8.10 (s,1 H).

Example 30 1 -4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-c/]pyrimiclin-5-yl)phenyl)-3-phenyl pyrrolidin-2-one

To a stirred solution of 4-chloro-7/-/-pyrrolo[2,3-c]pyrimidine (10.0 g, 65.4 mmol, 1 equiv) in DMF (60 mL) was added NaH (60%) (4.6 g, 195 mmol, 3 equiv) at 0 °C and Stirred for 10 minutes, 2-iodopropane (13 mL, 130 mmol, 2 equiv) was added slowly drop wise at 0°C. The reaction mixture stirred at RT for 3 h. The reaction mixture was cooled to 0 °C, diluted with cold water (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organics were combined and dried over Na₂S0₄, filtered, and concentrated in vacuo to give 4- chloro-7-isopropyl-7/-/-pyrrolo[2,3-c]pyrimidine (9 g, 71 %) as color less liquid. LC-MS (ES) m/z = 196.1 [M+H]⁺ . H NMR (400 MHz, CDCI₃) δ 1.53 - 1.57 (m, 6 H), 5.09 - 5.15 (m, 1 H), 6.61 (d, J=3.6 Hz, 1 H), 7.34 (d, J=3.6 Hz, 1 H), 8.26 (s, 1 H).

To a stirred solution of 4-chloro-7-isopropyl-7/-/-pyrrolo[2,3-c]pyrimidine (5.0 g, 25.6 mmol) in DCM was added /V-bromosuccinimide (5.02 g, 28.2 mmol, 1.1 equiv) in one portion at 15 °C. The reaction mixture stirred at RT for 30 minutes and monitored by TLC showed the complete conversion. The reaction mixture quenched with water (100 mL) and extracted with DCM (2 x 100mL). The organics were combined and dried over Na₂S0₄, filtered, and concentrated in vacuum to give crude compound of 5-bromo-4-chloro-7- isopropyl-7H-pyrrolo[2,3-c(]pyrimidine obtained. Purification: Purified by flash chromatography using 80g silica gel cartridge and eluting with of 5% ethyl acetate in n- hexane. The collected fractions with pure product were concentrated to give 5-bromo-4- chloro-7-isopropyl-7/-/-pyrrolo[2,3-c]pyrimidine (3.5 g, 50 %) as a light brown solid. LC-MS (ES) m/z = 274, 276 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ 1.51 - 1.55 (m, 6 H), 5.08 - 5.19 (m, 1 H), 7.35 (s, 1 H), 8.26 (s, 1 H).

To a stirred solution of 5-bromo-4-chloro-7-isopropyl-7/-/-pyrrolo[2,3-c]pyrimidine (2.5 g, 9.1 mmol) in NH₄OH (30 ml_) was heated in a stainless steel autoclave at 100°C for 16h. Reaction mixture was monitored by TLC, starting material was completed. The reaction mixture was cooled to room temperature, and the suspension was filtered. The filtrate was washed with water (2 x 30 ml_), dried under vacuum to give 5-bromo-7-isopropyl-7/-/- pyrrolo[2,3-c]pyrimidin-4-amine(1.6 g, 69%) as pale yellow solid. LC-MS (ES) m/z = 255.2, 257.3 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 1.38 - 1.40 (m, 6 H), 4.86 - 4.93 (m, 1 H), 6.65 (br s, 2 H), 7.53 (s, 1 H), 8.07 (s, 1 H).

Stage - 1 :To a stirred solution of 1-(4-bromophenyl)-3-phenylpyrrolidin-2-one (0.1 g, 0.316 mmol) in 1 ,4-dioxane was added bis(pinacolato)diboron (0.08 g, 0.3 mmol) and potassium carbonate (0.131 g, 1.0 mmol). The reaction mixture was degassed with N₂ for 15 minutes, PdCl₂(dppf)-CH₂Cl₂ adduct (0.018 g, 0.02 mmol) was added and the reaction mixture was stirred for 3 hours at 100 °C in a sealed tube. The Reaction mixture was monitored by TLC and LCMS. LCMS showed desired product. Crude reaction mixture was directly forwarded for next stage without doing workup and purification. LCMS (ES) m/z = 364.2 [M+H]⁺. (Crude LC-MS showed 74% of the product)

Stage - 2: To a stirred reaction mixture of 3-phenyl-1-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)pyrrolidin-2-one was added 5-bromo-7-isopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-amine (0.063 g, 0.2 mmol, 1.0 equiv) and 2 ml of sat. NaHC0₃ solution under argon atmosphere, then again added PdCl₂(dppf)-CH₂Cl₂ adduct (9 mg, 0.01 mmol, 0.05 equiv) and heated to 100 °C for 16h. The Reaction mixture was cooled to RT, diluted with water (30 mL) and extracted with ethyl acetate (2 x 20ml_). The organics were combined and dried over Na₂S0₄, filtered, and concentrated in vacuo to give crude compound. Crude product was purified by flash chromatography on silica gel and compound was eluted with 3% MeOH/DCM. The fractions containing the desired product were combined and concentrated to afford 1-4-(4-amino-7-isopropyl-7/-/-pyrrolo[2,3- d]pyrimidin-5-yl)phenyl)-3-phenylpyrrolidin-2-one (17 mg, 17%) as off-white solid. LCMS (ES) m/z = 412.3 [M+H]⁺. H NMR (400 MHz, DMSOc/6) δ 1.57 - 1.59 (m, 6 H), 2.15 - 2.31 (m, 1 H), 2.55 - 2.66 (m, 1 H), 3.93 - 3.98 (m, 3 H), 4.93 - 5.00 (m, 1 H), 6.18 (br s, 2H), 7.25 - 7.42 (m, 5 H), 7.49 (d, J=8.8 Hz, 3 H), 7.81 ( d, J=8.8 Hz, 2 H), 8.15 (s, 1 H).

Example 31

1-4-(4-amino-7-isopropyl-7H-pyrrolo[2,3- lpyrimidin-5-yl)-3-fluoroph

phenylpyrrolidin-2-one

To a stirred solution of 1-(4-bromo-3-fluorophenyl)-3-phenylpyrrolidin-2-one (0.1 g, 0.3 mmol) in 1 ,4-dioxane (10 mL) was added bis(pinacolato)diboron (0.075 g, 0.3 mmol, 1.0 equiv) and potassium carbonate (0.123 g, 0.9 mmol, 3.0 equiv). The reaction mixture was degassed with N₂ for 15 minutes, PdCl₂(dppf)-CH₂Cl₂ adduct (0.012 g, 0.014 mmol, 0.05 equiv) was added and the reaction mixture was stirred for 3 hours at 100 °C in a sealed tube. The reaction was cooled to room temperature, 5-bromo-7-isopropyl-7/-/-pyrrolo[2,3- d]pyrimidin-4-amine (0.076 g, 0.298 mmol, 1.0 equiv) and saturated aqueous NaHC0₃ (2 mL) were added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.012 g, 0.014 mmol, 0.05 equiv)) was added, the vessel was sealed, and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organics were combined and dried over Na₂S0₄, filtered, and concentrated in vacuo to give crude compound. Crude product was purified by flash chromatography on silica gel and compound was eluted with 4% MeOH/DCM. The fractions containing the desired product were combined and concentrated to afford 1-4-(4-amino-7-isopropyl-7/-/-pyrrolo[2,3- d]pyrimidin-5-yl)-3-fluorophenyl)-3-phenylpyrrolidin-2-one (0.015 g, 11.7%) as a pale yellow solid. LCMS (ES) m/z = 430.2 [M+H]⁺. H NMR (400 MHz, DMSOc/6) δ 1.52 - 1.58 (m, 6 H), 2.16 - 2.25 (m, 1 H), 2.55 - 2.66 (m, 1 H), 3.91 - 4.00 (m, 3 H), 4.93 - 5.00 (m, 1 H), 5.98 (br s, 2 H), 7.26 - 7.41 (m, 5 H), 7.43 (t, J=8.6 Hz, 2 H), 7.58 - 7.60 (m, 1 H), 7.82 - 7.85 (m, 1 H), 8.13 (s, 1 H).

Example 32

1-4-(4-amino-7-(1 -methylpiperidin-4-yl)-7H-pyrrolo[2,3-c/lpyrimidin-5-yl)-3- fluorophenyl)-3-(3,5-difluorophenyl)pyrrolidin-2-one

To a mixture of 1-(4-bromo-3-fluorophenyl)-3-(3,5-difluorophenyl)pyrrolidin-2-one (350 mg, 0.9 mmol) in 1 ,4-dioxane (18 ml_) was added bis(pinacolato)diboron (240 mg, 0.9 mmol, 1 equiv), and potassium acetate (280 mg, 2.8 mmol, 1 equiv). The reaction mixture was degassed with N₂ for 5 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (40 mg, 0.05 mmol, 0.05 equiv) was added and degassed with N₂ for further 5 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction mixture was cooled to room temperature, 5-bromo-7-(1-methylpiperidin-4-yl)-7/-/-pyrrolo[2,3-d]pyrimidin-4-amine (300 mg, 0.94 mmol, 1.0 equiv) & saturated aqueous NaHC0₃ (6 ml_) followed by PdCI₂(dppf)- CH₂CI₂ adduct (40 mg, 0.05 mmol, 0.05 equiv) were added and the reaction mixture was degassed with N₂ for 5 minutes. The vessel was sealed and the reaction mixture was stirred for 16 hours at 100 °C. The crude was filtered through celite and the filtrate was extracted in ethyl acetate. The organic layer was dried over Na₂S0₄ and concentrated to obtain dark oily compound. The crude was purified over silica gel flash column chromatography, compound eluted out as a mixture in 8% MeOH:DCM. The fractions were evaporated to obtain crude which was further purified over preparative HPLC instrument. Analytical conditions: Column: Inertsil ODS 3V (250 mm x 4.6 mm x 5 mic), Mobile Phase A/B : 0.01 % TFA in water/ Acetonitrile, Flow rate: 1 mL/min. The pure fractions were evaporated to obtain 1-4-(4-amino-7-(1-methylpiperidin-4-yl)-7/-/- pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-3-(3,5-difluorophenyl)pyrrolidin-2-one (30 mg, 6 %) as off white solid. LCMS (ES) m/z = 521.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 1.87 - 2.05 (m, 2 H), 2.07 - 2.25 (m, 4 H), 2.26 (s, 3 H), 2.28 - 2.31 (m, 2 H), 2.58 - 2.63 (m, 1 H), 2.88 - 2.90 (m, 2 H), 3.90 - 3.99 (m, 3 H), 4.06 - 4.1 1 (m, 1 H), 4.53 (br s, 1 H), 5.96 (br s, 2 H), 7.10 - 7.17 (m, 3 H), 7.41 - 7.45 (m, 2 H), 7.56 - 7.59 (m, 1 H), 7.79 - 7.83 (m, 1 H), 8.12 (s, 1 H).

Example 33 1-4-(4-aminothieno[2,3-d] rrolidin-2-one

To a stirred solution methyl 2-aminothiophene-3-carboxylate (10 g, 63.7 mmol, 1 equiv), in formamide ( 10 mL) was heated at 190 °C for 8h, then stirred at RT for overnight. The reaction mixture was poured onto ice water (300 mL) and stirred for 10 minutes, the solid precipitated was filtered and washed with water ( 50 mL), dried under vacuum to give product as brown solid, Yield (5.5 g, 57 %). LC-MS (ES) m/z = 153.1 [M+H]⁺. ¹H NMR (400 MHz, DMSOd6) δ 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).

A mixture of thieno[2,3-c]pyrimidin-4(1 /-/)-one (3 g, 19.7 mmol, 1 equiv), bromine ( 3 mL) and AcOH (30mL) was stirred at RT for 2h. The reaction mixture was concentrated under reduced pressure. The obtained residue was washed with water (2 x 10 mL) and dried to give desired product as light brown solid. Yield (4.5 g, 98 %). LC-MS (ES) m/z = 231.0, 233.0 [M+H]⁺. H NMR (400 MHz, DMSOc/6) δ 7.53 (s, 1 H), 8.12 (s, 1 H), 12.61 (brs, 1 H).

6-bromothieno[2,3-d]pyrimidin-4(1 /-/)-one (4.5 g, 19.5 mmol, 1 equiv) and POCI₃ (80 mL) were refluxed for 6h. The reaction mixture was concentrated; the residue was washed with cold water and hexane to give product as brown solid, yield (4 g, 82 %). LC-MS (ES) m/z = 248.9, 250.9 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ ppm 7.48 (s, 1 H), 8.81 (s, 1 H).

To a stirred solution of 6-bromo-4-chlorothieno[2,3-c]pyrimidine (1 g, 4.0 mmol, 1 equiv) in THF (40 mL) was added 2M LDA in THF solution (3 mL, 6.0 mmol, 1.5 equiv) drop wise at -78 °C under nitrogen. The reaction was stirred for 1 h at -78 °C after which a mixture of water (1.25 mL) and THF (5 mL) was added slowly. The mixture was then warmed to 0 °C, poured onto water (60 mL), and extracted with DCM (2 x 30 mL). The combined organic extracts were combined and dried over Na₂S0₄, filtered and concentrated. Purification: Purified by flash column chromatography, 24g silica column with 10% EtOAc in hexane as mobile phase to give 5-bromo-4-chlorothieno[2,3-c]pyrimidine as yellow solid. Yield (0.46 g, 46 %). LC-MS (ES) m/z = 248.9 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ 7.66 (s, 1 H), 8.87 (s, 1 H).

A suspension of 5-bromo-4-chlorothieno[2,3-c]pyrimidine (0.46 g, 1.8 mmol, 1 equiv) in aqueous NH₄OH (30 mL) was heated in a stainless steel autoclave at 100 °C for overnight (18h). The reaction mixture was cooled to 25 °C and the suspension was filtered. The solid was washed with water, and dried under vacuum to give product as light yellow solid, yield (0.23 g, 55%). LC-MS (ES) m/z = 230.0, 232.0 [M+H]⁺. H NMR (400 MHz, DMSOc/6) δ 7.45 - 7.00 (br s, 2 H), 7.76 (s, 1 H), 8.31 (s, 1 H).

To a mixture of 1-(4-bromophenyl)-3-phenylpyrrolidin-2-one (400 mg, 1.3 mmol, 1 equiv), bis(pinacolato)diboron (320 mg, 1.3 mmol, 1 equiv), and potassium acetate (370 mg, 3.8 mmol, 3 equiv) was added 1 ,4-dioxane (16 ml_), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (50 mg, 0.06 mmol, 0.05 eq) was added and again degassed with N₂ for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. To this reaction mixture, 5-bromothieno[2,3-c]pyrimidin-4-amine (230 mg, 1.00 mmol, 1 equiv) and saturated aqueous NaHC0₃ (6 ml_) were added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (50 mg, 0.06 mmol, 0.05 eq) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The reaction mixture was cooled to RT and filtered through celite bed, washed with EtOAc (100 ml_), the filtrate was dried over Na₂S0₄ and concentrated. The crude was purified by flash column chromatography with 24 g silica gel column and 3% MeOH in DCM as mobile phase. Finally compound was washed with n-pentane (5 x 3ml_) and diethyl ether (3 x 5 ml_) to get desired product as light yellow solid. Yield (120 mg, 24%). LCMS (ES) m/z = 387.1 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.16 - 2.26 (m, 1 H), 2.56 - 2.66 (m, 1 H), 3.95 - 4.02 (m, 3 H), 5.30 - 6.80 (br s, 2 H), 7.25 - 7.29 (m, 1 H), 7.31 - 7.38 (m, 4 H), 7.46 (s, 1 H), 7.50 (d, J=8.8 Hz, 2 H), 7.87 (d, J=8.8 Hz, 2 H),8.33 (s, 1 H). 99.82% of purity by HPLC@ 254 nM.

Example 34

1-4-(4-aminothieno[3,2-c]pyridin-3- enylpyrrolidin-2-one

To a mixture of 1-(4-bromophenyl)-3-phenylpyrrolidin-2-one (400 mg, 1.3 mmol, 1 equiv), bis(pinacolato)diboron (320 mg, 1.3 mmol, 1 equiv), and potassium acetate (370 mg, 3.8 mmol, 3 equiv) was added 1 ,4-dioxane (16 mL), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (51.5 mg, 0.06 mmol, 0.05 eq) was added and again degassed with N₂ for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 3- bromothieno[3,2-c]pyridin-4-amine (289 mg, 1.265 mmol) and saturated aqueous NaHC0₃ (6 mL) was added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (51.5 mg, 0.063 mmol, 0.05 eq) 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, washed with EtOAc (100 mL), the filtrate was dried over Na₂S0₄ and concentrated. The crude material was purified by flash column chromatography with 24 g silica gel column and 3% MeOH in DCM as mobile phase. Finally compound was washed with ether (3 x 5 mL) and dried to get desired product as off white solid, yield (100 mg, 22%). LCMS (ES) m/z = 386.1 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.17 - 2.26 (m, 1 H), 2.56 - 2.65 (m, 1 H), 3.95 - 4.00 (m, 3 H), 5.38 (s, 2 H), 7.25 - 7.29 (m, 2 H), 7.32 - 7.38 (m, 4 H), 7.44 (s, 1 H), 7.48(d, J=8 Hz, 2 H), 7.81 - 7.87 (m, 3 H). 99.71 % of purity by HPLC@ 290 nM.

Example 35 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimidi^

yl)pyrrolidin-2-one

5-methylthiazol-2-amine (2.0 g, 17.5 mmol, 1.0 equiv) was taken in con. HCI (35%) (9 ml) and cooled in ice-salt mixture (— 5°C). A solution of NaN0₂ (1.33 g, 19.2 mmol, 1.1 equiv) in water (10 ml) was added drop wise over 15 min and stirred for 1 h at 0°C and slowly warmed to room temperature. Reaction mixture was heated to 60°C and stirred for about 2h. Reaction mixture was monitored by TLC and LCMS. After consumption of starting material reaction mixture was diluted with ice water and extracted with DCM (3 x 50 mL). Combined organic layers were washed with water and brine solution, dried over Na₂S0₄, filtered and concentrated to get crude product as black oil, yield (1.3g, 75%). LC- MS (ES) m/z = 134.1 [M+H]⁺. H NMR (400 MHz, DMSOcfe) δ ppm 2.40 (s, 3 H), 7.38 (s, 1 H).

pyrrolidin-2-one (3.0 g, 35.2 mmol, 1.0 equiv), 1-bromo-4-iodobenzene (9.95 g, 35.2 mmol, 1.0 equiv), DMEDA (0.37 ml, 3.5 mmol, 0.1 equiv) , CsF (13.36 g, 88.0 mmol, 2.5 equiv) and Cul (0.335 g, 1.8 mmol, 0.05 equiv) were taken in EtOAc (100 ml) and stirred for 30h at room temperature. The reaction mixture was diluted with water and extracted with EtOAc (3 x 100mL). Combined organic layers were washed with water and brine solution and dried over Na₂S0₄, filtered and concentrated to get crude product. The crude product was purified by flash chromatography to give 1-(4-bromophenyl) pyrrolidin-2-one as white solid, yield (1.6g, 19%). LC-MS (ES) m/z = 240.0, 242.0 [M+H]⁺. ¹H NMR (400 MHz, DMSOd6) δ ppm 2.00 - 2.08 (m, 2 H), 2.48 - 2.50 (m, 2 H), 3.80 (t, J=6.8 Hz, 2 H), 7.53 (d, J=9.2 Hz, 2 H), 7.62 (d, J=9.2 Hz, 2 H).

To a stirred solution of 1-(4-bromophenyl) pyrrolidin-2-one (0.5 g, 2.1 mmol, 1.0 equiv) and 2-chloro-5-methylthiazole (0.276 g, 2.1 mmol, 1.0 equiv) in toluene (20 ml) was added NaHMDS (2M in THF) (2.01 ml, 4.2 mmol, 2.0 equiv) at -78°C and stirred for 1 h. After consumption of starting material, reaction mixture was quenched with sat. NH₄CI solution and extracted with EtOAc (3 x 100 ml_). Combined organic layers were washed with water and brine solution, dried over Na₂S0₄, filtered and concentrated to get crude product and was purified by flash chromatography using with 30% EtOAc/Hexane eluent, yield (0.55g, 56%). LC-MS (ES) m/z = 337.0, 339.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.42 (s, 3 H), 2.58 - 2.65 (m, 1 H), 3.86 - 3.94 (m, 2 H), 4.33 (t, J=10.4 Hz, 1 H), 7.43 (d, J=1.2 Hz, 1 H), 7.57 (d, J=8.8 Hz, 2 H), 7.65 (d, J=8.8 Hz, 2 H).

Stage-1

To a stirred solution of 1-(4-bromophenyl)-3-(5-methylthiazol-2-yl)pyrrolidin-2-one (0.5 g, 1.5 mmol, 1.0 equiv) in dioxane was added bis(pinacolato)diboron (0.376 g, 1.5 mmol, 1.0 equiv), potassium acetate (0.362 g, 3.7 mmol) and PdCl₂(dppf)-CH₂Cl₂ adduct (0.06 g, 0.07 mmol, 0.05 equiv) under argon atmosphere and heated to 100°C for 3h in a sealed tube. The reaction mixture was monitored by TLC and LCMS. After consumption of starting material, LCMS showed boronic ester and boronic acid mixture. Crude reaction mixture was directly forwarded to next stage without workup and purification.

Stage-2

To a stirred reaction mixture of 3-(5-methylthiazol-2-yl)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)pyrrolidin-2-one was added (0.403 g, 1.8 mmol, 1.2 equiv) of 5- bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine and 3 ml of sat. NaHC0₃ solution followed by PdCI₂(dppf)-CH₂Cl₂ adduct (0.06 g, 0.07 mmol, 0.05 equiv) under argon atmosphere and heated to 100 °C for overnight in a sealed tube. Reaction mixture was monitored by LCMS. After consumption of starting material, Reaction mixture was filtered through celite and dried over Na₂S0₄, filtered and concentrated to get crude product. Crude product was purified by flash chromatography, compound was eluted with 2% MeOH/DCM and concentrated to get 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5- yl)phenyl)-3-(5-methylthiazol-2-yl)pyrrolidin-2-one as off-white solid, yield (0.05g, 8.4% & 0.09 g, Impure). LCMS (ES) m/z = 405.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.43 (s, 3 H), 2.59 - 2.65 (m, 1 H), 3.73 (s, 3 H), 3.95 - 3.99 (m, 2 H), 4.35 (t, J=9.2 Hz, 1 H), 6.03 (s, 2 H), 7.29 (s, 1 H), 7.44 - 7.47 (m, 3 H), 7.77 (d, J=8.4 Hz, 2 H), 8.14 (s, 1 H). Example 36

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

To a stirred solution of 1-(4-bromophenyl) pyrrolidin-2-one (2.0 g, 8.3 mmol, 1.0 equiv) and 2-chloro-5-fluoropyridine (1.7 ml, 16.6 mmol, 2.0 equiv) in THF (50 mL) was added NaHMDS (1 M in THF) (17 mL, 16.6 mmol, 2.0 equiv) at -10°C and stirred for 3h at 0°C. Reaction mixture was monitored by LCMS and TLC. After consumption of starting material, reaction mixture was quenched with sat. NH₄CI solution and extracted with EtOAc (3 x 100 mL). Combined organic layers were washed with water and brine solution, dried over Na₂S0₄, filtered and concentrated to get crude product. Crude product was purified by flash chromatography on silica gel and compound was eluted with 30% EtOAc/Hexane, yield (0.9 g, 32.5%), off-white solid. LC-MS (ES) m/z = 335.0, 337.0 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ 2.53 - 2.60 (m, 1 H), 2.68 - 2.77 (m, 1 H), 3.87 - 3.93 (m, 1 H), 3.99 - 4.04 (m, 2 H), 7.37 - 7.44 (m, 2 H), 7.47 (d, J=8.8 Hz, 2 H), 7.57 (d, J=8.8 Hz, 2 H), 8.42 (d, J=2.0 Hz, 1 H).

Stage-1 :

To a stirred solution of 1-(4-bromophenyl)-3-(5-fluoropyridin-2-yl)pyrrolidin-2-one (0.85 g, 2.5 mmol, 1.0 equiv) in dioxane (20 mL) was added bis(pinacolato)diboron (0.711 g, 2.8 mmol, 1.1 equiv), potassium acetate (0.662 g, 6.4 mmol) under argon atmosphere, followed by PdCI₂(dppf)-CH₂Cl₂ adduct (0.103 g, 0.13 mmol, 0.05 equiv) and heated to 100 °C for 3h in sealed tube. Reaction mixture was monitored by TLC and LCMS. LCMS showed desired product. Crude reaction mixture was directly forwarded to next stage without work up and purification.

Stage-2:

To a stirred reaction mixture of 3-(5-fluoropyridin-2-yl)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)pyrrolidin-2-one was added 5-bromo-7-methyl-7/-/-pyrrolo[2,3- d]pyrimidin-4-amine (0.576 g, 2.5 mmol, 1.0 equiv), 5 ml of sat. NaHC0₃ solution under argon atmosphere, followed by addition of PdCl₂(dppf)-CH₂Cl₂ adduct (0.103 g, 0.13 mmol, 0.05 equiv) under argon atmosphere and heated to 100 °C for overnight. Reaction mixture was monitored by LCMS and after consumption of starting material, Reaction mixture was cooled to RT, filtered through celite and washed with DCM. The filtrate was and dried over Na₂S0₄ and concentrated to get crude product. Crude product was purified by flash chromatography on silica gel and compound was eluted with 2% MeOH/DCM and concentrated to get 1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(5- fluoropyridin-2-yl)pyrrolidin-2-one as off-white solid, yield (0.19 g, 19%). LCMS (ES) m/z = 403.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.52 - 2.54 (m, 2 H), 3.73 (s, 3 H), 3.96 - 4.02 (m, 2 H), 4.14 - 4.17 (m, 1 H), 6.03 (br s, 2 H), 7.28 (s, 1 H), 7.45 (d, J=8.4 Hz, 2 H), 7.50 - 7.53 (m, 1 H), 7.70 - 7.75 (m, 1 H), 7.78 (d, J=8.4 Hz, 2 H), 8.14 (s, 1 H), 8.54 (d, J=2.8 Hz, 1 H).

Example 37

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

To a stirred solution of 1-(4-bromophenyl) pyrrolidin-2-one (2.0 g, 8.3 mmol, 1.0 equiv) and 2-chloro-6-methylpyridine (1.8 ml, 16.6 mmol, 2.0 equiv) in THF (50 ml) was added NaHMDS (1 M in THF) (17 ml, 16.6 mmol, 2.0 equiv) at -10°C and stirred for 3h at 0°C. Reaction mixture was monitored by LCMS and TLC. After 3h, reaction mixture was quenched with sat. NH₄CI solution and extracted with EtOAc (3 x 100ml_). Combined organic layers were washed with water and brine solution and dried over Na₂S0₄, filtered and concentrated to get crude product. Crude product was purified by flash chromatography on Silica gel and compound was eluted with 30% EtOAc/Hexane, yield (1.1 g, 44 %), off-white solid. LC-MS (ES) m/z = 331.0, 333.0 [M+H]⁺. H NMR (400 MHz, CDCIs) δ 2.43 (s, 3 H), 2.46 - 2.49 (m, 2 H), 3.87 - 4.05 (m, 3 H), 7.12 - 7.18 (m, 2 H), 7.55 (d, J=8.8 Hz, 2 H), 7.62 - 7.68 (m, 3 H).

Stage-1 :

To a stirred solution of 1-(4-bromophenyl)-3-(6-methylpyridin-2-yl)pyrrolidin-2-one (0.7 g, 2.1 mmol, 1.0 equiv) in dioxane (14 ml_) was added bis(pinacolato)diboron (0.536 g, 2.1 1 mmol, 1.0 equiv), potassium acetate (0.518 g, 5.3 mmol, 2.5 equiv) under argon atmosphere, followed by addition of PdCl₂(dppf)-CH₂Cl₂ adduct (0.086 g, 0.11 mmol, 0.05 equiv) under argon atmosphere, the reaction mixture was heated to 100 °C for 3h in a sealed tube. Reaction mixture was monitored by TLC and LCMS. LCMS showed desired product. Crude reaction mixture was directly forwarded for next stage without work up and purification.

Stage-2:

To a stirred reaction mixture of 3-(6-methylpyridin-2-yl)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)pyrrolidin-2-one was added 5-bromo-7-methyl-7/-/-pyrrolo[2,3- d]pyrimidin-4-amine (0.479 g, 2.1 mmol, 1.0 equiv) of and 8 ml of sat. NaHC0₃ solution under argon atmosphere, followed by addition of PdCl₂(dppf)-CH₂Cl₂ adduct (0.086 g, 0.11 mmol, 0.05 equiv) under argon atmosphere, the reaction mixture was heated to 100 °C and stirred for overnight. Reaction mixture was monitored by LCMS and after consumption of starting material, Reaction mixture was filtered through celite and washed with DCM. The filtrate was and dried over Na₂S0₄ and concentrated to get crude product. Crude product was purified by flash chromatography on Silica gel and compound was eluted with 2% MeOH/DCM as impure fraction, it was re purified by prep HPLC(Column :Column : Inertsil ODS 3V (250 mm X 4.6 mm X 5 mic), Mobile phase (A) : 0.01 % Ammonia in water, Mobile phase(B) : ACN, Flow rate : 1.0 mL/min) to get 1-4-(4-amino-7- methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(6-methylpyridin-2-yl)pyrrolidin-2-one as off-white solid, yield (0.07g, 10%). LCMS (ES) m/z = 399.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.44 (s, 3 H), 2.49 - 2.53 (m, 2 H), 3.73 (s, 3 H), 3.92 - 4.07 (m, 3 H), 6.03 (br s, 2 H), 7.13 - 7.20 (m, 2 H), 7.29 (s, 1 H), 7.46 (d, J=8.4 Hz, 2 H), 7.65 (t, J=7.6 Hz, 1 H), 7.79 (d, J=8.4 Hz, 2 H), 8.14 (s, 1 H). Example 38

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3- lpyrimidin-5-yl)phenyl)-3-(4,6- dimethylpyrimidin-2-yl)- pyrrolidin-2-one

To a stirred solution of 1-(4-bromophenyl) pyrrolidin-2-one (2.0 g, 8.33 mmol, 1.0 equiv) and 2-chloro-4,6-dimethylpyrimidine (1.42 g, 10.0, 1.2 equiv) in THF (50 mL) was added NaHMDS (1 M in THF) (17 mL, 16.6 mmol, 2.0 equiv) at -10°C and stirred for 1 h. Reaction progress was monitored by LCMS and TLC. The reaction mixture was quenched with sat. NH₄CI solution and extracted with EtOAc (3 x 50mL). Combined organic layer was washed with water and brine solution, dried over Na₂S0₄, concentrated to get crude product. Crude product was purified by flash chromatography on Silica gel and compound was eluted with 40% EtOAc/Hexane to get desired product as off white solid, yield (1.2 g, 42 %). LC-MS (ES) m/z = 346.0 and 348.1 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ 2.46 (s, 6H), 2.56 - 2.71 (m, 2 H), 3.86 - 3.92 (m, 1 H), 4.03 - 4.08 (m, 1 H), 4.1 1 - 4.18 (m, 1 H), 6.92 (s, 1 H), 7.47 (d, J=8.8 Hz, 2 H), 7.60 (d, J=8.8 Hz, 2 H).

Stage-1 :

To a stirred solution of 1-(4-bromophenyl)-3-(4,6-dimethylpyrimidin-2-yl)pyrrolidin-2-one (0.7 g, 2.0 mmol, 1.0 equiv) in dioxane (14 mL) was added bis(pinacolato)diboron (0.514 g, 2.0 mmol, 1.0 equiv), potassium acetate (0.49 g, 5.0 mmol, 2.5 equiv) under argon atmosphere, followed by addition of PdCI₂(dppf)-CH₂Cl2 adduct (0.086 g, 0.105 mmol, 0.05 equiv) under argon atmosphere, the reaction mixture was heated to 100 °C for 3h in a sealed tube. Reaction mixture was monitored by TLC and LCMS. LCMS showed desired product. Crude reaction mixture was directly forwarded for next stage without work up and purification.

Stage-2:

To a stirred reaction mixture of 3-(4,6-dimethylpyrimidin-2-yl)-1-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one was added 5-bromo-7-methyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine (0.59 g, 2.6 mmol, 1.3 equiv) and 8 ml of sat. NaHC0₃ solution under argon atmosphere, followed by addition of PdCl₂(dppf)-CH₂Cl₂ adduct (0.086 g, 0.105 mmol, 0.05 equiv) under argon atmosphere, overnight stirring with heating at 100 °C continued.. Aftre this time, reaction mixture LCMS indicated consumption of starting material and was filtered through celite and washed with DCM. The filtrate was and dried over Na₂S0₄ and concentrated to get crude product. Crude product was purified by flash chromatography on silica gel and compound was eluted with 2% MeOH/DCM and as 50% impure fraction, it was re-purified by prep HPLC (Column : Inertsil ODS 3V (250 mm X 4.6 mm X 5 mic), Mobile phase (A) : 0.01 % Ammonia in water, Mobile phase (B): ACN, Flow rate: 1.0 mL/min) to get 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrimidin-5- yl)phenyl)-3-(4,6-dimethylpyrimidin-2-yl)pyrrolidin-2-one as off-white solid, yield (0.19 g, 22.8%). LCMS (ES) m/z = 414.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.40 (s, 6 H), 2.49 - 2.53 (m, 2 H), 3.73 (s, 3 H), 3.97 - 4.14 (m, 3 H), 6.04 (br s, 2 H), 7.16 (s, 1 H), 7.29 (s, 1 H), 7.46 (d, J=8.4 Hz, 2 H),7.79 (d, J=8.4 Hz, 2 H), 8.14 (s, 1 H). Example 39

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimidin-5-yl)phenyl)-3-(4,6-dimethyl pyridin-2-yl)pyrrolidin-2-one

To a stirred solution of 1-(4-bromophenyl)pyrrolidin-2-one (2 g, 8.3 mmol) and 2-chloro- 4,6-dimethylpyridine (1.5 g, 10.8 mmol, 1.3 equiv) in THF (25 mL) was added NaHMDS (1 M in THF) drop wise manner at -10°C. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution and extracted in ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain crude compound. The crude was purified over silica gel flash column chromatography. The compound co-eluted with the starting material in 15 % EtOAc:Hexanes. The fractions were evaporated to obtain mixture which was treated with 1 N HCI and extracted in ethyl acetate. The aqueous layer was basified with saturated NaHC0₃ and extracted in ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain 1-(4-bromophenyl)-3-(4,6-dimethylpyridin-2-yl)pyrrolidin-2-one (0.25 g, 9%) as an off white solid. LCMS (ES) m/z = 345.0, 347.0 [M+H]⁺. H NMR (400 MHz, DMSOc/6) δ 2.26 (s, 3 H), 2.38 (s, 3 H), 2.42 - 2.49 (m, 2 H), 3.86 - 3.88 (m, 1 H), 3.93 - 3.99 (m, 2 H), 3.90 - 3.99 (m, 2 H), 6.97 (s, 1 H), 7.0 (s, 1 H), 7.55 (d, J=8.4 Hz, 2 H), 7.66 (d, J=8.4 Hz, 2 H).

To a mixture of 1-(4-bromophenyl)-3-(4,6-dimethylpyridin-2-yl)pyrrolidin-2-one (250 mg, 0.7 mmol) in 1 ,4-dioxane (18 ml_) was added bis(pinacolato)diboron (180 mg, 0.7 mmol, 1 equiv), and potassium acetate (210 mg, 2.2 mmol, 1 equiv). The reaction mixture was degassed with N₂ for 5 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (30 mg, 0.04 mmol, 0.05 equiv) was added and degassed with N₂ for further 5 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (160 mg, 0.72 mmol, 1.0 equiv), saturated aqueous NaHC0₃ (6 ml_), PdCl₂(dppf)-CH₂Cl₂ adduct (30 mg, 0.04 mmol, 0.05 equiv) were added and the reaction mixture was degassed with N₂ for 5 minutes. The vessel was sealed and the reaction mixture was stirred for 16 hours at 100 °C. The crude was filtered through celite and the filtrate was extracted with ethyl acetate. The organic layer was dried over Na₂S0₄ and concentrated to obtain dark oily compound. The crude product was purified over silica gel flash column chromatography. The compound eluted in 5% MeOH:DCM mobile phase. The pure fractions were evaporated to obtain 1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(4,6- dimethylpyridin-2-yl)pyrrolidin-2-one (25 mg, 8.3 %) as off white solid. LCMS (ES) m/z = 413.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.30 (s, 3 H), 2.48 (s, 3 H), 2.57 - 2.60 (m, 1 H), 2.69 - 2.72 (m, 1 H), 3.84 (s, 3 H), 3.94 - 3.99 (m, 2 H), 4.10 - 4.1 1 (m, 1 H), 5.06 (br s, 2 H), 6.88 (s, 1 H), 6.92 (s, 1 H), 7.01 (s, 1 H), 7.48 (d, J=8.4 Hz, 2 H), 7.78 (d, J=8.4 Hz, 2 H).

Example 40

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimidin-5-yl)phenyl)-3-(6-(trifluoromethyl^ pyridin-2-yl)pyrrolidin-2-one

Run-1 :

To a solution of 1-(4-bromophenyl) pyrrolidin-2-one (930 mg, 3.9 mmol, 1.0 equiv) and 2- chloro-6-(trifluoromethyl)pyridine (701 mg, 3.9 mmol, 1 equiv) in toluene (10 mL) was added 0.6 M NaHMDS in toluene (12.9 mL, 7.8 mmol, 2 equiv) at -78 °C drop wise over a period of 5 minutes. The reaction mixture was stirred at - 78 °C for 1 h. Reaction mixture was quenched with sat. NH₄CI solution, extracted into EtOAc (2 x 100 ml). The combined organics were dried over Na₂S0₄ and concentrated, yield (1.5 g, crude). LC-MS (ES) m/z = 385.0, 387.0 [M+H]⁺. Run-2

To a solution of 1-(4-bromophenyl) pyrrolidin-2-one (2.0 g, 8.3 mmol, 1.0 equiv) and 2- chloro-6-(trifluoromethyl)pyridine (1.8 g, 10.0 mmol, 1.2 equiv) in toluene (30 mL) was added 2M NaHMDS in THF (8.3 ml, 16.6 mmol, 2 equiv) at -78 °C drop wise over a period of 5 minutes. The reaction mixture was stirred at - 78 °C for 1 h. The reaction mixture was quenched with sat NH₄CI solution, extracted into EtOAc (2 x 100 mL). The combined organics were dried over Na₂S0₄ and concentrated.

Purification: Run-1 and Run-2 crude product was combined and purified with 100 - 200 silica gel, 80 g column, CombiFlashORf, using 15 % EtOAc : Hexane as mobile phase to obtain desired product as white solid yield (450 mg, 9.57%). LC-MS (ES) m/z = 385.0, 337.0 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ 2.46 - 2.68 (m, 1 H), 2.84 - 2.92 (m, 1 H), 3.85 - 3.94 (m, 1 H), 4.05 - 4.10 (m, 2 H), 7.49 (d, J=8.8 Hz, 2 H), 7.56 (d, J=8.8 Hz, 2 H), 7.60 (d, J=8 Hz, 1 H), 7.66 (d, J=8 Hz, 1 H), 7.86 (t, J=8 Hz, 1 H).

To a mixture of 1-(4-bromophenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one (450 mg, 1.2 mmol, 1 equiv), bis(pinacolato)diboron (296 mg, 1.2 mmol, 1 equiv), and potassium acetate (343 mg, 3.5 mmol, 3 equiv) was added 1 ,4-dioxane (20 ml_), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (47.5 mg, 0.06 mmol, 0.05 equiv) was added and again degassed with N₂ for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction mixture was cooled to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo [2, 3-d] pyrimidin-4-amine (265 mg, 1.168 mmol, 1 equiv) and saturated aqueous NaHC0₃ (8 ml_) was added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCI₂ (dppf)-CH₂Cl₂ adduct (47.5 mg, 0.058 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The mixture was poured on to water and extracted into EtOAc (2 x 100 ml_) dried over Na₂S0₄ and concentrated. Purification: Crude product was purified using 100 - 200 silica gel, 24 g column and 3 % MeOH in DCM as mobile phase to obtain desired product as off white solid, yield (72 mg, 13.63%). LCMS (ES) m/z = 453.1 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.54 - 2.58 (m, 2 H), 3.73 (s, 3 H), 3.98 - 4.05 (m, 2 H), 4.30 (t, J=8.8 Hz, 1 H), 6.02 (br.s., 2 H), 7.29 (s, 1 H), 7.47 (d, J=8.4 Hz, 2 H), 7.79 (m, 3 H), 7.84 (d, J=8 Hz, 1 H), 8.10 (t, J=7.6 Hz, 1 H), 8.14 (s, 1 H). 98.29% of purity by HPLC at 254 nM.

Example 41

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

(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one

To a stirred solution of 1-bromo-2-fluoro-4-iodobenzene (3.00 g, 35.3 mmol, 1.0 equiv), pyrrolidin-2-one (10.60 g, 35.3 mmol, 1.0 equiv) and CsF (13.39 g, 881.3 mmol, 2.5 equiv) in EtOAc was added DMEDA (0.38 mL, 3.525 mmol, 0.1 equiv) followed by the addition of Cul (0.336 g, 1.8 mmol, 0.05 equiv) reaction mixture was stirred at room temperature for overnight. After consumption of the starting material the reaction mixture was filtered through Celite. The filtrate was washed with water (1 x 25 mL) followed by the brine (2 x 30 mL). The organic phase was dried over Na₂S0₄, filtered and evaporated to afford the desired product 1-(4-bromo-3-fluorophenyl)pyrrolidin-2-one (7.14 g, Crude) as a pale yellow solid, crude product was forwarded to next step without purification. LC-MS (ES) m/z = 258.0, 260.0 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ 2.14 - 2.21 (m, 2 H), 2.62 (t, J=8.0 Hz, 2 H), 3.82 (t, J=8.0 Hz, 2 H), 7.28 (s, 1 H), 1 H), 7.62 - 7.66 (m, 1 H).

To a stirred solution of 1-(4-bromo-3-fluorophenyl)pyrrolidin-2-one (1.00 g, 3.9 mmol, 1.0 equiv) and 2-chloro-6-(trifluoromethyl)pyridine (0.844 g, 4.7 mmol, 1.2 equiv) in 20 mL toluene at -78°C was added 0.6M NaHMDS (13.0 mL, 7.8 mmol, 2.0 equiv) drop wise and the resulting mixture was stirred at -78°C for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc. The combined organic phase was washed with brine, dried over Na₂S0₄, filtered and evaporated. The crude product was purified by silica gel flash chromatography. The product was eluted at a solvent gradient of 19% EtOAc: Hex. The fractions were concentrated to afford the desired product 1-(4-bromo-3-fluorophenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one as yellow solid (yield: 0.585 g, 37.5%). LC-MS (ES) m/z = 403, 405 [M+H]⁺. H NMR (400 MHz, CDCIs) δ 2.55 - 2.63 (m, 1 H), 2.85 - 2.94 (m, 1 H), 3.87 - 3.93 (m, 1 H), 4.05 - 4.11 (m, 2 H), 7.29 (s, 1 H), 7.51 (t, J=8.00 Hz, 1 H), 7.60 (d, J=8.00 Hz, 1 H), 7.66 (d, J=8.00 Hz, 2 H), 7.86 (t, J=8.00 Hz, 1 H).

To a stirred and degassed solution of 1-(4-bromo-3-fluorophenyl)-3-(6-(trifluoromethyl) pyridin-2-yl)pyrrolidin-2-one (0.300 g,0.7 mmol, 1.0 equiv), bis(pinacolato)diboron (0.190 g, 0.7 mmol, 1.0 equiv), and potassium acetate (0.219 g, 22.3 mmol, 3.0 equiv) in 15 mL 1 ,4-dioxane was added Pd(dppf)CI₂.DCM complex (0.030g, 0.04 mmol, 0.05 equiv) and heated in a sealed vessel for 3 hours at 100°C. After consumption of the starting material, the reaction mixture was proceeded for Suzuki coupling without any work up. The reaction mixture was cooled to room temperature, 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c] pyrimidin-4- amine (0.186 g, 0.8 mmol, 1.1 equiv) and saturated aqueous NaHC0₃ (6 mL) were added & degassed under argon thoroughly and added Pd(dppf)CI₂.DCM complex (0.062 g, 0.08 mmol, 0.1 equiv). The vessel was sealed, and the reaction mixture was heated to 100 °C for overnight. After consumption of the starting material, the reaction mixture was cooled to room temperature and filtered through Celite, washed with 5% MeOH:DCM. The filtrate was separated and the combined organic phase was washed brine (2 x 30 mL), dried over Na₂S0₄, filtered and evaporated. The crude was purified by flash chromatography using a solvent gradient of 2.0 - 2.5% MeOH:DCM as mobile phase. The pure fractions were concentrated and the solid obtained was triturated in ACN, filtered and dried to afford the desired product 1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)-3- fluorophenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one as white solid (0.115 g, 24%). LC-MS (ES) m/z = 382.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 0.89 - 0.94 (m, 6 H), 1.22 - 1.30 (m, 1 H), 1.62 - 1.73 (m, 3 H), 2.31 - 2.34 (m, 1 H), 2.62 - 2.66 (m, 1 H), 3.73 (s, 3 H), 3.85 - 3.77 (m, 2 H), 5.96 (br s, 2 H), 7.29 (s, 1 H), 7.39 (t, J=8.0 Hz, 1 H), 7.54 (d, J=8.0Hz, 1 H), 7.78 - 7.81 (m, 1 H), 8.14 (s, 1 H).

Example 42

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimidin-5-yl)phenyl)-3-(2,6-dimethyl pyrimidin-4-yl)pyrrolidin-2-one

To a stirred solution of 1-(4-bromophenyl)pyrrolidin-2-one (2.0 g, 8.3 mmol, 1.0 equiv) and 4-chloro-2,6-dimethylpyrimidine (1.0 mL, 8.3 mmol, 1.0 equiv) in THF (50 mL) was added NaHMDS (1.0 M in THF) at 0 °C and the reaction mixture was stirred at 0 °C for 1 h. After consumption of the SM, the reaction mixture was quenched with NH₄CI solution and extracted with EtOAc (2 x 40 mL) and washed with brine and dried over Na₂S04, filtered, and concentrated. Purification: Purified by flash column chromatography using silica gel column, compound was eluted at 45-50 % EtOAc in Hexane to get 1-4-bromophenyl)-3- (2,6-dimethylpyrimidin-4-yl)pyrrolidin-2-one (2.2 g, 69.4%) as pale yellow solid. LC-MS (ES) m/z = 346.0, 348.0, [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.41 (s, 3 H), 2.43 -

2.55 (m, 2 H), 2.57 (s, 3 H), 3.87 - 3.75 (m, 2 H), 4.05 (t, J=8.80 Hz, 1 H), 7.21 (s, 1 H),

7.56 (d, J=9.20 Hz, 2 H), 7.65 (d, J=8.80 Hz, 2 H).

To a stirred solution of 1-(4-bromophenyl)-3-(2,6-dimethylpyrimidin-4-yl)pyrrolidin-2-one (0.6 g, 1.734 mmol, 1.0 equiv), was added bis(pinacolato)diboron (0.441 g, 1.7 mmol, 1.0 equiv), and potassium acetate (0.510 g, 5.2 mmol, 3.0 equiv), and the mixture was degassed with Argon for 10 minutes, PdCI₂(dppf)-CH₂CI₂ adduct (0.071 g, 0.09 mmol, 0.05 equiv) was added and again degassed with Argon for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (0.394 g, 1.734 mmol, 1.0 equiv) and saturated aqueous NaHC0₃ (6 mL) were added, and Argon gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.071 g, 0.09 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 °C. The crude mixture was filtered through celite and the filtrate was dried over Na₂S0₄ and concentrated. Purification: Crude material was purified by flash column chromatography using silica gel column, compound was eluted at 8-10 % MeOH :DCM as mobile phase.yield: (0.055 g, 7.7 %) as off white solid. LCMS (ES) m/z = 414.2 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ 2.50 (s, 3 H), 2.57 - 2.61 (m, 1 H), 2.67 (s, 3 H), 2.71 - 2.78 (m, 1 H), 3.84 (s, 3 H), 3.91 - 4.00 (m, 2 H), 4.09 - 4.15 (m, 1 H), 5.23 (br s, 2 H), 6.94 (s, 1 H), 7.13 (s, 1 H), 7.49 (d, J=8.40 Hz, 2 H), 7.76 (d, J=8.0 Hz, 2 H), 8.33 (s, 1 H).

Example 43

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimidin-5-yl)phenyl)-3-hyclroxy-3-(6- (trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one

To a stirred solution of 1-(4-bromophenyl) pyrrolidin-2-one (1 g, 4.166 mmol, 1 equiv) and 2-chloro-6-(trifluoromethyl)pyridine (1.5 g, 8.3 mmol, 2 equiv) in toluene (20 mL) was added 2M NaHMDS in THF (4.16 mL, 8.3 mmol, 2 equiv) at 0 °C drop wise over a period of 10 minutes. The reaction mixture was stirred for 4h at RT under air atmosphere. The reaction was quenched with sat. NH₄CI solution (100 mL), extracted in EtOAc (2 x 100 mL), the organics were combined, dried over Na₂S0₄ and concentrated. Purification: Crude product was purified using 100 - 200 silica gel, 40g column in flash column (CombiFlashORf), using 10 % EtOAc in Hexane as mobile phase to get desired product as white gummy solid..yield (600 mg, 35.92%). LC-MS (ES) m/z = 401.0, 403.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.30 - 2.37 (m, 1 H), 2.70 - 2.76 (m, 1 H), 3.95 (t, J=6.4 Hz, 2 H), 6.75 (s, 1 H), 7.58 (d, J=8.8 Hz, 2 H), 7.67 (d, J=9.6 Hz, 2 H), 7.82 (d, J=7.2 Hz, 1 H), 8.03 (d, J=8.4 Hz, 1 H), 8.15 (t, J=7.6 Hz, 1 H).

To a mixture of 1-(4-bromophenyl)-3-hydroxy-3-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2- one (500 mg, 1.3 mmol, 1 equiv), bis(pinacolato)diboron (316 mg, 1.3 mmol, 1 equiv), and potassium acetate (366 mg, 3.740 mmol, 3 equiv) was added 1 ,4-dioxane (23 mL), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (50.5 mg, 0.06 mmol, 0.05 equiv) was added and again degassed with N₂ for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel tube. The reaction mixture cooled to room temperature, 5-bromo-7-methyl-7/-/-pyrrolo [2, 3-d] pyrimidin-4- amine (283 mg, 1.2 mmol, 1 equiv) and saturated aqueous NaHC0₃ (7 mL) were added and N₂ gas was bubbled through the mixture for 10 minutes. PdCI₂ (dppf)-CH₂CI₂ adduct (50.5 mg, 0.06 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 RT and poured on to water and extracted into EtOAc (2 x 100 mL) dried over Na₂S0₄ and concentrated. Purification: The crude was purified using 100-200 silica gel with CombiFlashORf chromatography eluting with 3 % MeOH in DCM as mobile phase, pure fractions were concentrated, washed with acetonitrile (3 x 3 mL) and dried to get desired product as off white solid.yield (85 mg, 14.5%). LCMS (ES) m/z = 469.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.34 - 2.40 (m, 1 H), 2.76 - 2.82 (m, 1 H), 3.73 (s, 3 H), 3.96 - 4.06 (m, 2 H), 6.03 (br s, 2 H), 6.74 (s, 1 H), 7.29 (s, 1 H), 7.48 (d, J=8.4 Hz, 2 H), 7.79 (d, J=8.4 Hz, 2 H), 7.83 (d, J=7.2 Hz, 1 H), 8.05 (d, J=10.8 Hz, 1 H), 8.16 (t, J=8.6 Hz, 2 H). 99.64% of purity by HPLC @ 254 nM. Example 44

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimiclin-5-yl)phenyl)-3-methoxy-3-(6- (trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one

To a stirred solution of 1-(4-bromophenyl) pyrrolidin-2-one (1.5 g, 6.3 mmol, 1 equiv) and 2-chloro-6-(trifluoromethyl)pyridine (1.69 g, 9.4 mmol, 1.5 equiv) in toluene (30 mL) was added 2M NaHMDS in THF (6.25 mL, 12.5 mmol, 2 equiv) at 0 °C drop wise over a period of 10 minutes. The reaction mixture was stirred for 5h at RT under in air atm. The reaction mixture was quenched with sat NH₄CI solution (100 mL), extracted with EtOAc (2 x 100 mL), the organics were combined, dried over Na₂S0₄ and concentrated. Purification: Crude product was purified by 100-200 silica gel, 40g column in flash column chromatography (CombiFlash®Rf10 % EtOAc in Hexane mobile phase to get desired product as off white gummy solid, yield (780 mg, crude). LC-MS (ES) m/z = 401.0, 403.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.30 - 2.37 (m, 1 H), 2.70 - 2.76 (m, 1 H), 3.95 (t, J=6.8 Hz, 2 H), 6.75 (s, 1 H), 7.58 (d, J=9.2 Hz, 2 H), 7.67 (d, J=9.2 Hz, 2 H), 7.82 (d, J=7.2 Hz, 1 H), 8.03 (d, J=8.4 Hz, 1 H), 8.15 (t, J=7.6 Hz, 1 H).

To a stirred solution of 60% NaH (94 mg, 2.4 mmol, 1.3 equiv) in THF ( 10 mL) was added 1 -(4-bromophenyl)-3-hydroxy-3-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one (730 mg, 1.8 mmol, 1 equiv) in THF( 3 mL) drop wise at 0 °C. The reaction mixture was stirred for 30 minutes at room temperature, iodomethane (0.147 mL, 2.4 mmol, 1.3 equiv) was added at 0 °C and stirred at RT for 3h.The reaction mixture was quenched with ice water (5 mL), extracted in EtOAc (10 mL), the organics layer was washed with water (5 mL) and brine solution (5 mL), dried over Na₂S0₄ filtered and concentrated to get desired product as light yellow solid.yield (690 mg, crude). LC-MS (ES) m/z = 415.0, 417.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.56 - 2.63 (m, 1 H), 2.74 - 2.80 (m, 1 H), 3.33 (s, 3 H), 3.93 - 3.97 (m, 2 H), 7.58 (d, J=9.2 Hz, 2 H), 7.66 (d, J=8.8 Hz, 2 H), 7.88 (d, J =7.2 Hz, 1 H), 7.95 (d, J=8 Hz, 1 H), 8.17 (t, J=7.6 Hz, 1 H).

To a mixture of 1-(4-bromophenyl)-3-methoxy-3-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin- 2-one (500 mg, 1.2 mmol, 1 equiv), bis(pinacolato)diboron (306 mg, 1.2 mmol, 1 equiv), and potassium acetate (354 mg, 3.6 mmol, 3 equiv) was added 1 ,4-dioxane (23 mL), and the mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (49 mg, 0.06 mmol, 0.05 equiv) was added and again degassed with N₂ for 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel tube. The reaction mixture cooled to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo [2, 3-d] pyrimidin-4- amine (273 mg, 1.204 mmol, 1 equiv) and saturated aqueous NaHC0₃ (7 mL) were added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCI₂ (dppf)-CH₂CI₂ adduct (49 mg, 0.06 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 RT and poured on to water and extracted with EtOAc (2 x 100 mL) dried over Na₂S0₄ and concentrated. Purification: Purified by flash column chromatography using 3 % MeOH in DCM mobile phase and 24g column, pure fractions were collected and concentrated the desired product was washed with diethyl ether ( 3 x 5 mL) and dried to get pure product as off white solid.yield (55 mg, 9.48%). LCMS (ES) m/z = 483.5 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.58 - 2.65 (m, 1 H), 2.80 - 2.86 (m, 1 H), 3.35 (s, 3 H), 3.72 (s, 3 H), 4.02 (t, J=8 Hz, 2 H), 6.04 (br s, 2 H), 7.29 (s, 1 H), 7.45 (d, J=8.8 Hz, 2 H), 7.78 (d, J=8.4 Hz, 2 H), 7.89 (d, J=8 Hz, 1 H), 7.98 (d, J=8 Hz, 1 H), 8.14 (s, 1 H), 8.18 (t, J=8 Hz, 1 H). 99.16% of purity by HPLC at 284 nM. Example 45

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

A stirred solution of dihydrofuran-2(3H)-one (10 g, 1 16.3 mmol) and phosphorous tribromide (2.2 mL, 23.3 mmol, 0.2 equiv) was heated to 100°C, bromine (9.0 mL, 174.5 mmol, 1.5 equiv) was added drop wise and stirred for 1 hour. Thionyl chloride ( 11.0 mL, 151.2 mmol, 1.3 equiv) was added in a drop wise fashion and stirred for 3 hours. Reaction mixture was cooled to RT and the solvents were evaporated to obtain crude material, which was dissolved in acetonitrile. 4-bromoaniline (19.9 g, 116.3 mmol, 1.0 equiv) and potassium phosphate (24.68 g, 116.3 mmol, 1.0 equiv) were added to above reaction mixture and stirred at room temperature for 1 hour. 50% NaOH solution (35 mL) was added and stirred overnight. The reaction mixture was filtered and the filtrate was concentrated and extracted with ethyl acetate (2 x 50 mL). The organic layer was evaporated and purified over silica gel flash column chromatography. The compound eluted out in 9-11 % EtOAc:Hexanes. The fractions were evaporated to obtain 3-bromo-1- (4-bromophenyl)pyrrolidin-2-one (16.5 g, 44.6%). LCMS (ES) m/z = 317.9, 319.9 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.28 - 2.35 (m, 1 H), 2.70 - 2.79 (m, 1 H), 3.82 - 3.95

Run 1 :

To a stirred solution of 1 /-/-indazole ( 0.11 g, 0.9 mmol, 1.5 equiv) in THF (5 mL) was added sodium hydride (0.04 g, 0.9 mmol, 1.5 equiv) in portions at 0 °C. The reaction mixture was stirred at the same temperature for 10 minutes. 3-bromo-1-(4- bromophenyl)pyrrolidin-2-one ( 0.2 g, 0.6 mmol) in THF (3 mL) was added in a drop wise manner at the same temperature and the reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated to obtain 1-(4-bromophenyl)-3-(1 /-/-indazol-1-yl)pyrrolidin-2-one as an oily compound. LCMS (ES) m/z = 356.0, 358.0 [M+H]⁺. Run 2: To a stirred solution of 1/-/-indazole ( 0.56 g, 0.5 mmol, 1.5 equiv) in THF (25 ml_) was added sodium hydride (0.19 g, 0.5 mmol, 1.5 equiv) in portions at 0°C. The reaction mixture was stirred at the same temperature for 10 minutes. 3-bromo-1-(4- bromophenyl)pyrrolidin-2-one ( 1 g, 3.1 mmol) in THF (10 ml_) was added in a drop wise manner at the same temperature and the reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was quenched with ice water and extracted in ethyl acetate. The organic layer was dried over sodium sulphate and concentrated to obtain crude which was purified by silica gel flash column chromatography. The compound eluted out in 35 % EtOAc: Hexanes. The pure fractions were concentrated to obtain 1-(4-bromophenyl)-3-(1 /-/-indazol-1-yl)pyrrolidin-2-one ( 0.4 g, 30.76%) as white solid. LCMS (ES) m/z = 356.0, 358.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.63 - 2.76 (m, 2 H), 3.94 - 4.04 (m, 1 H), 4.06 - 4.09 (m, 1 H), 5.89 - 5.93 (m, 1 H), 7.15 - 7.19 (m, 1 H), 7.40 - 7.43 (m, 1 H), 7.59 (d, J=8.8 Hz, 2 H), 7.66 - 7.71 (m, 3 H), 7.79 (d, J=8 Hz, 2 H), 8.15 (s, 1 H).

To a stirred solution of 1-(4-bromophenyl)-3-(1 /-/-indazol-1-yl)pyrrolidin-2-one (370 mg, 1.0 mmol) in 1 ,4-Dioxane (18 ml_) was added bis(pinacolato)diboron (260 mg, 1.0 mmol, 1 equiv), and potassium acetate (302 mg, 3.1 mmol, 1 equiv). The reaction mixture was degassed with N₂ for 5 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (42 mg, 0.05 mmol, 0.05 equiv) was added and degassed with N₂ for further 5 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-4-amine (233 mg, 1.0 mmol, 1.0 equiv), saturated aqueous NaHC0₃ (6 ml_) was added. PdCl₂(dppf)-CH₂Cl₂ adduct (42 mg, 0.05 mmol, 0.05 equiv) was added and the reaction mixture was degassed with N₂ for 5 minutes. The vessel was sealed and the reaction mixture was stirred overnight at 100 °C. The crude was filtered through celite and the filtrate was extracted in ethyl acetate. The organic layer was dried over Na₂S0₄ and concentrated to obtain dark oily compound. The crude was purified over silica gel flash column chromatography. The compound eluted out in 1 % MeOH: DCM. The pure fractions were evaporated to obtain 1-(4-(4- amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(1 /-/-indazol-1-yl)pyrrolidin-2-one (140 mg, 31.9 %) as an off white solid. LCMS (ES) m/z = 424.2 [M+H]⁺. H NMR (400 MHz, DMSOc/6) δ 2.65 - 2.77 (m, 2 H), 3.73 (s, 3 H), 4.0 - 4.07 (m, 1 H), 4.11 - 4.15 (m, 1 H), 5.91 - 5.95 (m, 1 H), 6.04 (br s, 2 H), 7.16 - 7.20 (m, 1 H), 7.31 (s, 1 H), 7.41 - 7.44 (m, 1 H), 7.49 (d, J=8.4 Hz, 2 H), 7.70 (d, J=8.4 Hz, 2 H), 7.79 - 7.84 (m, 3 H), 8.15 (s, 1 H), 8.16 (s, 1 H).

Example 46

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimidin-5-yl)phenyl)-3-(1H-inclol-1- yl)pyrrolidin-2-one

To a stirred solution of 1 /-/-indole (0.33 g, 2.8 mmol) in THF (20 mL) was added NaH (60%) (0.34 g, 8.5 mmol, 3 equiv) at 0 °C and stirred for 10 minutes, 3-bromo-1-(4- bromophenyl)pyrrolidin-2-one (0.9 g, 2.8 mmol, 1 equiv) in THF solution was added slowly drop wise at 0°C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was cooled to 0 °C, quenched with 50 mL of cold water and extracted with ethyl acetate (2 x 20 mL). The organics were combined and dried over Na₂S0₄, filtered, and concentrated in vacuo to give desired crude product. The crude compound was purified by flash column chromatography on Silica gel and compound was eluted with 25-30% ethyl acetate in n- hexane. The fractions containing the desired product were combined and concentrated to afford 1-(4-bromophenyl)-3-(1 /-/-indol-1-yl)pyrrolidin-2-one (0.45 g, 45%) as off white solid. LC-MS (ES) m/z = 355.0, 357.0 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.27 - 2.31 (m, 1 H), 2.66 - 2.73 (m, 1 H), 3.90 - 4.01 (m, 2 H), 5.65 - 5.70(m, 1 H), 6.50 (d, J=4.0 Hz, 1 H), 7.04 (t, J=8.0 Hz, 1 H), 7.12 (t, J=8.0 Hz, 1 H), 7.42 - 7.49 (m, 2 H), 7.56 (d, J=8.0 Hz, 1 H), 7.61 (d, J=8.0 Hz, 2 H), 7.73 (d, J=8.0 Hz, 2 H).

To a stirred solution of 1-(4-bromophenyl)-3-(1 /-/-indol-1-yl)pyrrolidin-2-one (0.35 g, 1.0 mmol, 1.0 equiv) in 1 ,4-dioxane (10 mL) was added bis(pinacolato)diboron (0.25 g, 1.0 mmol, 1.0 equiv) and potassium carbonate (0.28 g, 3.0 mmol, 3.0 equiv). The reaction mixture was degassed with N₂ for 15 minutes, PdCl₂(dppf)-CH₂Cl₂ adduct (0.04 g, 0.05 mmol, 0.05 equiv) was added and the reaction mixture was stirred for 3 hours at 100 °C in a sealed tube. The reaction was cooled to room temperature, 5-bromo-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-4-amine (0.22 g, 1.0 mmol, 1.0 equiv) and saturated aqueous NaHC0₃ (4 mL) were added, and N₂ gas was bubbled through the mixture for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (0.04 g, 0.05 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to RT & diluted with ethyl acetate (30 mL) and filtered through celite; filtrate was washed with water (20 mL). The organics were dried over Na₂S0₄, filtered, and concentrated in vacuo to give crude compound. Crude product was purified by flash chromatography on Silica gel and compound was eluted with 5% MeOH/DCM. The fractions containing the desired product were combined and concentrated to afford yellow solid. This material was repurified via prep HPLC (gradient (0.01 % Ammonia in water: CH₃CN). The fractions containing the desired product were combined and concentrated under vacuum to afford 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3- (1 H-indol-1-yl)pyrrolidin-2-one (0.03 g, 7.2 %) as off white solid. LCMS (ES) m/z = 423.5 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.65 - 2.72 (m, 2 H), 3.74 (s, 3 H), 4.00 - 4.06 (m, 2 H), 5.70 (t, J=9.6 Hz, 1 H), 6.03 (bs, 2 H), 6.51 - 6.52 (m, 1 H), 7.05 (t, J=7.2 Hz, 1 H), 7.14 (t, J=7.4 Hz, 1 H), 7.31 (s, 1 H), 7.43 - 7.46 (m, 2 H), 7.50 - 7.52 (m, 2 H), 7.57 (d, J=7.6 Hz, 1 H), 7.86 (d, J=8.4 Hz, 2 H), 8.15 (s, 1 H).

Example 47

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimidin-5-yl)phenyl)-3-(3,5-dimethyl-1 ^ pyrazol-1 -yl)pyrrolidin-2-one

A stirred solution of dihydrofuran-2(3/-/)-one (4 g, 46.5 mmol) and phosphorous tribromide (1 ml_, 9.3 mmol, 0.2 equiv) were heated to 100°C. Bromine (4.0 ml_, 69.7 mmol, 1.5 equiv) was added drop wise and stirred for 1 hour. Thionyl chloride (8 ml_) was added in a drop wise fashion and heated for 3 hours. The solvents were evaporated to obtain crude. 4-bromoaniline (8.0 g, 46.5 mmol, 1.0 equiv) and triethylamine (20 ml_, 139.5 mmol, 3.0 equiv) were added to above crude material and stirred at room temperature for 1 hour. 50% NaOH solution (35 ml_) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 3 hours. Solvents were evaporated to obtain 2,4- dibromo-/V-(4-bromophenyl)butanamide ( 2.5 g, crude) which was used as such in the next step without further purification. LCMS (ES) m/z = 397.8, 399.8 [M+H]⁺.

To a stirred solution of 2,4-dibromo-/V-(4-bromophenyl)butanamide ( 2.5 g, 6.3 mmol) in THF ( 30 ml_) was added sodium hydride ( 0.37 g, 9.4 mmol, 1.5 equiv) in portions at 0°C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted in ethyl acetate, dried over sodium sulphate and concentrated to obtain 3-bromo-1-(4-bromophenyl)pyrrolidin-2-one (1.5 g, 75%) as white solid. LCMS (ES) m/z = 317.9, 319.9 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.28 - 2.40 (m, 1 H), 2.65 - 2.79 (m, 1 H), 3.82 - 3.87 (m, 1 H), 3.88 - 3.95

To a stirred solution of 3,5-dimethyl-1 /-/-pyrazole ( 0.3 g, 3.0 mmol, 1.5 equiv) in THF (15 ml_) was added sodium hydride (0.18 g, 4.5 mmol, 1.5 equiv) in portions at 0°C. The reaction mixture was stirred at the same temperature for 10 minutes. 3-bromo-1-(4- bromophenyl)pyrrolidin-2-one ( 0.98 g, 3.0 mmol) in THF (5 ml_) was added in a drop wise manner at the same temperature and the reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was quenched with ice water and extracted in ethyl acetate. The organic layer was dried over sodium sulphate and concentrated to obtain crude which was purified by silica gel flash column chromatography. The compound eluted out in 25 % EtOAc: Hexanes. The pure fractions were concentrated to obtain 1-(4-bromophenyl)-3-(3,5-dimethyl-1 /-/-pyrazol-1-yl)pyrrolidin- 2-one (0.5 g, 50%) as off-white solid. LCMS (ES) m/z = 334.2, 336.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.07 (s, 3 H), 2.23 (s, 3 H), 2.55 - 2.64 (m, 2 H), 3.83 - 3.89 (m, 1 H), 3.93 - 3.97 (m, 1 H), 5.28 (t, J=9.2 Hz, 1 H), 5.83 (s, 1 H), 7.59 (d, J=8.8 Hz, 2 H), 7.68 (d, J=8.8 Hz, 2 H).

To a stirred solution of 1-(4-bromophenyl)-3-(3,5-dimethyl-1/-/-pyrazol-1-yl)pyrrolidin-2-one (400 mg, 1.2 mmol) in 1 ,4-dioxane (15 ml_) was added bis(pinacolato)diboron (304 mg, 1.2 mmol, 1 equiv), and potassium acetate (352 mg, 3.6 mmol, 3 equiv).The reaction mixture was degassed with N₂ for 10 minutes. PdCl₂(dppf)-CH₂Cl₂ adduct (48 mg, 0.06 mmol, 0.05 equiv) was added and degassed with N₂ for further 10 minutes. The reaction mixture was stirred for 3 hours at 100 °C in a sealed vessel. The reaction mixture was filtered over celite and the filtrate was concentrated and purified over silica gel flash column chromatography. The compound eluted out in 35 % EtOAc: Hexanes. The pure fractions were evaporated to obtain 3-(3,5-dimethyl-1 H-pyrazol-1-yl)-1-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (0.4 g, 88%) as a gummy solid. LCMS (ES) m/z = 382.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 1.27 (s, 12 H), 2.07 (s, 3 H), 2.23 (s, 3 H), 2.55 - 2.64 (m, 2 H), 3.83 - 3.89 (m, 1 H), 3.93 - 3.97 (m, 1 H), 5.28 - 5.30 (m, 1 H), 5.83 (s, 1 H), 7.89 (m, 4 H).

Run1 : To a stirred solution of 3-(3,5-dimethyl-1 /-/-pyrazol-1-yl)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (41 mg, 0.1 mmol), 5-bromo-7-methyl-7H- pyrrolo[2,3-c]pyrimidin-4-amine (25 mg, 0.1 mmol, 1 equiv) and potassium phosphate (46 mg, 0.2 mmol, 2 equiv) in 1 ,4-dioxane: water (3 ml_: 1 ml_) was added Pd₂(dba)₃ ( 5 mg, 0.005 mmol, 0.05 equiv) and the reaction mixture was degassed with N₂ for 5 minutes. Tri-tert-butylphosphonium tetrafluoroborate (3 mg, 0.01 mmol, 0.1 equiv) was added and the reaction mixture was further degassed for 5 minutes. The vial was sealed and the reaction mixture was heated to 100°C overnight. The reaction mixture was filtered through celite and the filtrate was concentrated to obtain crude compound which was purified along with run 2. LCMS (ES) m/z = 402.2 [M+H]⁺.

Run 2:

To a stirred solution of 3-(3,5-dimethyl-1 /-/-pyrazol-1-yl)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (120 mg, 0.3 mmol), 5-bromo-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-4-amine (70 mg, 0.3 mmol, 1 equiv) and potassium phosphate (130 mg, 0.6 mmol, 2 equiv) in 1 ,4-Dioxane: water (3 ml_: 0.7 ml_) was added Pd₂(dba)₃ (14 mg, 0.02 mmol, 0.05 equiv) and the reaction mixture was degassed with N₂ for 5 minutes. Tri-tert-butylphosphonium tetrafluoroborate (9 mg, 0.03 mmol, 0.1 equiv) was added and the reaction mixture was further degassed for 5 minutes. The vial was sealed and the reaction mixture was heated to 100°C overnight. The reaction mixture was filtered through celite and the filtrate was concentrated to obtain crude (run 1 & 2) which was purified over silica gel flash column chromatography. The compound eluted out as a mixture in 3 % MeOH:DCM. The fractions were evaporated to obtain crude which was further purified by preparative HPLC instrument. Analytical conditions: Column: kinetex C18 (50 mm x 2.1 mm x 1.7 mic), Mobile Phase A/B : 0.01 % TFA in water/ Acetonitrile, Flow rate: 0.7 mL/min. The pure fractions were evaporated to obtain triflate salt of the product. The salt was neutralized with sat. NaHC03 solution and extracted in 10 % MeOH:DCM. The organic layer was dried over sodium sulphate and concentrated to obtain 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(3,5-dimethyl-1 H- pyrazol-1-yl)pyrrolidin-2-one (20 mg, 4%) as off white solid. LCMS (ES) m/z = 402.2 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ 2.31 (s, 3 H), 2.49 (s, 3 H), 2.64 - 2.66 (m, 2 H), 3.89 (s, 3 H), 3.92 - 3.96 (m, 1 H), 4.0 - 4.04 (m, 1 H), 5.30 (m, 1 H), 5.84 (s, 1 H), 6.03 (brs, 2 H), 7.30 (s, 1 H), 7.48 (d, J=8 Hz, 2 H), 7.80 (d, J=8 Hz, 2 H), 8.14 (s, 1 H). Example 48

1 -(4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimidin-5-yl)-3-(trifluoromethyl)pheny

(3,5-difluorophenyl)pyrrolidin-2-one

To a stirred solution of 2-(3,5-difluorophenyl)acetic acid (8.0 g, 46.5 mmol, 1.0 equiv) in THF (250 mL) was added 1.0 M LHMDS solution (106.9 mL, 109.9 mmol, 2.3 equiv) drop wise over a period of 10 min at -78°C. After completion of LHMDS addition, the cooling bath was removed, the mixture was allowed to stir at room temperature. After 1 hour, allyl bromide (13.0 mL, 151.1 mmol, 3.25 equiv) was added in one portion at 0°C. The temperature rose to 22°C and the reaction mixture became clear solution. After stirring for additional 30 minutes the reaction mixture became milky. The reaction mixture was stirred for 16h. The reaction mixture was diluted with 1 N HCI (30 mL) and extracted with ethyl acetate (3 x 100 mL). The organics were combined and washed with saturated aqueous NaHC0₃ (2 x 70mL) and brine solution (80 mL), dried over Na₂S0₄ and filtered. The organic solvent was evaporated under reduced pressure to afford crude product 2-(3,5- difluorophenyl)pent-4-enoic acid as brown liquid (1 1.5 g). LC-MS (ES) m/z = 21 1.1 [M-H]⁺.

To a stirred solution of 2-(3,5-difluorophenyl)pent-4-enoic acid (3.5 g, 16.5 mmol, 1.0 equiv) and 4-bromo-3-(trifluoromethyl)aniline (3.56 g, 14.8 mmol, 0.9 equiv) in DCM (50 mL) at room temperature was added DIPEA (3.16 mL, 18.1 mmol, 1.1 equiv), followed by HATU (6.89 g, 18.1 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred at room temperature for about 2 h. Water (50 mL) was added to the reaction mixture and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine, & dried over Na₂S0₄, filtered and concentrated to afford the crude product N-(4-bromo-3- (trifluoromethyl)phenyl)-2-(3,5-difluorophenyl)pent-4-enamide (3.1g) as dark brown liquid. LC-MS (ES) m/z = 434, 436 [M+H]⁺. This material was used as such in the next step.

To A/-(4-bromo-3-(trifluoromethyl)phenyl)-2-(3,5-difluorophenyl)pent-4-enamide (3.1 g, 7.1 mmol, 1.0 equiv) in THF (83 mL) and water (17 mL) was added 2.5 wt% osmium tetroxide solution in t-butanol (7.2 mL, 0.7 mmol, 0.1 equiv) followed by sodium periodate (6.1 g, 28.5 mmol, 4.0 equiv), and the reaction mixture was stirred at room temperature for 12 h. An aqueous solution of sodium thiosulfate was added, and extracted the compound with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried ove Na₂S0₄, filtered and concentrated to afford crude product 1-(4-bromo-3- (trifluoromethyl)phenyl)-3-(3,5-difluorophenyl)-5-hydroxypyrrolidin-2-one (3.8 g) as brown liquid. LC-MS (ES) m/z = 436, 438 [M+H]⁺. This material was used as such in the next step.

To 1-(4-bromo-3-(trifluoromethyl)phenyl)-3-(3,5-difluorophenyl)-5-hydroxypyrrolidin-2-one (3.0 g, 6.9 mmol, 1.0 equiv)) in dichloromethane (DCM) (30 mL) was added TFA (8.96 mL, 137.6 mmol, 20 equiv). The reaction mixture was stirred for 10 min and added triethyl silane (4.4 mL, 27.5 mmol, 4.0 equiv). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated and the residue obtained was basified with saturated aqueous NaHC0₃ and extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na₂S0₄), filtered and concentrated to afford crude product. The crude product was purified with Si0₂ column using flash column chromatography (gradient: 20% EtOAc / hexane). The fractions containing the desired product were combined and concentrated to afford 1-(4-bromo-3-(trifluoromethyl)phenyl)- 3-(3,5-difluorophenyl)pyrrolidin-2-one (2.3 g, 83%) as brown solid. LCMS (ES) m/z = 420, 422 [M+H]⁺. H NMR (400 MHz, CDCI₃) δ 2.27 - 2.37 (m, 1 H), 2.66 - 2.74 (m, 1 H), 3.86 - 3.95 (m, 3 H), 6.75 (t, J=8.8 Hz, 1 H), 6.88 (d, J=6.4 Hz, 2 H), 7.70 (d, J=8.8 Hz, 1 H), 7.81 (dd, J=2.4, 8.8 Hz, 1 H), 7.99 - 8.00 (m, 1 H).

To a mixture of 1-(4-bromo-3-(trifluoromethyl)phenyl)-3-(3,5-difluorophenyl)pyrrolidin-2- one (0.8 g, 1.9 mmol, 1.0 equiv), bis(pinacolato)diboron (0.48 g, 1.9 mmol, 1.0 equiv), and potassium acetate (0.56 g, 5.7 mmol, 3.0 equiv) was added 1 ,4-dioxane (20 ml_), and the mixture was degassed with N₂ for 10 minutes. PdCI₂ (dppf)-CH₂CI₂ adduct (0.077 g, 0.095 mmol, 0.05 equiv) was added, and the reaction mixture was stirred for 12 hours at 100 °C in a sealed vessel. The reaction was cooled to room temperature. 5-bromo-7-methyl-7/-/- pyrrolo[2,3-c]pyrimidin-4-amine (0.43 g, 1.9 mmol, 1.0 equiv) and saturated aqueous NaHC0₃ (16 ml_) were added, and degassed with N₂ for 10 minutes. PdCI₂(dppf)-CH₂CI₂ adduct (0.077 g, 0.095 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred for 18 h at 100 °C. The mixture was filtered through celite bed, and the filtrate was extracted with EtOAc (2 x 50 ml_). The combined organic layers were dried over Na₂S0₄, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by Si0₂ column via flash column chromatography (gradient: 3% MeOH / DCM). The fractions containing the desired product were combined and concentrated to afford yellow solid. The product was repurified by prep HPLC (gradient (0.01 % Ammonia in water: ACN). The fractions containing the desired product were combined and concentrated under reduced pressure and it was further freeze dried to afford 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-d]pyrimidin- 5-yl)-3-(trifluoromethyl)phenyl)-3-(3,5-difluorophenyl)pyrrolidin-2-one (30 mg, 3.2%) as off- white solid. LCMS (ES) m/z = 488.4 [M+H]⁺. H NMR (400 MHz, DMSOd6) δ ppm 2.31 -

2.35 (m, 1 H), 2.60 - 2.65 (m, 1 H), 3.73 (s, 3 H), 4.01 - 4.10 (m, 2 H), 4.11 - 4.15 (m, 1 H), 5.71 (bs, 2 H), 7.13 - 7.16 (m, 4 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.87 (s, 1 H), 8.13 (s, 1 H ),

8.36 (s,1 H). Example 49

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c/]pyrimidin-5-yl)-3-methylphenyl)-3-(3,5- difluorophenyl)pyrrolidin-2-one

To a stirred solution of 2-(3,5-difluorophenyl)pent-4-enoic acid (3.0 g, 14.1 mmol, 1.0 equiv) and 4-bromo-3-methylaniline (2.3 g, 12.7 mmol, 0.9 equiv) in DCM (30 mL) at room temperature was added DIPEA (2.71 mL, 15.6 mmol, 1.1 equiv), followed by HATU (5.91 g, 15.6 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred at room temperature for 60 min. The reaction mixture was diluted with DCM (100mL), the organic layer was washed with 1 N HCI (2 x 50 mL), saturated aqueous NaHC0₃ (2 X 50mL) and brine solution (60 mL). The organic layer was dried over Na₂S04 filtered and evaporated the organic solvent under reduced pressure to afford the crude A/-(4-bromo-3- methylphenyl)-2-(3,5-difluorophenyl)pent-4-enamide as yellow solid (4.0 g). LC-MS (ES) m/z = 380.0, 382.0 [M+H]⁺.

To a stirred solution of A/-(4-bromo-3-methylphenyl)-2-(3,5-difluorophenyl)pent-4-enamide (2.2 g, 5.8 mmol) in THF (55 mL) and water (12 mL) was added 2.5 wt% osmium tetroxide in t-BuOH (5.8 mL, 0.6 mmol, 0.1 equiv), followed by sodium periodate (4.9 g, 23.1 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 3 hours. After consumption of SM, an aqueous solution of sodium thiosulfate was added, and the resulting mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate (2 x 80 mL) and the combined organic layers were washed with aqueous NaHC0₃ and brine solution (60 mL), dried over Na₂S0₄, and evaporated the solvent under reduced pressure to get crude product. LCMS analysis indicated the presence of desired product and the diol intermediate. This crude material was re-dissolved in THF (55 mL) and Water (12 mL) and added sodium periodate (1.28 g, 6.027 mmol, 2 equiv). The resulting mixture was stirred for 3 hours at room temperature. After consumption of SM, an aqueous solution of sodium thiosulfate was added, and the resulting mixture was stirred for 10 min. The reaction mixture was extracted with ethyl acetate (2 x 80 mL) and the combined organic layers were washed with aqueous NaHC0₃ (50 mL) and brine solution (60 mL), dried over Na₂S0₄, and evaporated the solvent under reduced pressure to afford the crude product 1-(4-bromo-3-methylphenyl)-3-(3, 5-difluorophenyl)-5-hydroxypyrrolidin-2- one (3.55 g) as brown liquid. LC-MS (ES) m/z = 382.0, 384.0 [M+H]⁺.

To a stirred solution of 1-(4-bromo-3-methylphenyl)-3-(3,5-difluorophenyl)-5- hydroxypyrrolidin-2-one (3.5 g, 9.1 mmol, 1.0 equiv) in DCM (50 mL) was added triethylsilane (5.8 mL, 36.4 mmol, 4.0 equiv), followed by TFA (1 1.8 mL, 182.3 mmol, 20.0 equiv). The reaction mixture was stirred for 2 h at room temperature. After consumption of SM, the reaction mixture was quenched with saturated aqueous NaHC0₃ and extracted with DCM (100 mL). The organic layer was separated and washed with brine solution (30 mL), dried over Na₂S0₄, filtered and evaporated the solvent under reduced pressure to afford the crude product. The crude product was purified by flash chromatography using 100 - 200 silica gel (24g column) and eluted with 6% EtOAc in n-Hexane mobile phase to afford the titled product 1-(4-bromo-3-methylphenyl)-3-(3,5-difluorophenyl)pyrrolidin-2- one (0.57 g, 57%) as white solid. LCMS (ES) m/z = 366.0, 368.0 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ 2.17 - 2.28 (m, 1 H), 2.34 (s, 3 H), 2.53 - 2.59 (m, 1 H), 3.86 - 3.92 (m, 2 H), 4.02 (t, J=9.2 Hz, 1 H), 7.08 - 7.15 (m, 3 H), 7.48 - 7.58 (m, 2 H), 7.67 (d, J=2.0 Hz, 1 H).

To a mixture of 1-(4-bromo-3-methylphenyl)-3-(3,5-difluorophenyl)pyrrolidin-2-one (0.6 g, 1.6 mmol, 1.0 equiv), bis(pinacolato)diboron (0.41 g, 1.6 mmol, 1.0 equiv), and potassium carbonate (0.48 g, 4.9 mmol, 3.0 equiv) was added 1 ,4-dioxane (10 ml_), and the mixture was degassed with Ar gas for 10 minutes. PdCI₂ (dppf)-CH₂Cl₂ adduct (0.1 1 g, 0.08 mmol, 0.05 equiv) was added and degassed with Ar for 10 minutes. The reaction mixture was stirred for 3 h at 100 °C in a sealed vessel. After consumption of SM, the reaction mixture was cooled to room temperature. 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.37 g, 1.6 mmol, 1.0 equiv) and saturated aqueous NaHC0₃ (12 ml_) were added and degassed with argon for 10 min. PdCl₂(dppf)-CH₂Cl₂ adduct (0.1 1 g, 0.08 mmol, 0.05 equiv) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100°C. After consumption of SM, the reaction mixture was poured onto water and extracted with ethyl acetate (2 x 30 ml_). The combined organic layers were washed with brine solution (30 ml_), dried over Na₂S0₄ and evaporated the solvent under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography with 100 - 200 silica gel (24g column) and eluted with 3% MeOH in DCM mobile phase to afford the titled product 1-(4-(4-amino-7-methyl-7/-/-pyrrolo[2,3- d]pyrimidin-5-yl)-3-methylphenyl)-3-(3,5-difluorophenyl)pyrrolidin-2-one (0.1 g, 14%) as off white solid. LCMS (ES) m/z = 434.2 [M+H]⁺. H NMR (400 MHz, DMSO-d6) δ 2.21 - 2.27 (m, 4H), 2.54 - 2.61 (m, 1 H), 3.73 (s, 3 H), 3.93 - 4.07 (m, 3H), 5.54 (br, 2 H), 7.10 - 7.15 (m, 4 H), 7.25 (d, J=8.0 Hz, 1 H), 7.60 - 7.68 (m, 2 H), 8.13 (s, 1 H).

Example 50 - 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 I, below.

Table I

INGREDIENTS AMOUNTS

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- 7 mg

yl)phenyl)-3-phenylpyrrolidin-2-one

(Compound of Example 1)

Lactose 53 mg

Talc 16 mg

Magnesium Stearate 4 mg Example 51 - Injectable Parenteral Composition

An injectable form for administering the present invention is produced by stirring 1.7% by weight of 1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3- methyl-3-phenylpyrrolidin-2-one (Compound of Example 2) in 10% by volume propylene glycol in water.

Example 52 Tablet Composition

The sucrose, calcium sulfate dihydrate and a PERK inhibitor as shown in Table II 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 II

INGREDIENTS AMOUNTS

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- 12 mg

yl)phenyl)-3-(2,5-difluorophenyl)pyrrolidin-2-one

(Compound of Example 3)

calcium sulfate dihydrate 30 mg

sucrose 4 mg

starch 2 mg

talc 1 mg

stearic acid 0.5 mg

Biological Activity

PKR-like Endoplasmic Reticulum Kinase (PERK) Assay (HTRF Format)

Source of the PERK enzyme: GST-PERK (536-1 1 16) cytoplasmic domain was purchased from Invitrogen (www. i nvitrogen . com) catalogue#PV5106 (201 1).

Source of substrate: elF2a: 6-His-Full-length human elF2a is purified from baculovirus expression in Sf9 insect cells. The elF2 protein is buffer exchanged by dialysis into PBS, chemically modified by NHS-LC-Biotin and then buffer exchanged by dialysis into 50 mm TRIS pH 7.2 /250 mM NaCI/5 mM DTT. Protein is aliquoted and stored at -80°C. Quench Solution: The quench solution is freshly prepared and when added to the reactions gives final concentrations of 4 nM elF2a phospho-ser51-Antibody (purchased from Millipore, catalogue #07-760, www.millipore.com), 4 nM Eu-1024 labeled anti-rabbit IgG (purchased from Perkin Elmer, catalogue#AD0083), 40 nM Streptavidin Surelight APC (purchased from Perkin Elmer, catalogue* AD0201) and 15mM EDTA.

Reactions were performed in black 384-well polystyrene low volume plates (Grenier, #784076) in a final volume of 10 μΙ. The reaction volume contains, in final concentrations, 10mM HEPES, 5mM MgCI₂, 5μΜ ATP, 1 mM DTT, 2mM CHAPS, 40 nM biotinylated-6-His-EIF2a, and 0.4 nM GST-PERK (536-11 16). Assays were performed by adding GST-PERK solution to assay plates containing compounds and pre-incubated for 30 minutes at room temperature. The reaction is initiated by the addition of ATP and EIF2a substrate solution. Quench solution is added following a one hour incubation at room temperature. The plates are covered for 2 hours at room temperature prior to determination of signal. The resulting signal is quantified on a Viewlux Reader (PerkinElmer). The APC Signal is normalized to the Europium signal by transforming the data through an APC/Eu calculation.

Compounds under analysis were dissolved in DMSO to 1.0 mM and serially diluted 1 to 3 with DMSO through eleven dilutions. 0.1 μΙ of each concentration was transferred to the corresponding well of an assay plate. This creates a final compound concentration range from 0.00017 to 10 μΜ.

The data for concentration response curves were plotted as % Inhibition calculated with the data reduction formula 100*(1-(U1-C2)/(C1-C2)) versus concentration of compound where U is the unknown value, C1 is the average control value obtained for 1 % DMSO, and C2 is the average control value obtained for 0.1 M EDTA. Data were fitted with a curve described by: y = A B - A where A is the minimum y, B is the maximum y concentration [M], D is the slope factor, and x is the log₁₀ of the compound. The results for each compound were recorded as plC50s, calculated as follows:

plC50 = -Log10(K).

Abbreviations used:

APC, Allophycocyanin

ATP, adenosine triphosphate

BSA, bovine serum albumin

CHAPS, 3-[3-Cholamidopropyl)Dimethylammonio] -1-Propanesulfonate

DMSO, dimethyl sulfoxide

DTT, Dithiothreitol

EDTA, ethylenediaminetetraacetic acid

Eu, Europium

HEPES, N-(2-Hydroxyethyl)piperazine-N'-2-ethanesulfonic acid

HPLC, high performance/pressure liquid chromatography

KCI, Potassium chloride

M, molar

mg, milligram

MgCI₂, magnesium chloride

ml, milliliter

mM, millimolar

nM, nanomolar

pM, picomolar

MOPS, 3-morpholinopropanesulfonic acid

NaCI, Sodium chloride

NCBI, National Center for Biotechnology Information

PBS, phosphate buffered saline

Tris-HCI, Tris(hydroxymethyl)aminomethane hydrochloride

μΜ or uM, micromolar

Compounds of the invention are tested for activity against PERK in the above assay. The compounds of Examples 1 to 49 were tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a plC50 value: > 6.4 against PERK. The compound of Example 2 was tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a pICso value of 8 against PERK.

The compounds of Examples: 8, 9, 12, 13, 17, 27 and 29 were tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a pICso value: > 8.3 against PERK.

The compounds of Examples: 4, 21 , 22, 26 and 39 were tested generally according to the above PERK enzyme assay and in at least one experimental run exhibited a pICso value: > 7.4 against PERK.

In the above data, plC50 is defined as -log(IC50) where the IC50 value is expressed in molar units.

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

Claims

What is claimed is:

1. A compound according to Formula X:

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: halo,

C-|-6alkyl,

C-|-4alkyloxy,

-OH,

hydroxyC-|-4alkyl,

-COOH,

tetrazole,

-CF₃,

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

-CON(H)Ci-3alkyl,

-CH₂CH₂N(H)C(0)OCH₂aryl, diCi-4alkylaminoC-|-4alkyl, aminoCi-4alkyl,

-CN,

heterocycloalkyl,

heterocycloalkyl substituted with from 1 to 4 substituents

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

-COOH, -CF₃, -Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN,

-NC-2,

-NH₂,

-N(H)Ci_3alkyl, and

-N(Ci.₃alkyl)₂;

R⁴² is selected from:

aryl,

-COOH, -CF₃, -Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN,

heteroaryl,

Ci-4alkyloxy, -OH, -COOH, -CF₃, -Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN,

bicycloheteroaryl, and

bicycloheteroaryl substituted with from one to five substituents

independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl,

C-|-4alkyloxy, -OH, -COOH, -CF₃, -Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN;

R⁴³ is selected from: -H,

-NH₂,

-OH,

-CN,

Ci-6alkoxy,

Ci-6alkyl, and

44

R is selected from:

-NH₂,

-N(H)Ci-3alkyl,

-N(Ci-3alkyl)₂,

-OH,

C-|-6alkyl, and

45

R is selected from:

C-|-6alkyl, and

46

R is selected from: H, fluoro, chloro, bromo and iodo;

or R5 and R^ are optionally taken together to form a 5 to 6 member saturated or unsaturated ring containing up to one other heteroatom selected from oxygen and nitrogen; and R is selected from: H, Ci_4alkyl, -CF3, fluoro, chloro, bromo and iodo; or a salt thereof including a pharmaceutically acceptable salt thereof.

2. The compound of Claim 1 represented by the following Formula (II):

is selected from:

aryl,

-CF₃, -Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN,

heteroaryl, and

-COOH, -CF₃, -Ci-4alkylOCi-4alkyl, -N0₂, -NH₂ and -CN; is selected from: H and CH3_;

is selected from:

-NH₂,

-N(H)Ci-3alkyl,

-N(Ci-3alkyl)₂,

-OH,

C-|-6alkyl, and C-|-6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF₃, -Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN;

13

R is selected from: H, fluoro and chloro; and

14

R is selected from:

C-|-6alkyl, and

C-|-6alkyl substituteted with from one to five substituents independently selected from: fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF₃, -Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN; or a salt thereof including a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1 represented by the following Formula (XII):

wherein:

R is selected from: H and CH3_;

61

fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF3,

-Ci-4alkylOC-|-4alkyl, -N0₂, -NH₂ and -CN; and

,62

selected from: H, methyl, -CF3, fluoro and chloro; or a salt thereof including a pharmaceutically acceptable salt thereof.

4. The compound of Claim 1 represented by the following Formula (IV):

wherein:

30

R is selected from: H and CH3_{; anC}|

31

fluoro, chloro, bromo, iodo, Ci_4alkyl, Ci-4alkyloxy, -OH, -COOH, -CF3, -Ci-4alkylOCi_4alkyl, -N0₂, -NH₂ and -CN, or a salt thereof including a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 selected from: 1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-phenylpyrrolidin-2- one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(2,5- difluorophenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(3- (trifluoromethyl)phenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrimidin-5-yl)phenyl)-3-(2- (trifluoromethyl)phenyl)pyrrolidin-2-one; 1-(4-(4-amino-1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-phenylpyrrolidin^ one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3- phenylpyrrolidin-2-one;

1-(4-(4-amino-7-methyl-7 - -pyrrolo[2,3-c pyrimidin-5-yl)-3-fluorophenyl)-3- phenylpyrrolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-(^pyrimidin-5-yl)phenyl)-3-phenylpyrrolidin-2- one;

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

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3-(3- fluorophenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)phenyl)-3-(2,3-difluoro phenyl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3-(2,3- difluorophenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3-(3,4- difluorophenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3-(3,4- difluorophenyl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-<^pyrimidin-5-yl)-3-fluorophenyl)-3-(2,5- difluorophenyl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-2-fluorophenyl)-3-(3,5- difluorophenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3-(3- (trifluoromethyl)phenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-<^pyrimidin-5-yl)phenyl)-3-(3,5-dimethoxy phenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrirTiidiri-5-yl)phenyl)-3-(2- cyclopropylphenyl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3-(3- cyclopropylphenyl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-3-(2-methyl- 1 H-indol-3-yl)pyrrolidin-2-one;

1-( -(4-amino-7-isopropyl-7/-/-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-3-(3,5- difluorophenyl)pyrrolidin-2-one;

1-4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)phenyl)-3-phenyl pyrrolidin-

2-one;

1-4-(4-amino-7-isopropyl-7/-/-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-fluorophenyl)-3- phenylpyrrolidin-2-one;

1-4-(4-amino-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3- fluorophenyl)-3-(3,5-difluorophenyl)pyrrolidin-2-one; 1-4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl)-3-phenylpyrrolidin-2-one;

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

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-(^pyrimidin-5-yl)phenyl)-3-(5-methylthiazol-2- yl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-fluoropyridin-2- yl)pyrrolidin-2-one;

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

1-4-(4-amino-7-methyl-7/-/-pyrrolo[2,3-c]pyrirTiidin-5-yl)phenyl)-3-(4,6- dimethylpyrimidin-2-yl)- pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-<^pyrimidin-5-yl)phenyl)-3-(4,6-dimethyl pyridin-

2-yl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-(^pyrimidin-5-yl)phenyl)-3-(6-(trifluoromethyl) pyridin-2-yl)pyrrolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-3-(6- (trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one;

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-<^pyrimidin-5-yl)phenyl)-3-(2,6-dimethyl pyrimidin-4-yl)pyrrolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrirTiidin-5-yl)phenyl)-3-hydroxy-3-(6- (trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one; 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrirTiidin-5-yl)phenyl)-3-methoxy-3-(6- (trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one;

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

1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-(^pyrimidin-5-yl)phenyl)-3-(3,5-dimethyl-1 H- pyrazol-1-yl)pyrrolidin-2-one;

1-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-(^pyrimidin-5-yl)-3-(trifluoromethyl)phenyl)-3- (3,5-difluorophenyl)pyrrolidin-2-one; and 1-4-(4-amino-7-methyl-7H-pyrrolo[2,3-c]pyrirTiidin-5-yl)-3-methylphenyl)-3-(3,5- difluorophenyl)pyrrolidin-2-one; or a salt thereof including a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound of Formula (X) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

7. A method of treating or lessening the severity of a disease selected from: cancer, pre-cancerous syndromes, Alzheimer's disease, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, and arrhythmias, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula X, as described in claim 1 or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 wherein the mammal is a human.

9. A method of treating or lessening the severity of a disease selected from: cancer, pre-cancerous syndromes, Alzheimer's disease, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, myocardial infarction, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 wherein the mammal is a human.

11. The method according to claim 7 wherein said cancer is selected from: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid.

12. The method according to claim 9 wherein: said cancer is selected from brain

(gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid.

13. Use of a compound of Formula (X), as described in claim 1 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or lessening the severity of cancer.

14. The method of inhibiting PERK activity in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula X, as described in claim 1 or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 wherein the mammal is a human.

16. A method of treating cancer in a mammal in need thereof, which comprises: administering to such mammal a therapeutically effective amount of

a) a compound of Formula (X), as described in claim 1 or a pharmaceutically acceptable salt thereof; and

b) at least one anti-neoplastic agent.

17. The method claim 16, wherein the at least one anti-neoplastic agent is selected from the group consisting of: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis, inhibitors, immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism.

18. A pharmaceutical combination as claimed in claim 16 for use in therapy.

19. The use of a pharmaceutical combination as claimed in claim 16 for the preparation of a medicament useful in the treatment of cancer.

20. The method according to claim 7 wherein said cancer is selected from: breast cancer, inflammatory breast cancer, ductal carcinoma, lobular carcinoma, colon cancer, pancreatic cancer, insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, skin cancer, melanoma, metastatic melanoma, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,

lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia,

malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,

neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.

21. The method of claim 20 wherein the mammal is a human.

22. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound of Formula (X) as described in claim 1 or a pharmaceutically acceptable salt thereof, which process comprises bringing the compound of Formula (X) or a pharmaceutically acceptable salt thereof into association with a pharmaceutically acceptable excipient.

23. The method according to claim 7 wherein said pre-cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplasia syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.

24. The method of claim 16, wherein the at least one anti-neoplastic agent is pazopanib.

25. A method of treating or lessening the severity of ocular diseases in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of Formula X, as described in claim 1 or a pharmaceutically acceptable salt thereof.

26. A method according to claim 25 wherein the ocular disease is selected from: rubeosis irides; neovascular glaucoma; pterygium; vascularized glaucoma filtering blebs; conjunctival papilloma; choroidal neovascularization associated with age-related macular degeneration (AMD), myopia, prior uveitis, trauma, or idiopathic; macular edema; retinal neovascularization due to diabetes; age-related macular degeneration (AMD); macular degeneration (AMD); ocular ischemic syndrome from carotid artery disease; ophthalmic or retinal artery occlusion; sickle cell retinopathy; retinopathy of prematurity; Eale's Disease; and VonHippel-Lindau syndrome.

27. A method according to claim 25 wherein the ocular disease is selected form: age-related macular degeneration (AMD) and macular degeneration.

28. A method of treating or lessening the severity of neurodegeneration in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of Formula X, as described in claim 1 or a pharmaceutically acceptable salt thereof.

The compound of claim 1 selected from:

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

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

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

1-(4-(4-amino-1-methyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-phenylpyrrolidin-2- one; or a salt thereof including a pharmaceutically acceptable salt thereof.