SUBSTITUTED 3,4-DIHYDROPYRROLO[1 ,2-A]PYRAZIN-1 (2H)-ONE DERIVATIVES AS KINASE INHIBITORS

The invention relates to certain pyrrolopyrazinone derivatives and pharmaceutically acceptable salts thereof that selectively inhibit ERK and thus possess anti-cancer activity. The invention also relates to use of said pyrrolopyrazinone derivatives and

pharmaceutically acceptable salts thereof in methods of treatment of the human or animal body, for example in prevention or treatment of cancer. The invention also relates to processes and intermediate compounds involved in the preparation of said

pyrrolopyrazinone derivatives and to pharmaceutical compositions containing said pyrrolopyrazinone derivatives and pharmaceutically acceptable salts thereof.

Protein kinases play a key regulatory role in almost every aspect of cell biology. The mammalian MAP kinases consist of cytoplasmic protein serine/threonine kinases that participate in the transduction of cellular signals from the plasma membrane to the nucleus. There are multiple MAPK signaling cascades each consisting of 3 components: a MAPK kinase kinase (MAP3K), a MAPK kinase (MAP2K) and a MAPK. The activated MAP kinases phosphorylate numerous substrates including other protein kinases, protein phosphatases, transcription factors and other functional proteins. The RAS-RAF-MEK- ERK signaling cascade participates in the regulation of cell cycle progression, cell proliferation, survival, metabolism and transcription.

ERK1 and ERK2 are ubiquitously expressed MAPK kinases that participate in the RAS-RAF-MEK-ERK signaling cascade, which both contain unique N- and C-terminal extensions that provide signaling specificity, in addition to a 31-amino-acid-residue insertion within the kinase domain that provide additional functional specificity. ERK1 and ERK2 are activated in a wide variety of cell types by mitogenic and other stimuli, resulting in activation of multiple isoforms of RAS (HRAS, NRAS and KRAS). Activation of RAS leads to recruitment and activation of RAF isoforms (ARAF, BRAF and CRAF) and subsequent activation of MEK1 and MEK2, dual-specificity protein kinases that mediate the phosphorylation of tyrosine and threonine of ERK1 and ERK2. ERK1 and ERK2 have a large number of identified cytoplasmic and nuclear substrates (reference Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions; Growth Factors 2006, 24, 21-44). The RAS-RAF-MEK-ERK signaling cascade is deregulated in a variety of diseases including brain injury, cancer, cardiac hypertrophy, diabetes and inflammation.

Specifically in cancer, mutations in KRAS occur in approximately 58% of pancreatic, 33% of colorectal and 31% of biliary cancers, and NRAS mutations in 18% of melanomas. Oncogenic mutations in RAS result in elevated ERK activity across multiple tumours. In addition, BRAF mutations occur in approximately 40-60% of melanomas, 40% of thyroid cancers and 20% of colorectal cancers (reference Vakiani E, Solit DB. KRAS and BRAF; drug targets and predictive biomarkers; Journal of Pathology 2011 , 223, 219-29). These observations indicate that the RAS-RAF-MEK-ERK signaling cascade is an attractive pathway for anti-cancer therapies across a broad range of human tumours.

International Patent Application WO2007/042784 describes substituted pyrimidine derivatives of Formula (a) as inhibitors of one or more protein kinases including aurora kinase, cyclin-dependent kinases (CDKs), FMS-like tyrosine linase 3 (FLT3) and glycogen synthase kinase 3 (GSK3). The substituents for compound of formula (a) are described in WO2007/042784, and for example in all compounds exemplified therein R ¹ and R ² are both methyl groups.

(a)

We have found a series of chemical compounds which have selectivity for inhibition of ERK over other kinases on the same signalling cascade.

Where inhibition of ERK is referred to herein, it should be understood to mean inhibition of ERK1 and ERK2, particularly ERK2. Furthermore, compounds described herein are also generally selective inhibitors of ERK over one or more other kinases, such as CDK2, as described hereinafter in the Examples.

According to one aspect there is provided a compound of the Formula (I): H

(I)

wherein:

R ¹ is selected from: -CH ₂ OMe, cyclopropyl (optionally substituted with one substituent selected from fluoro and methyl) and HET-1;

wherein:

either HET-1 is a 5-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, S and O; when HET-1 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-1 is optionally substituted with methyl; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted; or

HET-1 is a 6-membered heteroaryl ring containing 1, 2 or 3 ring nitrogen atoms; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted;

R ² is selected from hydrogen, C _1-3 alkyl and -CH ₂ OMe;

R ³ is selected from hydrogen, methyl and -CH ₂ OMe;

or R ² and R ³ taken together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuryl or tetrahydropyranyl ring;

R ⁴ is selected from hydrogen, methyl, ethyl and -CH ₂ OMe;

R ⁵ is selected from chlorine and methyl;

R ⁶ is HET-2;

wherein either HET-2 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted; or

HET-2 is a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted;

or a pharmaceutically-acceptable salt thereof.

In one embodiment there is provided a compound of Formula (I) as defined above.

In one embodiment there is provided a pharmaceutically-acceptable salt of a compound of Formula (I).

The term "optionally substituted" will be understood to mean "substituted or unsubstituted".

Suitable examples of HET-1 as a 5-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, S and O include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl and thiadiazolyl.

When HET-1 as thus defined is a 5-membered ring, suitable examples of such groups include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl.

When HET-1 as thus defined is a 5-membered ring, suitable examples of such groups include 1,2,4-triazolyl, isoxazolyl, pyrazolyl, thiazolyl and 1,2,3-triazolyl.

For the avoidance of doubt, it will be understood that the suitable examples of HET-1 above may optionally be substituted as defined above for HET-1.

When HET-1 as thus defined is a 5-membered ring suitable examples of such groups include (wherein the squiggly line denotes the point of attachment to the rest of the molecule):

wherein R ⁷ is selected from hydrogen, fluoro, methyl, fluoromethyl, trifluoromethyl and methoxy and is attached to any available carbon atom within the heteroaryl ring; and wherein R ⁸ is selected from hydrogen and methyl.

When HET-1 is a 5-membered ring, suitably it is

When HET-1 is a 5-membered ring, suitably it is

For the avoidance of doubt, no definitions of HET-1 and HET-2 (substituted or unsubstituted) are intended to encompass non-aromatic ring systems.

Suitable examples of HET-1 as a 6-membered heteroaryl ring include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

When HET-1 as thus defined is a 6-membered ring, suitable examples of such groups include pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

For the avoidance of doubt, it will be understood that the suitable examples of HET-1 above may optionally be substituted as defined above for HET-1.

When a HET-1 as thus defined is a 6-membered ring, suitable examples of such roups include:

wherein R ⁷ is selected from hydrogen, fluoro, methyl, fluoromethyl, trifluoromethyl and methoxy and is attached to any available carbon atom within the heteroaryl ring; and wherein R ⁸ is selected from hydrogen and methyl.

-1 is a 6-membered ring, suitably it is selected from

Suitable examples of HET-2 as 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, S and O include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl.

When HET-2 as thus defined is a 5-membered ring, suitable examples of such groups include isoxazolyl, pyrazolyl and thiazolyl.

For the avoidance of doubt, it will be understood that the suitable examples of HET-2 above may optionally be substituted as defined above for HET-2.

When HET-2 is a 5-membered ring, suitable it is pyrazolyl.

When HET-2 is a 5-membered ring, suitably it is wherein R is selected from hydrogen and methyl.

When HET-2 is a 5-membered ring, suitably it is

Suitable examples of HET-2 as a 6-membered heteroaryl ring include pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

When HET-2 as thus defined is a 6-membered ring, suitable examples of such groups include pyridyl, pyridazinyl, and pyrimidinyl. For the avoidance of doubt, it will be understood that the suitable examples of HET-2 above may optionally be substituted as defined above for HET-2.

When a HET-2 as thus defined is a 6-membered ring, suitable examples of such groups include:

wherein R is selected from hydrogen and methyl, and is attached on a ring carbon atom.

-2 is a 6-membered ring, suitably it is selected from

In one aspect, R ¹ is selected from -CH ₂ OMe.

In one aspect, R ¹ is selected from cyclopropyl (optionally substituted with one substituent selected from fluoro and methyl).

In one aspect, R ¹ is selected from HET-1; wherein

either HET-1 is a 5-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, S and O; when HET-1 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-1 is optionally substituted with methyl; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted; or

HET-1 is a 6-membered heteroaryl ring containing 1, 2 or 3 ring nitrogen atoms; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted.

In one aspect, R ¹ is selected from HET-1; wherein

either HET-1 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, S and O; when HET-1 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-1 is optionally substituted with methyl; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifiuoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted; or HET-1 is a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifiuoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted.

In one aspect, R ¹ is selected from HET-1; wherein HET-1 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, S and O; when HET-1 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-1 is optionally substituted with methyl; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifiuoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted.

In one aspect, R ¹ is selected from HET-1; wherein HET-1 is a 5-membered heteroaryl ring containing 2 heteroatoms independently selected from N, S and O; when HET-1 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-1 is optionally substituted with methyl; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifiuoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted.

In one aspect, R ¹ is selected from HET-1; wherein HET-1 is a 5-membered heteroaryl ring containing 2 heteroatoms independently selected from N, S and O; when HET-1 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-1 is optionally substituted with methyl; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifiuoromethyl or methoxy provided that no more than 1 ring carbon atom is substituted.

In one aspect, R ¹ is selected from HET-1; wherein HET-1 is a 5-membered heteroaryl ring containing 2 heteroatoms independently selected from N, S and O; and, wherein HET-1 is optionally substituted with methyl on a ring nitrogen atom.

In one aspect, R ¹ is selected from HET-1; wherein HET-1 is a 5-membered heteroaryl ring containing 2 heteroatoms independently selected from N, S and O; and, wherein HET-1 is substituted with methyl on a ring nitrogen atom. In one aspect, R ¹ is selected from HET-1; wherein HET-1 is a 6-membered heteroaryl ring containing 1, 2 or 3 ring nitrogen atoms; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted.

In one aspect, R ¹ is selected from HET-1; wherein HET-1 is a 6-membered heteroaryl ring containing 1, 2 or 3 ring nitrogen atoms; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl or trifluoromethyl, provided that no more than 2 ring carbon atoms are substituted.

In one aspect, R ¹ is selected from HET-1; wherein HET-1 is a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted.

In one aspect, R ¹ is selected from HET-1; wherein HET-1 is a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 1

1 is selected from

In one aspect, R i is .

In one aspect, R i is In one aspect, R ¹ i

In one aspect, R ¹ is

In one aspect, R ¹

In one aspect, R ¹

In one aspect, R ¹ is

In one aspect, R ¹ is

In one aspect, R ¹ is

In one aspect, R ¹ is

In one aspect, R ² is selected from hydrogen, methyl and -CH ₂ OMe. In one aspect, R ² is hydrogen.

In one aspect, R ² is methyl.

In one aspect, R ² is -CH ₂ OMe.

In one aspect, R ³ is selected from hydrogen, methyl and -CH ₂ OMe. In one aspect, R ³ is hydrogen.

In one aspect, R ³ is methyl.

In one aspect, R ³ is -CH ₂ OMe.

In another aspect, R ² and R ³ are taken together with the carbon atom to which they are attached form a cyclopropyl ring.

In one aspect, R ⁴ is selected from hydrogen, methyl and -CH ₂ OMe.

In one aspect, R ⁴ is hydrogen.

In another aspect R ⁴ is methyl.

In another aspect R ⁴ is -CH ₂ OMe.

In one aspect, R ⁵ is chlorine.

In another aspect R ⁵ is methyl.

In one aspect, R ⁶ is HET-2; wherein either HET-2 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted; or

HET-2 is a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted.

In one aspect, R ⁶ is HET-2, wherein HET-2 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted.

In one aspect, R ⁶ is HET-2, wherein HET-2 is a 5 membered heteroaryl ring containing 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted. In one aspect, R ⁶ is HET-2, wherein HET-2 is a 5 membered heteroaryl ring containing 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl.

In one aspect, R ⁶ is HET-2, wherein HET-2 is a 5 membered heteroaryl ring containing 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl.

In one aspect, R ⁶ is HET-2, wherein HET-2 is a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted.

In one aspect, R ⁶ is HET-2, wherein HET-2 is a 6-membered heteroaryl ring containing 2 ring nitrogen atoms; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted.

In one aspect, R ⁶ is HET-2, wherein HET-2 is a 6-membered heteroaryl ring containing 1 ring nitrogen atom; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted. In one aspect, R ⁶ i is In one aspect, R ⁶ is

In one aspect, R ⁶ i is

In one aspect, R ⁶ is

In a further aspect, there is provided a compound of formula (I) or a

pharmaceutically-acceptable salt thereof, wherein:

R ¹ is selected from methoxyethyl, cyclopropyl (optionally substituted with one subsituent selected from fluoro and methyl), and HET-1; wherein

either HET-1 is a 5-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, S and O; when HET-1 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-1 is optionally substituted with methyl; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted; or

HET-1 is a 6-membered heteroaryl ring containing 1, 2 or 3 ring nitrogen atoms; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted;

R ² is selected from hydrogen, methyl and -CH ₂ OMe;

R ³ is selected from hydrogen, methyl and -CH ₂ OMe;

or R ² and R ³ are taken together with the carbon atom to which they are attached form a cyclopropyl ring;

R ⁴ is selected from hydrogen, methyl and -CH ₂ OMe;

R ⁵ is selected from chlorine and methyl; R ⁶ is HET-2, wherein either HET-2 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted; or

HET-2 is a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted.

In a further aspect, there is provided a compound of formula (I) or a

pharmaceutically-acceptable salt thereof, wherein:

R ¹ is HET-1 wherein either HET-1 is a 5-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, S and O; when HET-1 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-1 is optionally substituted with methyl; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted; or

HET-1 is a 6-membered heteroaryl ring containing 1, 2 or 3 ring nitrogen atoms; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted;

R ² is selected from hydrogen, methyl and -CH ₂ OMe;

R ³ is selected from hydrogen, methyl and -CH ₂ OMe;

or R ² and R ³ are taken together with the carbon atom to which they are attached form a cyclopropyl ring;

R ⁴ is selected from hydrogen, methyl, and -CH ₂ OMe;

R ⁵ is selected from chlorine and methyl;

R ⁶ is HET-2, wherein either HET-2 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted; or HET-2 is a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted.

In a further aspect, there is provided a compound of formula (I) or a

pharmaceutically-acceptable salt thereof, wherein:

R ¹ is HET-1 wherein either HET-1 is a 5-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, S and O; when HET-1 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-1 is optionally substituted with methyl; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted; or

HET-1 is a 6-membered heteroaryl ring containing 1, 2 or 3 ring nitrogen atoms; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted;

R ² is selected from hydrogen, methyl and -CH ₂ OMe;

R ³ is selected from hydrogen and methyl;

or R ² and R ³ are taken together with the carbon atom to which they are attached form a cyclopropyl ring;

R ⁴ is selected from hydrogen and methyl;

R ⁵ is methyl;

R ⁶ is HET-2, wherein either HET-2 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted; or

HET-2 is a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted.

In a further aspect, there is provided a compound of formula (I) or a

pharmaceutically-acceptable salt thereof, wherein: R ¹ is HET-1 wherein either HET-1 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, S and O; when HET-1 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-1 is optionally substituted with methyl; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted; or

HET-1 is a 6-membered heteroaryl ring containing lor 2 ring nitrogen atoms; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted;

R ² is selected from hydrogen, methyl and -CH ₂ OMe;

R ³ is selected from hydrogen and methyl;

or R ² and R ³ are taken together with the carbon atom to which they are attached form a cyclopropyl ring;

R ⁴ is selected from hydrogen and methyl;

R ⁵ is methyl;

R ⁶ is HET-2, wherein either HET-2 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted; or

HET-2 is a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted.

In a further aspect, there is provided a compound of formula (I) or a

pharmaceutically-acceptable salt thereof, wherein:

R ¹ is HET-1 wherein HET-1 is a 6-membered heteroaryl ring containing 1 ring nitrogen atom; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted;

R ² is selected from hydrogen, methyl and -CH ₂ OMe;

R ³ is selected from hydrogen and methyl; R ⁴ is selected from hydrogen and methyl;

R ⁵ is methyl;

R ⁶ is HET-2, wherein either HET-2 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted; or

HET-2 is a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted.

In a further aspect, there is provided a compound of formula (I) or a

pharmaceutically-acceptable salt thereof, wherein:

R ¹ is HET-1 wherein HET-1 is a 6-membered heteroaryl ring containing 1 ring nitrogen atom; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted;

R ² is selected from hydrogen, methyl and -CH ₂ OMe;

R ³ is selected from hydrogen and methyl;

R ⁴ is selected from hydrogen and methyl;

R ⁵ is methyl;

R ⁶ is HET-2, wherein HET-2 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted.

In a further aspect, there is provided a compound of formula (I) or a

pharmaceutically-acceptable salt thereof, wherein:

R ¹ is HET-1 wherein HET-1 is a 6-membered heteroaryl ring containing 1 ring nitrogen atom; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted;

R ² is selected from hydrogen, methyl and -CH ₂ OMe; R ³ is selected from hydrogen and methyl;

R ⁴ is selected from hydrogen and methyl;

R ⁵ is methyl;

R ⁶ is HET-2, wherein HET-2 is a 5-membered heteroaryl ring containing 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl; and, each ring carbon atom of HET-2 is optionally substituted with fluoro, methyl or methoxy provided that no more than 1 ring carbon atom is substituted.

In a further aspect, there is provided a compound of formula (I) or a

pharmaceutically-acceptable salt thereof, wherein:

R ¹ is HET-1 wherein HET-1 is a 6-membered heteroaryl ring containing 1 ring nitrogen atom; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted;

R ² is selected from hydrogen, methyl and -CH ₂ OMe;

R ³ is selected from hydrogen and methyl;

R ⁴ is selected from hydrogen and methyl;

R ⁵ is methyl;

R ⁶ is HET-2, wherein HET-2 is a 5-membered heteroaryl ring containing 2 heteroatoms independently selected from N, S and O; when HET-2 includes one or more ring nitrogen atoms, a ring nitrogen atom of HET-2 is optionally substituted with methyl.

In a further aspect, there is provided a compound of formula (I) or a

pharmaceutically-acceptable salt thereof, wherein:

R ¹ is -CH ₂ OMe or HET-1 wherein HET-1 is selected from pyrazolyl, pyridyl, pyrimidyl and pyrazinyl and wherein HET-1 is optionally substituted on a ring nitrogen atom with methyl; and, each ring carbon atom of HET-1 is optionally substituted with fluoro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or methoxy provided that no more than 2 ring carbon atoms are substituted;

R ² is selected from hydrogen, methyl and -CH ₂ OMe;

R ³ is selected from hydrogen and methyl;

R ⁴ is selected from hydrogen and methyl;

R ⁵ is methyl; R ⁶ is HET-2, wherein HET-2 is selected from pyrazolyl, pyridyl, pyrimidyl and pyridazinyl and wherein HET-2 is optionally substituted with methyl on a ring nitrogen atom and optionally substituted on a ring carbon atom with methyl.

In a further aspect, there is provided a compound of formula (I) or a

pharmaceutically-acceptable salt thereof, wherein:

R ² is selected from hydrogen, methyl and -CH ₂ OMe;

R ³ is selected from hydrogen and methyl;

R ⁴ is selected from hydrogen and methyl;

R ⁵ is methyl; and

R ⁶ is selected from

In a further aspect, there is provided a compound of formula (I) or a pharmaceutically-acceptable salt thereof, wherein:

R ² is selected from hydrogen, methyl and -CH ₂ OMe;

R ³ is selected from hydrogen and methyl;

R ⁴ is selected from hydrogen and methyl; R ⁵ is methyl; and

R ⁶ is

In a further aspect, there is provided any one or more of the specific examples or a pharmaceutically-acceptable salt thereof.

In a further aspect, there is provided the specific examples described herein or a pharmaceutically-acceptable salt thereof, wherein any one or more of the examples is excluded.

In a further aspect, there is provided a compound selected from:

(3R)-3-methyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5-yl)am ino)pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(3 S)-3-methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

3 - (methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2- ((6-methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(3S)-2-(2-methoxyethyl)-3-methyl-7-[5-methyl-2-[(2-methyl pyrazol-3- yl)amino]pyrimidin-4-yl] -3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 -one;

4- methyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5-yl)amino)pyrimi din-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

7'-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2'-((6-methylpyridin-2- yl)methyl)-2',4'-dihydro- 1 Ή-spiro [cyclopropane- 1 ,3'-pyrrolo[ 1 ,2-a]pyrazin]- 1 '-one;

2'-(2-methoxyethyl)-7'-(5-methyl-2-((l-methyl-lH-pyrazol- 5-yl)amino)pyrimidin-4-yl)- 2',4'-dihydro- 1 'H-spiro[cyclopropane-l ,3'-pyrrolo[ 1 ,2-a]pyrazin]- 1 '-one;

7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2- yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-7-(5-chloro-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-3-methyl-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

3, 3 -dimethyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6- (trifluoromethyl)pyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

2-(2-methoxyethyl)-3 ,3 -dimethyl-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one; 3 ,3 -dimethyl-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

3 ,3 -dimethyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)methyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

7-(5-Methyl-2-((2-methylpyridin-3-yl)amino)pyrimidin-4-yl)-2 -((6-methylpyridin-2- yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-4-(methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)- 2-((6-methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[l,2-a]py razin-l(2H)-one;

(R)-4-(methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)- 2-((6-methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[l,2-a]py razin-l(2H)-one;

(R)-3-(methoxymethyl)-7-(5-methyl-2-(pyrimidin-4-ylamino) pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-2-((5-fluoro-6-methylpyridin-2-yl)methyl)-3-(methoxym ethyl)-7-(5-methyl-2-((l- methyl- 1 H-pyrazol-5-yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)- one;

(S)-2-((5-fluoro-6-methylpyridin-2-yl)methyl)-3-(methoxymeth yl)-7-(5-methyl-2-((l- methyl- 1 H-pyrazol-5-yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)- one;

(S)-3-methyl-7-(5-methyl-2-((3-methylpyridazin-4-yl)amino)py rimidin-4-yl)-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3 -methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- methylpyridin-3 -yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3-methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-2-((6-(fluoromethyl)pyridin-2-yl)methyl)-3-methyl-7-( 5-methyl-2-((l-methyl-lH- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one; and (S)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- methylpyrimidin-4-yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazi n-l(2H)-one; and / or a compound selected from (i?)-3-(methoxymethyl)-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl) 2-((2-methylpyrimidin-4-yl)methyl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

7'-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2'-((6-methylpyridin-2- yl)methyl)-2,2',3,4',5,6-hexahydro- 1 'H-spiro[pyran-4,3'-pyrrolo[ 1 ,2-a]pyrazin]- 1 '-one; 2'-(cyclopropylmethyl)-7'-(5-methyl-2-(pyrimidin-4-ylamino)p yrimidin-4-yl)-2,2',3,4',5,6- hexahydro- 1 'H-spiro[pyran-4,3'-pyrrolo[ 1 ,2-a]pyrazin]-l'-one;

7'-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2'-((6-methylpyridin-2- yl)methyl)-2',4'-dihydro- 1 Ή-spirofcyclobutane- 1 ,3'-pyrrolo[ 1 ,2-a]pyrazin]-l'-one;

2'-(2-methoxyethyl)-7'-(5-methyl-2-((l-methyl-lH-pyrazol-5-y l)amino)pyrimidin-4-yl)-

2',4'-dihydro- H-spiro[cyclobutane-l,3'-pyrrolo[l,2-a]pyrazin]- -one;

(R)-7-(2-(( 1,3 -dimethyl- 1 H-pyrazol-5 -yl)amino)-5 -methylpyrimidin-4-yl)-3 -

(methoxymethyl)-2-((2-methylpyrimidin-4-yl)methyl)-3,4-di hydropyrrolo[l,2-a]pyrazin- l(2H)-one;

2-((l -methyl- 1 H-pyrazol-5 -yl)methyl)-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-2-((6-(fluoromethyl)pyridin-2-yl)methyl)-3 -(methoxymethyl)-7-(5 -methyl-2-(( 1 - methyl- 1 H-pyrazol-5-yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)- one;

3,4-dimethyl-7-(5-methyl-2-((3-methylpyridazin-4-yl)amino)py rimidin-4-yl)-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

3, 4-dimethyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3-(methoxymethyl)-7-(5-methyl-2-((3-methylpyridazin-4-yl )amino)pyrimidin-4-yl)-2-

((6-methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

3, 3 -dimethyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-2-((6-(difluoromethyl)pyridin-2-yl)methyl)-3-(methoxymet hyl)-7-(5-methyl-2-((l- methyl- 1 H-pyrazol-5-yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)- one;

2-(2-methoxyethyl)-3 ,4-dimethyl-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one; 3 ,4-dimethyl-7-(5 -methyl-2-(pyrimidin-4-ylamino)pyrimidin-4-yl)-2-((3-meth

yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

7'-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2'-((3-methylpyrazin-2- yl)methyl)-2',4'-dihydro- 1 'H-spiro[cyclobutane- 1 ,3'-pyrrolo[ 1 ,2-a]pyrazin]-l'-one;

(R)-3-(methoxymethyl)-7-(5-methyl-2-((3-methylpyridazin-4-yl )amino)pyrimidin-4-yl)-2-

((3-methylpyrazin-2-yl)methyl)-3,4-dihydropyrrolo[l,2-a]p yrazin-l(2H)-one;

(R)-3-(methoxymethyl)-7-(5-methyl-2-((3-methylpyridazin-4-yl )amino)pyrimidin-4-yl)-2-

((2-methylpyrimidin-4-yl)methyl)-3,4-dihydropyrrolo[l,2-a ]pyrazin-l(2H)-one;

(R)-3 -(methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-

2-((3 -methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

7-(2-(( 1,3 -dimethyl- 1 H-pyrazol-5 -yl)amino)-5-methylpyrimidin-4-yl)-3,4-dimethyl-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

3, 4-dimethyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

7-(2-(( 1,3 -dimethyl- lH-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-3,4-dimethyl- 2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3-methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((3-

(trifluoromethyl)pyrazin-2-yl)methyl)-3,4-dihydropyrrolo[ l,2-a]pyrazin-l(2H)-one;

7-(2-((l,3-dimethyl-lH-pyrazol-5-yl)amino)-5-methylpyrimidin -4-yl)-3,3-dimethyl-2-((2- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3-(methoxymethyl)-7-(5-methyl-2-(pyrimidin-4-ylamino)pyr imidin-4-yl)-2-((2- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-7-(2-(( 1,3 -dimethyl- 1 H-pyrazol-5 -yl)amino)-5-methylpyrimidin-4-yl)-2-((6-

(fluoromethyl)pyridin-2-yl)methyl)-3 -(methoxymethyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- l(2H)-one;

(R)-3 -(methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl) 2-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)- one;

3, 3 -dimethyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3-(methoxymethyl)-7-(5-methyl-2-(pyrimidin-4-ylamino) pyrimidin-4-yl)-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one; 3 ,3 -dimethyl-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-(thiazol- 4-ylmethyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

4-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)methyl)-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6- (trifluoromethyl)pyrazin-2-yl)methyl)-3,4-dihydropyrrolo[l,2 -a]pyrazin-l(2H)-one;

(S)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

7'-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2'-((2-methylpyridin-3 - yl)methyl)-2',4'-dihydro- 1 'H-spiro[cyclobutane- 1 ,3'-pyrrolo[ 1 ,2-a]pyrazin]-l'-one;

(R)-2-((6-(fluoromethyl)pyridin-2-yl)methyl)-3-(methoxyme thyl)-7-(5-methyl-2-((2- methylpyrimidin-4-yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one; 7-(2-((l,3-dimethyl-lH-pyrazol-5-yl)amino)-5-methylpyrimidin -4-yl)-3,3-dimethyl-2-((6- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-2-((6-(fluoromethyl)pyridin-2-yl)methyl)-3-(methoxyme thyl)-7-(5-methyl-2-((3- methylpyridazin-4-yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one; 2-(2-methoxyethyl)-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4- dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

7-(2-((l,3-dimethyl-lH-pyrazol-5-yl)amino)-5-methylpyrimidin -4-yl)-3,3-dimethyl-2- (thiazol-4-ylmethyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-2-((l,3-dimethyl-lH-l,2,4-triazol-5-yl)methyl)-3-meth yl-7-(5-methyl-2-((l-methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2 -a]pyrazin-l(2H)-one; 2'-(cyclopropylmethyl)-7'-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)- 2,2',3,4',5,6-hexahydro- H-spiro[pyran-4,3'-pyrrolo[l,2-a]pyrazin]- -one;

(R)-3 -(methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)- 2-((2-methylpyridin-3 -yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3 -(methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4- yl)-2-((6-methylpyrimidin-4-yl)methyl)-3,4-dihydropyrrolo[l, 2-a]pyrazin-l(2H)-one; 2'-(cyclopropylmethyl)-7'-(5-methyl-2-((3-methylpyridazin-4- yl)amino)pyrimidin-4-yl)- 2,2',3,4',5,6-hexahydro- H-spiro[pyran-4,3'-pyrrolo[l,2-a]pyrazin]- -one;

7-(5-chloro-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2- yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one; (R)-2-((6-(fluoromethyl)pyridin-2-yl)methyl)-3-(methoxymethy l)-7-(5-methyl-2- (pyrimidin-4-ylamino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin-l(2H)-one; (R and 5)-3-(Methoxymethyl)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3, 4-dihydropyrrolo[l,2- ajpyrazin- 1 (2H)-one;

(3R,4S)-3-(methoxymethyl)-4-methyl-7-(5-methyl-2-((l-methyl- lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3, 4-dihydropyrrolo[l,2- ajpyrazin- 1 (2H)-one;

(3R,4R)-3-(methoxymethyl)-4-methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3, 4-dihydropyrrolo[l,2- ajpyrazin- 1 (2H)-one;

7'-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2'-((6-methylpyridin-2 yl)methyl)-2',4'-dihydro- 1 'H-spiro[oxetane-3,3'-pyrrolo[ 1 ,2-a]pyrazin]-l'-one;

(5)-3-Methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- methyl-2H-l,2,3-triazol-4-yl)methyl)-3,4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one; (S)-2-((3-fluoro-6-methylpyridin-2-yl)methyl)-3-methyl-7-(5- methyl-2-((l-methyl-lH- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

(S)-7-(2-((l,3-dimethyl-lH-pyrazol-4-yl)amino)-5-methylpy rimidin-4-yl)-3-methyl-2-((6 methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-2-(cyclopropylmethyl)-3 -(methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-2-((l,3-dimethyl-lH-l,2,4-triazol-5-yl)methyl)-3-meth yl-7-(5-methyl-2-((l-methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2 -a]pyrazin-l(2H)-one; (S)-7-(2-((l,3-dimethyl-lH-pyrazol-4-yl)amino)-5-methylpyrim idin-4-yl)-3-methyl-2-((2 methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

2-((6-(fluoromethyl)pyridin-2-yl)methyl)-7-(5-methyl-2-(( l -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-2-((5 -fluoro-6-methylpyridin-2-yl)methyl)-3 -methyl-7-(5 -methyl-2-(( 1 -methyl- 1 H- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

(S)-2-(cyclopropylmethyl)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one; 2-((5-fluoro-6-methylpyridin-2-yl)m

4-yl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3-methyl-7-(5-methyl-2-(pyrimidin-4-ylamino)pyrimidin-4- yl)-2-((3- yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-7-(2-(( 1,3 -dimethyl- lH-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-3-

(methoxymethyl)-2-(thiazol-4-ylmethyl)-3,4-dihydropyrrolo [l,2-a]pyrazin-l(2H)-one;

(S)-2-((4-(difluoromethyl)pyridin-2-yl)methyl)-3-methyl-7 -(5-methyl-2-((l -methyl- 1 H- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

2-(2-methoxyethyl)-3 -(methoxymethyl)-7-(5 -methyl -2-(( 1 -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-7-(2-((l,3-dimethyl-lH-pyrazol-5-yl)amino)-5-methylpyrim idin-4-yl)-3-methyl-2-((2- methyl-2H-l,2,3-triazol-4-yl)methyl)-3,4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one;

(S)-7-(2-((l,3-dimethyl-lH-pyrazol-4-yl)amino)-5-methylpyrim idin-4-yl)-2-((6-

(fluoromethyl)pyridin-2-yl)methyl)-3 -methyl-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-2-((2,5-dimethyl-2H-l,2,3-triazol-4-yl)methyl)-3-meth yl-7-(5-methyl-2-((l-methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2 -a]pyrazin-l(2H)-one;

(S)-7-(2-((l,3-dimethyl-lH-pyrazol-5-yl)amino)-5-methylpy rimidin-4-yl)-2-((6-

(fluoromethyl)pyridin-2-yl)methyl)-3 -methyl-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6-

(trifluoromethyl)pyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-2-(( 1,3 -dimethyl- 1 H-pyrazol-5 -yl)methyl)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

7-(5-methyl-2-(pyridazin-4-ylamino)pyrimidin-4-yl)-2-((6-met hylpyridin-2-yl)methyl)-

3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-2-(( 1 -(difluoromethyl)- 1 H-pyrazol-5 -yl)methyl)-3 -methyl-7-(5 -methyl -2-(( 1 -methyl - lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2 -a]pyrazin-l(2H)-one; (R)-2-((6-(difluoromethyl)pyridin-2-yl)methyl)-3-methyl-7-(5 -methyl-2-((l-methyl-lH- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

7-(2-((l,5-dimethyl-lH-pyrazol-4-yl)amino)-5-methylpyrimi din-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-7-(2-((l,3-dimethyl-lH-pyrazol-5-yl)amino)-5-methylpy rimidin-4-yl)-3-methyl-2-((6- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one; (S)-7-(2-((2-methoxypyridin-4-yl)am

methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3 -(methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)

2-(thiazol-2-ylmethyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-7-(2-((l,3-dimethyl-lH-pyrazol-5-yl)amino)-5-methylpyrim idin-4-yl)-3-methyl-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-7-(2-((l,3-dimethyl-lH-pyrazol-4-yl)amino)-5-methylpyrim idin-4-yl)-3-methyl-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-2-((6-(difluoromethyl)pyridin-2-yl)methyl)-3-methyl-7-(5 -methyl-2-((l -methyl- 1 H- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

(S)-3-methyl-7-(5-methyl-2-(pyridazin-4-ylamino)pyrimidin-4- yl)-2-((6-methylpyridin-2- yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-2-(cyclopropylmethyl)-3-(methoxymethyl)-7-(5-methyl-2-(p yrimidin-4- ylamino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

7-(5-methyl-2-((5 -methyl- lH-imidazol-4-yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2 - yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)methyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

(R)-3 -(methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)

2-((2-methylthiazol-4-yl)methyl)-3,4-dihydropyrrolo[l,2-a ]pyrazin-l(2H)-one;

(S)-7-(2-((l,3-dimethyl-lH-pyrazol-4-yl)amino)-5-methylpyrim idin-4-yl)-3-methyl-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-7-(2-(( 1,3 -dimethyl- lH-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-3-methyl-2-(( 6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2-methylpyrimidin-

4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3 -(methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)

2-((2-methylthiazol-5-yl)methyl)-3,4-dihydropyrrolo[l,2-a ]pyrazin-l(2H)-one;

2-((6-methoxypyridin-2-yl)methyl)-7-(5-methyl-2-((l -methyl- lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3 -(methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)

2-(thiazol-4-ylmethyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one; 2-((6-(difluoromethyl)pyridin-2-yl)methyl)-3,3-dimethyl-7-(5 -methyl-2-((l-m

pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2 -a]pyrazin-l(2H)-on^

(R)-2-((4,6-dimethylpyridin-2-yl)m

5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

2-(cyclopropylmethyl)-7-(5 -methyl -2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)- 3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3 -methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((4- methylisoxazol-3-yl)methyl)-3,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(+/-)-2-(2-methoxyethyl)-3 -(methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- methylthiazol-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- methylthiazol-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3 -methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((4- methylisoxazol-3-yl)methyl)-3,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

3, 3 -dimethyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- methyl-2H-l,2,3-triazol-4-yl)methyl)-3,4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one;

(S)-7-(2-((l,3-dimethyl-lH-pyrazol-5-yl)amino)-5-methylpyrim idin-4-yl)-3-methyl-2-((2- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3-methyl-7-(5-methyl-2-((5-methylpyridazin-4-yl)amino)py rimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-2-((4-(difluoromethyl)pyridin-2-yl)methyl)-3-methyl-7-(5 -methyl-2-((l-methyl-lH- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

(R)-2-(( 1 -(difluoromethyl)- 1 H-pyrazol-3 -yl)methyl)-3 -(methoxymethyl)-7-(5 -methyl-2-

(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- l(2H)-one;

(S)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-(thiazol- 4-ylmethyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3-methyl-7-(5-methyl-2-(pyrimidin-4-ylamino)pyrimidin-4- yl)-2-((6-methylpyridin-2- yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one; (R)-3-methyl-7-(5-methyl-2-(pyrimidin-4-ylamino)pyrimidin-4- yl)-2-((6-m yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

2-((6-(difluoromethyl)pyridin-2-yl)methyl)-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-2-((5-fluoro-4-methylpyridin-2-yl)methyl)-3-methyl-7- (5-methyl-2-((l-methyl-lH- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

(R)-3 -methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- methylpyridin-3 -yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2-methylpyridin-3 - yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3-methyl-7-(5-methyl-2-((2-methylpyridin-4-yl)amino)pyri midin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-7-(2-((l,3-dimethyl-lH-pyrazol-5-yl)amino)-5-methylpy rimidin-4-yl)-3-methyl-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

2-((5-fluoro-6-methylpyridin-2-yl)methyl)-7-(5-methyl-2-( (l -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

7-(2-((l,3-dimethyl-lH-pyrazol-5-yl)amino)-5-methylpyrimi din-4-yl)-3,3-dimethyl-2-((2- methyl-2H-l,2,3-triazol-4-yl)methyl)-3,4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one;

(R)-2-((6-methoxypyrimidin-4-yl)methyl)-3 -methyl-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyr azol- 5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-2-(2-methoxyethyl)-3-methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3-methyl-2-((l-methyl-lH-l,2,3-triazol-4-yl)methyl)-7 -(5-methyl-2-((l-methyl-lH- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

(R)-2-(( 1 -(difluoromethyl)- 1 H-pyrazol-3 -yl)methyl)-3 -methyl-7-(5 -methyl -2-(( 1 -methyl - lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2 -a]pyrazin-l(2H)-one; (R)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- methyl-2H-l,2,3-triazol-4-yl)methyl)-3,4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one;

(R)-2-(cyclopropylmethyl)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one; (R)-3 -methyl-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-7-(5-chloro-2-((l-methyl-lH-pyrazol-5-yl)amino)pyrimi din-4-yl)-2-(2-methoxyethyl)-

3- methyl-3,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-7-(2-(( 1,3 -dimethyl- 1 H-pyrazol-5 -yl)amino)-5 -methylpyrimidin-4-yl)-3 - (methoxymethyl)-2-(thiazol-4-ylmethyl)-3,4-dihydropyrrolo[l, 2-a]pyrazin-l(2H)-one; 7-(5-methyl-2-(pyrimidin-4-ylamino)pyrimidin-4-yl)-2-((6-met hylpyridin-2-yl)methyl)- 3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-2-((6-methoxypyrimidin-4-yl)methyl)-3 -methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol- 5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-7-(2-(( 1,3 -dimethyl- 1 H-pyrazol-5 -yl)amino)-5 -methylpyrimidin-4-yl)-3 - (methoxymethyl)-2-((2-methyl-2H-l,2,3-triazol-4-yl)methyl)-3 ,4-dihydropyrrolo[l,2- ajpyrazin- 1 (2H)-one;

2-((5-methoxy-6-methylpyridin-2-yl)methyl)-7-(5-methyl-2-((l -methyl- lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

2-((l,3-dimethyl-lH-pyrazol-5-yl)methyl)-7-(5-methyl-2-((l-m ethyl-lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-2-(( 1 ,3 -dimethyl- 1 H-pyrazol-5 -yl)methyl)-3 -methyl-7-(5 -methyl-2-(( 1 -methyl- 1 H- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

(S)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2-

(trifluoromethyl)pyrimidin-4-yl)methyl)-3,4-dihydropyrrol o[l,2-a]pyrazin-l(2H)-one;

(R)-3-methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-(thiazol-

4- ylmethyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3-methyl-7-(5-methyl-2-((3-methylisothiazol-4-yl)amino)p yrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3-methyl-7-(5-methyl-2-((3-methylpyridazin-4-yl)amino )pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-3-methyl-2-((l-methyl-lH-pyrazol-5-yl)methyl)-7-(5-me thyl-2-((l-methyl-lH- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one; (S)-3-methyl-2-((l-methyl-lH-l,2,3-triazol-5-yl)methyl)-7-(5 -methyl-2-((l-methyl-lH- pyrazol-5 -yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-2-((3, 5 -dimethylisoxazol-4-yl)methyl)-3-methyl-7-(5-methyl-2-((l -methyl- 1H pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

7-(2-((2-fluoropyridin-3-yl)amino)-5-methylpyrimidin-4-yl )-2-((6-methylpyridin-2- yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(R)-3 -(methoxymethyl)-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)- 2-((2-methyl-2H-l,2,3-triazol-4-yl)methyl)-3,4-dihydropyrrol o[l,2-a]pyrazin-l(2H)-one; 7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2-methylthiazol-4- yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(S)-2-((5-fluoro-6-methylpyridin-2-yl)methyl)-3-methyl-7-(5- methyl-2-((l-methyl-lH- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

(R)-2-((5 -fluoro-4-methylpyridin-2-yl)methyl)-3 -methyl-7-(5 -methyl-2-(( 1 -methyl- 1 H- pyrazol-5-yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a] pyrazin-l(2H)-one;

(R)-7-(2-(( 1,5 -dimethyl- lH-pyrazol-3 -yl)amino)-5-methylpyrimidin-4-yl)-3-methyl-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

7-(2-((3-methoxy-l -methyl- lH-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one; and

(S)-3-methyl-7-(5-methyl-2-((2-methylpyrimidin-4-yl)amino )pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one.

In a further aspect, there is provided a compound selected from:

(3 R)-3-Methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(3 S)-3-Methyl-7-(5 -methyl -2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(3 S)-3-Methyl-7-(5 -methyl -2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(5)-3-Methyl-7-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- methyl-2H-l,2,3-triazol-4-yl)methyl)-3,4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one;

7-(5-Methyl-2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2- yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one; and (3 S)-3-Methyl-7-(5 -methyl -2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one.

In a further aspect, there is provided (3R)-3-Methyl-7-(5-methyl-2-((l-methyl-lH- pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl) methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one; or a pharmaceutically-acceptable salt thereof.

In a further aspect, there is provided (3 S)-3-Methyl-7-(5-methyl-2-((l -methyl- 1H- pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((3-methylpyrazin-2-yl) methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one; or a pharmaceutically-acceptable salt thereof.

In a further aspect, there is provided (3 S)-3-Methyl-7-(5-methyl-2-((l -methyl- 1 H- pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((2-methylpyrimidin-4-y l)methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one; or a pharmaceutically-acceptable salt thereof.

In a further aspect, there is provided (5)-3-Methyl-7-(5-methyl-2-((l-methyl-lH- pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((2-methyl-2H-l,2,3-tri azol-4-yl)methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one; or a pharmaceutically-acceptable salt thereof.

In a further aspect, there is provided 7-(5 -Methyl-2-((l -methyl- lH-pyrazol-5 - yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3, 4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one; or a pharmaceutically-acceptable salt thereof.

In a further aspect, there is provided (3 S)-3-Methyl-7-(5-methyl-2-((l -methyl- 1H- pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6-methylpyrimidin-4-y l)methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one; or a pharmaceutically-acceptable salt thereof.

The compounds of Formula (I) have two chiral centres and it will be recognised that the compound of Formula (I) may be prepared, isolated and/or supplied with or without the presence, in addition, of one or more of the other 3 possible enantiomeric and/or diastereomeric isomers of the compound of Formula (I) in any relative proportions. The preparation of enantioenriched/ enantiopure and/or diastereoenriched/ diastereopure compounds may be carried out by standard techniques of organic chemistry that are well known in the art, for example by synthesis from enantioenriched or enantiopure starting materials, use of an appropriate enantioenriched or enantiopure catalyst during synthesis, and/or by resolution of a racemic or partially enriched mixture of stereoisomers, for example via chiral chromatography. For use in a pharmaceutical context it may be preferable to provide the compound of Formula (I) or pharmaceutically-acceptable salt thereof without large amounts of the other stereoisomeric forms being present.

Accordingly, in one embodiment there is provided a composition comprising a compound of Formula (I) or a pharmaceutically-acceptable salt thereof, optionally together with one or more of the other stereoisomeric forms of the compound of Formula (I) or pharmaceutically-acceptable salt thereof, wherein the compound of Formula (I) or pharmaceutically-acceptable salt thereof is present within the composition with a diastereomeric excess (%de) of > 90%.

In a further embodiment the %de in the above-mentioned composition is > 95%.

In a further embodiment the %de in the above-mentioned composition is > 98%.

In a further embodiment the %de in the above-mentioned composition is > 99%.

In a further embodiment there is provided a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, optionally together with one or more of the other stereoisomeric forms of the compound of Formula (I) or

pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%>ee) of > 90%>.

In a further embodiment the %ee in the above-mentioned composition is > 95%. In a further embodiment the %ee in the above-mentioned composition is > 98%. In a further embodiment the %ee in the above-mentioned composition is > 99%. In a further embodiment there is provided a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, optionally together with one or more of the other stereoisomeric forms of the compound of Formula (I) or

pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%>ee) of > 90%> and a diastereomeric excess (%>de) of > 90%>.

In further embodiments of the above-mentioned composition the %ee and %de may take any combination of values as listed below:

• The %ee is <5% and the %de is≥ 80%.

• The %ee is <5% and the %de is≥ 90%. • The %ee is <5% and the %de is≥ 95%.

• The %ee is <5% and the %de is≥ 98%.

• The %ee is≥ 95% and the %de is≥ 95%.

• The %ee is≥ 98% and the %de is≥ 98%.

• The %ee is≥ 99% and the %de is≥ 99%.

In a further embodiment there is provided a pharmaceutical composition which comprises a compound of the Formula (I) or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

In one embodiment there is provided a pharmaceutical composition which comprises a compound of the Formula (I) or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I) or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of > 90%>.

In a further embodiment the %ee in the above-mentioned composition is > 95%.

In a further embodiment the %ee in the above-mentioned composition is > 98%.

In a further embodiment the %ee in the above-mentioned composition is > 99%.

In one embodiment there is provided a pharmaceutical composition which comprises a compound of the Formula (I) or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I) or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is present within the composition with a diastereomeric excess (%>de) of > 90%>.

In a further embodiment the %de in the above-mentioned composition is > 95%.

In a further embodiment the %de in the above-mentioned composition is > 98%.

In a further embodiment the %de in the above-mentioned composition is > 99%.

In one embodiment there is provided a pharmaceutical composition which comprises a compound of the Formula (I) or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I) or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of > 90% and a diastereomeric excess (%de) of > 90%.

In further embodiments of the above-mentioned pharmaceutical composition the %ee and %de may take any combination of values as listed below:

• The %ee is≥ 95% and the %de is≥ 95%.

• The %ee is≥ 98% and the %de is≥ 98%.

• The %ee is≥ 99% and the %de is≥ 99%.

The compounds of Formula (I) and pharmaceutically acceptable salts thereof may prepared, used or supplied in amorphous form, crystalline form, or semicrystalline form and any given compound of Formula (I) or pharmaceutically acceptable salt thereof may be capable of being formed into more than one crystalline / polymorphic form, including hydrated (e.g. hemi-hydrate, a mono-hydrate, a di-hydrate, a tri-hydrate or other stoichiometry of hydrate) and/or solvated forms. It is to be understood that the present invention encompasses any and all such solid forms of the compound of Formula (I) and pharmaceutically acceptable salts thereof.

In further embodiments there is provided a compound of Formula (I), which is obtainable by the methods described in the 'Examples' section hereinafter.

The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes will be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include ¹³ C and ¹⁴ C.

A suitable pharmaceutically acceptable salt of a compound of the Formula (I) is, for example, an acid addition salt.

A further suitable pharmaceutically acceptable salt of a compound of the Formula (I) is, for example, a salt formed within the human or animal body after administration of a compound of the Formula (I) to said human or animal body.

A suitable pharmaceutically acceptable salt of a compound of the Formula (I) may also be, for example, an acid-addition salt of a compound of the Formula (I), for example an acid-addition salt with a inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulphuric acid or trifluoroacetic acid. Pharmaceutically acceptable salts of a compound of the Formula (I) may also be an acid-addition salt with an acid such as one of the following: acetic acid, adipic acid, benzene sulfonic acid, benzoic acid, cinnamic acid, citric acid, D,L-lactic acid, ethane disulfonic acid, ethane sulfonic acid, fumaric acid, L-tartaric acid, maleic acid, malic acid, malonic acid, methane sulfonic acid, napadisylic acid, phosphoric acid, saccharin, succinic acid or toluene sulfonic acid (such as /?-toluenesulfonic acid).

The compound of Formula (I) or pharmaceutically acceptable salt thereof may be prepared as a co-crystal solid form. It is to be understood that a pharmaceutically acceptable co-crystal of a compound of the Formula (I) or pharmaceutically acceptable salts thereof, form an aspect of the present invention.

It is to be understood that a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) also forms an aspect of the present invention. Accordingly, the compounds of the invention may be administered in the form of a pro-drug, which is a compound that is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and/or the

pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in-vivo cleavable ester or amide derivatives that may be formed at the carboxy group in a compound of the Formula (I).

Accordingly, one aspect of the present invention includes those compounds of Formula (I) as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I) may be a synthetically-produced compound or a metabolically- produced compound.

A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.

(Academic Press, 1985);

b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);

c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113- 191 (1991);

d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

f) N. Kakeya, et al, Chem. Pharm. Bull, 32, 692 (1984);

g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S.

Symposium Series, Volume 14; and

h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) that possesses a carboxy group is, for example, an in- vivo cleavable ester thereof. An in- vivo cleavable ester of a compound of the Formula (I) containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for a carboxy group include (l-6C)alkyl esters such as methyl, ethyl and tert-butyl, (l-6C)alkoxymethyl esters such as methoxymethyl esters, (l-6C)alkanoyloxymethyl esters such as

pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1 -cyclohexylcarbonyloxyethyl esters, 2-oxo-l,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl esters and (l-6C)alkoxycarbonyloxy-(l-6C)alkyl esters such as methoxycarbonyloxymethyl and 1 -methoxycarbonyloxy ethyl esters.

A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) which have a carboxy group is for example an in-vivo cleavable amide such as a

N-Ci-ealkyl and N,N-di-(Ci_6alkyl)amide such as N-methyl, N-ethyl, N-propyl, N,N- dimethyl, N-ethyl-N-methyl or N,N-diethylamide.

The in-vivo effects of a compound of the Formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I). As stated hereinbefore, the in-vivo effects of a compound of the Formula (I) may also be exerted by way of metabolism of a precursor compound (a pro-drug).

For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined' or 'defined herein' the said group

encompasses the first occurring and broadest definition as well as each and all of the alternative definitions for that group.

Another aspect of the present disclosure provides a process for preparing a compound of the Formula (I), or a pharmaceutically acceptable salt thereof. A suitable process is illustrated by the following representative process variants in which, unless otherwise stated R ¹ to R ⁶ has any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedures of organic chemistry or are

commercially available. The preparation of such starting materials is described in conjunction with the following representative process variants and within the

accompanying Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.

( I D (')

A compound of formula (I) may be prepared from a compound of formula (II), wherein L ¹ is a suitable leaving group (such as halogen, or -S0 ₂ Me, etc), by reaction with a compound of formula (XII), wherein P ¹ is hydrogen, with a suitable base (such as NaH, Na ₂ C03, CS2CO3 or K2CO3) in a suitable solvent (such as N,N-dimethylformamide or N,N- dimethylacetamide) or in the presence of a suitable Pd catalyst and phosphine ligand with a suitable base (such as CS2CO3) in a suitable solvent (such as dioxane), under conditions of ambient or elevated temperatures (such as achieved by heating or by microwave irradiation). Alternatively, a compound of formula (I) may be prepared from a compound of formula (II), wherein L ¹ is a suitable leaving group (such as halo, or -S0 ₂ Me, etc.), by reaction with a compound of formula (XII), wherein P ¹ is a suitable group other than hydrogen (such as formyl or trifluoroacetamide) with a suitable base (such as NaH, Na ₂ C03, CS2CO3 or K2CO3) in a suitable solvent (such as N,N-dimethylformamide or N,N- dimethylacetamide) or in the presence of a suitable Pd catalyst and phosphine ligand with a suitable base (such as CS2CO3) in a suitable solvent (such as dioxane), under conditions of elevated temperatures (such as achieved by heating or by microwave irradiation), followed by removal of the protecting group P ¹ in the presence of a suitable base such as sodium hydroxide in a suitable solvent and water.

It will be appreciated that a compound of formula (I) may be transformed into another compound of formula (I) using conditions well known in the art.

Compounds of formula (XII) are either commercially available or well known in the art.

A compound of formula (I) may be prepared from a compound of formula (III), wherein P ² is a suitable protecting group (such as formyl, trifluoroacetamide or -Boc), by reaction with a compound of formula (XIII) wherein L ² is a suitable leaving group (such as halogen, or -OS0 ₂ Me, -Tos, etc), in the presence of a suitable base (such as sodium hydride or K2CO3) and a suitable solvent (such as N,N-dimethylformamide or acetone); and subsequent removal of the protecting group P ² in the presence of a suitable base (such as sodium hydroxide) in suitable solvent and water, or by anhydrous hydrogen chloride in dioxane. Compounds of formula (XIII) are either commercially available or well known in the art.

(IV) (III)

A compound of formula (III), wherein P ² is a suitable protecting group (such as formyl, trifluoroacetamide or -Boc) may be prepared from a compound of formula (IV), by reaction with a compound of formula (XIV) whereby L ³ is a suitable leaving group (such as halogen, etc) in the presence of a suitable base (such as K2CO3) and a suitable solvent (such as N,N-dimethylformamide).

Compounds of formula (XIV) are either commercially available or well known in the art.

(IV)

(V)

A compound of formula (IV) may be prepared from a compound of formula (V), wherein L ¹ is a suitable leaving group (such as halogen, or -S0 ₂ Me, etc), by reaction with a compound of formula (XII) in the presence of a suitable base (such as K2CO3) and in a suitable solvent (such as N,N-dimethylformamide) under conditions of elevated temperatures (such as achieved by heating or by microwave irradiation), or in the presence of a suitable Pd catalyst and phosphine ligand with a suitable base in a suitable solvent (such as dioxane).

A compound of formula (II) may be prepared from a compound of formula (V), by the reaction with compounds of the formula (XV), wherein L ⁵ is a suitable leaving group (such as halogen, or -OS0 ₂ Me, etc), in the presence of a suitable base (such as sodium hydride or K2CO3) and in a suitable solvent (such as N,N-dimethylformamide or N,N- dimethylacetamide) under conditions of ambient or elevated temperatures (such as achieved by heating or by microwave irradiation).

Compounds of formula (XV) are either commercially available or well known in the art.

Alternatively compounds of formula (II) may be prepared from compounds of formula (VI), wherein R ⁸ is an alkyl group (such as methyl), by the reaction with compounds of the formula (XVI) in the presence of suitable reducing reagent (such as NaBH ₃ CN) and a suitable solvent (such as tetrahydrofuran or acetonitrile) followed by subsequent lactamisation conditions in a suitable solvent (such as MeOH) with a suitable base (such as ammonia), or with a Lewis acid catalyst (such as trimethylaluminium).

Compounds of formula (XVI) are either commercially available or well known in the art.

(V)

(VII)

A compound of formula (V) wherein L ¹ is a suitable leaving group (such as halogen, or -S0 ₂ Me, etc) may be prepared from a compound of formula (VII), wherein R ⁷ is hydrogen or an alkyl group (such as methyl, etc), by reaction with a compound of formula (XVII) wherein L ⁴ is a suitable leaving group (such as halo, or OSO2CF3), in the presence of a suitable Pd catalyst and phosphine ligand in a suitable solvent (such as a mixture of N,N-dimethylformamide, dimethoxyethane, water and ethanol) under suitable conditions such as heating thermally or in a microwave reactor.

Compounds of formula (XVII) are either commercially available or well known in the art.

A compound of formula (VII), wherein R ⁷ is hydrogen or an alkyl group (such as methyl, etc), may be prepared from a compound of formula (IX), wherein R ⁸ is an alkyl group (such as methyl, etc), by reaction with either a compound of formula (X), wherein L ⁵ is a suitable leaving group (such as halo, or OSO2CF3) and P ³ is a suitable protecting group (such as formyl or -Boc), or a compound of formula (XI) wherein P ³ is a suitable protecting group (such as formyl or -Boc), in the presence of a suitable base (such as sodium hydride or K2CO3) and in a suitable solvent (such as N,N-dimethylformamide or N,N-dimethylacetamide) under conditions of ambient or elevated temperatures (such as achieved by heating or by microwave irradiation); followed by the removal of the protecting group P ³ in the presence of a suitable base (such as sodium hydroxide) in a suitable solvent and water or anhydrous hydrogen chloride in dioxane and then

lactamisation conditions in a suitable solvent (such as MeOH) with a suitable base (such as ammonia), or with a Lewis acid catalyst (such as trimethylaluminium).

Compounds of formula (IX), (X) and (XI) are either commercially available or well known in the art.

A compound of formula (VI), wherein R is an alkyl group (such as methyl, etc), may be prepared from a compound of formula (VIII), by reaction with either a compound of formula (X), wherein L ⁵ is a suitable leaving group (such as halo, or OSO2CF3) and P ³ is a suitable protecting group (such as formyl or -Boc), or a compound of formula (XI) wherein P ³ is a suitable protecting group (such as formyl or -Boc), in the presence of a suitable base (such as sodium hydride or K2CO3) in a suitable solvent (such as N,N- dimethylformamide or N,N-dimethylacetamide) under conditions of ambient or elevated temperatures (such as achieved by heating or by microwave irradiation); followed by the removal of the protecting group P ³ in the presence of a suitable base (such as sodium hydroxide) in a suitable solvent and water or anhydrous hydrogen chloride in dioxane. Compounds of formula (X) and (XI) are either commercially available or well known in the art.

A compound of formula (VIII) wherein L is a suitable leaving group (such as halogen, or -S0 ₂ Me, etc) may be prepared from a compound of formula (IX), wherein R ⁷ is hydrogen or an alkyl group (such as methyl, etc), by reaction with a compound of formula (XVII) wherein L ⁴ is a suitable leaving group (such as halo, or OSO2CF3), in the presence of a suitable Pd catalyst and phosphine ligand in a suitable solvent (such as a mixture of N,N-dimethylformamide, dimethoxyethane, water and ethanol), under suitable conditions (such as heating thermally or in a microwave reactor).

Alternatively, a compound of formula (I) may be prepared by treatment of a compound of formula (XVIII), where R ⁸ is a suitable alkyl group (such as methyl), with a compound of formula (XVI) in the presence of suitable reducing reagent (such as NaBHsCN) and a suitable solvent (such as tetrahydrofuran or acetonitrile) followed by subsequent lactamisation conditions in a suitable solvent (such as methanol) with a suitable base (such as ammonia), or with a Lewis acid catalyst (such as trimethylaluminium).

Compounds of formula (XVI) are either commercially available or well known in the art.

(XVIII)

A compound of formula (XVIII) may be prepared from a compound of formula (XIV), wherein L ¹ is a suitable leaving group (such as halogen, or -S0 ₂ Me, etc), by reaction with a compound of formula (XII) in the presence of a suitable base (such as K ₂ C0 ₃ ) and in a suitable solvent (such as N,N-dimethylformamide) under conditions of elevated temperatures (such as achieved by heating or by microwave irradiation), or in the presence of a suitable Pd catalyst and phosphine ligand with a suitable base in a suitable solvent (such as dioxane), followed by the removal of a suitable protecting group P ⁴ (such as -Boc) with a suitable acid (such as HC1) in a suitable solvent (such as MeOH).

Compounds of formula (XII) are either commercially available or well known in the art.

When a pharmaceutically acceptable salt of a compound of the Formula (I) is required it may be obtained by, for example, reaction of said compound with a suitable acid or suitable base.

When a pharmaceutically acceptable pro-drug of a compound of the Formula (I) is required, it may be obtained using a conventional procedure. For example, an in-vivo cleavable ester of compound of the Formula (I) may be obtained by, for example, reaction of a compound of the Formula (I) containing a carboxy group with a pharmaceutically acceptable alcohol. Further information on pro-drugs has been provided hereinbefore.

It will also be appreciated that, in some of the reactions mentioned hereinbefore, it may be necessary or desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable, and suitable methods for protection, are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an

arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as

palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.

Certain of the intermediates (for example, compounds of the Formulae II, III, IV, V, VI, VII, IX, VIII, XVIII and XIV particularly Formulae II, IV and XVIII) defined herein are novel and these are provided as a further features of the invention.

Biological Assavs-

The following assays were used to measure the effects of the compounds of the present invention. Biology

Compound Handling

All compounds or DMSO (dimethyl sulphoxide) for the ERK2 Enzyme Assay and A375 phospho-p90RSK assays were dispensed from source plates containing compounds at 10 mM in 100% (v/v) DMSO or 100% DMSO, directly into assay plates using an Echo 555 Acoustic dispenser (Labcyte Inc™). For the ERK2 Enzyme Assay, compound plate preparation followed two separate workflows. In Workflow A, 10 mM compound stocks were diluted 1 : 100 using a fixed-tip 96-head Agilent VPrep liquid handler (Agilent Technologies, Santa Clara, CA) to give four intermediate dilutions (10 mM, 100 μΜ, 1 μΜ, 10 nM). This intermediate dilution plate was then used by the Echo to generate final assay-ready compound plates with a 12 point dose range (10, 2.5, 1, 0.3, 0.1, 0.025, 0.01, 0.003, 0.001, 0.00025, 0.0001, 0.00001 μΜ) in order to calculate compound ICsos, with a Labcyte LX Series Reagent Dispenser (Labcyte Inc™) providing a DMSO backfill to give a total DMSO concentration in the assay of 1%. In Workflow B, lOmM compound stocks were diluted 1 : 10 using a Tecan Freedom Evo (Tecan Group Ltd., Switzerland), and then 1 : 100 using the Echo 555 and Labcyte LX to produce three intermediate dilutions across three Labcyte qualified source plates (1 mM, 10 μΜ, 100 nM). These intermediate dilution plates were then used by the Echo 555 to generate final assay-ready compound plates with a 12 point dose range (10, 3, 1, 0.25, 0.1, 0.03, 0.01, 0.0025, 0.001, 0.0003, 0.0001, 0.0000125 μΜ) in order to calculate compound ICsos, with a total DMSO concentration in the assay of 1%. For the CDK2 Kinase activity assay, compound plate preparation followed Workflow A, but used a 100 μΜ top concentration followed by half- log dilutions. For the A375 phospho-p90RSK Cellular Assay, the intermediate 1 : 100 dilution plate described in Workflow A was used by the Echo to dispense compounds and DMSO directly into the cell plates with a 12 point dose range (30, 10, 3.125, 1.25, 0.3, 0.1, 0.03125, 0.0125, 0.003, 0.001, 0.0003125, 0.00003 μΜ) in order to calculate compound IC50S, with a total DMSO concentration in the assay of 0.3%.

ERK2 Enzyme Assay

MEK U911 -activated ER 2 protein was expressed and purified in-house. Enzyme and substrate solutions were made up in assay buffer consisting of 50mM Tris (pH 7.5), lOmM MgC12, O.lmM EGTA (ethylene glycol tetraacetic acid), lOmM DTT

(dithiothreitol) and 0.01% (v/v) CHAPS (3-[(3-Cholamidopropyl)dimethylammonio]-l- propanesulfonate). 1.2nM ERK2 protein was prepared in assay buffer and ΙΟμΙ was dispensed into each well of a polypropylene, 384-well plate (#781201, Greiner) containing test and reference control compounds. Following a 15 minute pre-incubation of enzyme and compound at room temperature, ΙΟμΙ of substrate solution was added consisting of 16μΜ Erktide (IPTTPITTTYFFFK, #61777, AnaSpec) and 120μΜ ATP (adenosine triphosphate) (measured Km) in assay buffer. The reaction was allowed to progress for 20 minutes at room temperature before being quenched by the addition of 80μ1 1%> (v/v) formic acid. The assay plates were then run on the RapidFire Mass Spectrometry platform (Agilent) to measure substrate (unphosphorylated Erktide) and product (phosphorylated Erktide) levels. Data was analysed and IC50's (half maximal inhibitory concentration) were calculated using Genedata Screener® software.

A375 phospho-p90RSK Cellular Assay

The phospho-p90RSK cell assay was performed in the A375 cell line, a human malignant melanoma which has a BRAF mutation up-regulating the MAPK pathway and, hence, elevated endogenous levels of phospho-ERK and phospho-p90RSK. A375 cells were cultured in cell media composed of DMEM (Dulbecco's modified Eagle's medium), 10%) (v/v) Foetal Calf Serum and 1%> (v/v) L-Glutamine. After harvesting, cells were dispensed into black, 384-well Costar plates (#3712, Corning) to give 2400 cells per well in a total volume of 40μ1 cell media, and were incubated overnight at 37°C, 90% relative humidity and 5% C02 in a rotating incubator. Test compounds and reference controls were dosed directly into the cell plates using a Labcyte Echo 555 acoustic dispenser. The cell plates were then incubated for 2 hours at 37°C before being fixed by the addition of 20 μΐ 12% formaldehyde in PBS/A (4% final concentration), followed by a 20 minute room temperature incubation, and then a 2x wash with 150μ1 PBS/A (phosphate buffered saline containing albumin) using a BioTek ELx405 platewasher. Cells were permeabilised with 20μ1 0.1% Triton X-100 in PBS/A for 20 minutes at room temperature, and then washed lx with ΙΟΟμΙ PBS/A. Primary phospho-p90RSK (Thr359) (D1E9) rabbit monoclonal antibody (#8753, Cell Signaling Technology) was diluted 1 : 1000 in assay buffer (0.05% (v/v) Tween, 5% (v/v) Foetal Calf Serum, in PBS/A), 20μ1 added per well, and plates were incubated at 4°C overnight. Cell plates were washed 2x with 200μ1 PBS/T (phosphate buffered saline containing Tween-20), then 20μ1 1 :500 dilution in assay buffer of Alexa Fluor® 647 goat anti -rabbit IgG secondary antibody (#A31573, Molecular Probes, Life Technologies), with a 1 :5000 dilution of Hoechst 33342, was added per well. Following a 90 minute incubation at room temperature, plates were washed 2x with 200μ1 PBS/T, and 40μ1 PBS/A was added per well. Stained cell plates were covered with black lid seals, and then read on a Cellomics ArrayScanTM VTI imaging platform

(Thermo Scientific), using an XF53 filter with lOx objective, with a LED light source setup to analyse nuclear staining with Hoechst 33342 (405nm) and secondary antibody staining of phospho-p90RSK (647nm). Data was analysed and ICso's were calculated using Genedata Screener® software.

MEK Autophosphorylation ADP-Glo Assay

Activated MEK protein was supplied by MRC-PPU (DU911, Dundee, UK) or expressed and purified in-house. The MEK assay was performed with the ADP-Glo™ Kinase Assay Kit (Promega, Madison, WI, USA), in Greiner 384-well white low volume plates. 2μ1 of 6 nM activated MEK protein, in assay buffer consisting of 50 mM Tris (pH 7.5), 10 mM DTT, 0.1 mM EGTA, 0.01 % v/v Tween20 and 10 mM MgCl ₂ , was dispensed into each well of a plate containing test and reference control

compounds. Following a 15 minute pre-incubation of enzyme and compound at room temperature, 2 μΐ of substrate solution was added consisting of 20 μΜ ATP ( TMap _P ^ATP ) in assay buffer. The assay reaction was allowed to proceed for 90 min at room temperature before stopping the reaction by the addition of 2 μΐ of ADP-Glo reagent. Plates were then covered and incubated for 40 min at room temperature. 4 μΐ Kinase Detection Reagent was then added and plates were incubated for 30 min, before the luminescence signal was read with a PHERAstar plate reader (BMG Labtech GmbH, Offenburg, Germany). Data was analysed and ICso's (half maximal inhibitory concentration) were calculated using

Genedata Screener® software.

The following data were generated for the Examples (the data below may be a result from a single experiment or an average of two or more experiments):

Workflow 1 Workflow 2

Final ERK2 Enzyme ERK2 Enzyme p90RSK

Example No ICso ^M) ICso ^M) cell (μΜ)

1 <0.0004 0.0005 0.062

2 <0.0016 0.14

3 0.0006 0.14

3a 0.0013 0.24

3b <0.0003 0.0006 0.064

4 <0.0003 0.13

5 <0.0003 0.16

5a 0.0004 0.04

5b <0.0003 0.17

6 <0.0003 0.056

7 <0.0003 0.25

8 <0.0003 0.0004 0.1 1

9 <0.0003 0.044

10 0.0006 0.069

1 1 <0.0004 0.18

12 <0.0005 0.049

13 0.0005 0.19

14 <0.0006 0.14 a 0.0011 0.4b 0.001 0.18

<0.0004 0.066a 0.0032 0.58b 0.0007 0.11

<0.0003 0.16

<0.0003 0.15

<0.0004 0.0007 0.21

0.0006 0.0006 0.21

<0.0003 0.013

0.0004 0.0006 0.22

<0.0007 0.32

<0.0005 0.27

0.0005 0.086

0.0013 0.52

<0.0003 0.023

<0.0003 0.064

0.0007 1.5

<0.0004 0.58

<0.0003 0.033a <0.0003 0.052b <0.0003 0.11c <0.0003 0.18d 0.0013 0.83a <0.0003 0.02b 0.0003 0.19c <0.0003 0.035d 0.0023 0.94

<0.0004 0.051

<0.0005 0.44

<0.0007 0.098 a <0.0003 0.019b <0.0003 0.13a 0.0004 0.094b <0.0006 0.18c 0.0008 0.21d 0.0156 0.9

0.0012 0.5

<0.0003 0.37

<0.0003 0.29

0.0009 0.4a <0.0009 0.22b 0.0009 0.63c 0.0029 0.8d 0.0347 4.1a 0.0008 0.11b 0.0007 0.0018 0.3c 0.0006 0.55d 0.0201 1.4a 0.0012 0.29b 0.0055 0.93c 0.0019 0.57d 0.038 3.4

0.0052 0.014 0.71

0.0017 1.1

<0.0003 0.15

<0.0003 0.19

<0.0005 0.059

<0.0005 0.63

0.0009 0.26

<0.0003 0.22

0.0005 0.46 <0.0003 0.11

<0.0005 0.25

<0.0003 0.058

<0.0003 0.055

0.001 1

<0.0003 0.021

<0.0003 0.31

0.0011 0.99

0.003 2.1

0.0005 0.15

0.0004 0.18

0.0012 0.8

<0.0015 0.22a 0.0006 0.083b 0.0006 0.1c <0.0007 0.081d 0.0011 0.52

0.0005 0.15

<0.0003 0.0005 0.28

0.001 0.45

<0.0003 0.035

<0.0006 0.41

0.0004 0.2

<0.0005 0.66

0.0007 0.96

<0.0004 0.032

<0.0003 0.062

<0.0003 0.044

<0.0003 0.35

<0.0003 0.18

0.0007 2 <0.0003 0.067a <0.0003 0.5b 0.0042 1.5

<0.0005 0.71

<0.0003 0.068

<0.0004 0.72

<0.0003 0.041

<0.0007 0.099

0.0005 0.21

<0.0003 0.24

0.0017 0.27

<0.0003 0.086

0.0031 0.95

<0.0008 0.45

<0.0003 0.031

<0.0005 0.60 <0.0003 0.0771 <0.0003 0.152 <0.0004 0.0463 <0.0003 0.0784 <0.0005 0.225 0.0022 0.01 6.26 <0.0009 0.457 <0.0003 0.138 0.0009 0.689 0.001 0.230 0.0004 0.531 0.0048 0.004 0.572 <0.0003 0.0673 <0.0003 0.114 <0.0003 0.064 115 0.0052 0.81

116 <0.0003 0.09

117 <0.0004 0.26

118 0.0007 0.44

119 0.0004 0.15

120 <0.0007 0.2

121 0.0011 0.68

122 <0.0003 0.48

123 0.0005 0.53

124 <0.0003 0.21

125 <0.0003 0.068

126 <0.0003 0.26

127 <0.0004 0.14

128 <0.0003 0.047

129 <0.0004 0.039

130 <0.0003 0.046

131 <0.0005 0.38

132 <0.0003 0.15

133 <0.0004 0.28

134 <0.0003 0.41

135 <0.0003 0.03

136 <0.0007 0.38

137 <0.0003 0.034

138 <0.0003 0.079

139 0.0015 1.2

140 0.0004 0.54

141 <0.0003 0.31

142 0.0021 7.5

143 <0.0005 0.17

144 0.0008 0.27

145 0.0004 0.2 146 0.0007 0.15

147 <0.0003 0.18

148 0.0016 2.9

149 <0.0003 0.044

150 <0.0003 0.32

151 0.0012 2.6

152 0.003 1.4

153 0.0008 0.93

154 <0.0004 0.16

155 <0.0003 0.2

156 <0.0010 0.085

157 0.0006 0.51

158 <0.0003 0.02

159 <0.0003 0.035

160 <0.0003 0.22

161 <0.0003 2.6

162 0.002 0.22

163 <0.0005 0.17

164 0.0004 1

165 <0.0003 0.2

166 <0.0004 0.076

167 <0.0004 0.13

168 0.006 0.76

169 0.0027 0.9

170 0.0006 0.15

Compounds as claimed herein generally have ERK2 enzyme activity in the above assay of <0.5 mM, such as <0.2 mM, such as <0.5 μΜ, such as <0.05 μΜ, and in many cases O.005 μΜ.

Where tested, compounds of the examples are at least 200 fold, and generally at least 1000 fold, more selective for ER over MEK. Data previously reported is presented in the table below. Previously presented data are based on fewer replicates.

Example Workflow 1 ERK2 p90RSK cell (μΜ)

Enzyme (μΜ)

1 <0.0003 0.074

9 <0.0003 0.044

8 <0.0003 0.12

2 <0.0004 0.14

4 <0.0003 0.13

3a 0.0013 0.24

3b <0.0003 0.06

6 <0.0003 0.056

7 <0.0003 0.25

5a 0.0004 0.04

5b <0.0003 0.17

10 0.000568 0.069

11 <0.000343 0.18

12 <0.000364 0.049

13 0.000467 0.19

21 0.000447 0.32

20 <0.000334 0.24

19 <0.000306 0.15

18 <0.0003 0.16

23 0.0004 0.27

17a 0.003 0.58

17b 0.0007 0.11

16 <0.000335 0.066

15a 0.001 0.4

15b 0.001 0.18

14 <0.0004 0.14

22 <0.0003 0.013 CDK2 Kinase activity assay

The inhibitory activity of compound against CDK2 was determined with a Caliper off-chip incubation mobility shift assay, using a microfluidic chip to measure the conversion of a fluorescent labeled peptide to a phosphorylated product. A custom peptide substrate (FL-QSPK G-CONH2) was obtained from Cambridge Research Biochemicals (Cleveland, U.K.). The complex of recombinant full-length human cdk2 containing a C- terminal His6-tag and recombinant full-length human cyclin E containing an N-terminal GST-tag (expressed by baculovirus in Sf21 insect cells), was obtained from Millipore. Enzyme, peptide substrate, and ATP was incubated in the presence of compound in white Greiner 384-well low volume plates, in a total reaction volume of 12 μΕ. Enzymes and peptides were added separately to the compound plates and were incubated at room temperature. The kinase reaction [90 μΜ ATP ( TMap _P ^ATP ), 1 nM enzyme, 1.5 μΜ substrate] in phosphorylation buffer [50 mM HEPES (pH 7.5), 5 mM MgCb, 1 mM DTT, 0.05 % v/v CHAPSO] was quenched after a 60 minute incubation with the addition of a stop buffer (100 mM HEPES (pH 7.5), 5 % DMSO, 88 mM EDTA, 0.22 % (v/v) Caliper coating reagent no. 3, 0.033 % (v/v) Brij-35 solution). Stopped assay plates were then read using the Perkin Elmer LabChip EZReader. Data was analysed and ICso's (half maximal inhibitory concentration) were calculated using Genedata Screener® software.

Approximately 184 compounds of the Examples were tested and found to have ICso's against CDK2 in the range of 0.007-100 μΜ, and generally in the range of

0.1-10 μΜ. The compounds of the Examples, where tested, are at least 25 fold, and generally at least 200 fold, more selective for ERK2 over CDK2. Example 1 of the present application was found to have an IC50 against CDK2 of 0.27 μΜ and is therefore at least 675 fold more selective for ERK2 over CDK2 when Workflow 1 ERK2 Enzyme Assay as described herein was used to determine the IC50 against ERK2.

CDK7 Kinase activity assay

Activity of purified full-length human CDK7 (CDK7/ CyclinH 1 /MN AT 1 ) , which was purchased from SignalChem, was determined in-vitro using a mobility shift assay on a Caliper LC3000 Reader or LabChip EZ Reader (PerkinElmer/Caliper, Hopkinton, MA), which measures fluorescence of phosphorylated and unphosphorylated CDKJtide (5FAM- YSPTSPSYSPTSPSYSPTSPSKKK -NH2), Intonation, Boston, MA) and calculates a ratiometric value to determine percent turnover.

Phosphorylation of the CDKJtide in the presence and absence of the compound(s) was determined. Six micro litres (μΐ) of enzyme/substrate/adenosine triphosphate (ATP) mix consisting of 3 iiM CDK7, 1.5 μΜ CDK7tide, and 35 μΜ ATP in lx reaction buffer (50 mM HEPES (pH7.2), 1 mM DL-Dithiothreitol (DTT), 0.05 mg/ml BSA (Bovine Serum Albumin), 0.01% (vol/vol) Tween-20) was spotted into Greiner 384-well low volume plate with 0.1 μΐ of compound, which was dosed at 30, 3, 0.3, 0.03 and 0.003 μΜ of final test concentrations by an Echo Liquid Handler (Labcyte, Sunnyvale, CA) and preincubated for 10 minutes at room temperature. Reactions were initiated with 6 μΐ of metal mix consisting of 20 mM MgCL in lx reaction buffer and incubated at room temperature for 240 minutes. Reactions were stopped by addition of 5 μΐ of stop mix consisting of 150 mM HEPES (pH7.3), 68 mM ethylenediaminetetraacetic acid (EDTA, pH8.0), 2.55%> (vol/vol) dimethyl sulfoxide (DMSO), 0.33% (vol/vol) Coating Reagent 3 (PerkinElmer/Caliper, Hopkinton, MA), and 0.03%) (vol/vol) Triton X-100. Phosphorylated and unphosphorylated CDKJtides were detected by a Caliper LC3000 reader or LabChip EZ Reader in the presence of separation buffer consisting of 100 mM HEPES (pH7.3), 4 mM EDTA (pH8.0), 0.1% (vol/vol) Coating Reagent 3, 0.0015% (vol/vol) Brij-35, 5% (vol/vol) DMSO. The separation conditions used by the Caliper LabChip instrument were: Screen Pressure (PSI): -1.2; Upstream Voltage (V): -2500; Downstream Voltage (V): -500; Sample Sip Time (S): 0.2; Post-Sample Buffer Sip Time (S): 55.9; Final delay (S): 165.0. The data was captured by Reviewer (PerkinElmer/Caliper, Hopkinton, MA) and ICsos were processed using GeneData Screener (GeneData AG, Basel, Switzerland).

Example 1 of the present application was found to have an IC50 against CDK7 of 14.44 μΜ and is therefore at least 36000 fold more selective for ERK2 over CDK7 when Workflow 1 ERK2 Enzyme Assay as described herein was used to determine the IC50 against ER 2. Example 3b of the present application was found to have an IC50 against CDK7 of 19.41 μΜ and is therefore at least 64700 fold more selective for ERK2 over CDK7 when Workflow 1 ERK2 Enzyme assay as described herein was used to determine the IC50 against ERK2. CDK9 Kinase activity assay

Activity of CDK9 was determined in-vitro using a mobility shift assay on a Caliper LC3000 reader (Caliper/PerkinElmer), which measures fluorescence of a phosphorylated and unphosphorylated fluorescent peptide substrate and calculates a ratiometric value to determine percent turnover. Phosphorylation of the peptide in the presence and absence of the compound of interest was determined. Enzyme/substrate/adenosine triphosphate (ATP) mix (3 nM CDK9/CycTl, 6 μΜ ATP, 1.5 μΜ CDK9 peptide substrate (FITC-X- GSRTPMY-NH2 (X: epsilon aminocaproic acid)), 50 mM HEPES (pH7.2), 1 mM dithiothreitol, 0.01% tween 20, 50 μ§/ι Ε bovine serum albumin, (final assay

concentration)) (5 μΐ) was preincubated with 2 μΐ of compound for 15 minutes at

25°C. Reactions were initiated with 5 μΐ of 24 mM MgCb (10 mM final assay

concentration) in buffer (50 mM HEPES (pH7.2), 1 mM dithiothreitol, 0.01% tween 20, 50 μg/mL bovine serum albumin, (final assay concentration) and incubated at 25 °C for 90 minutes and reactions were stopped by addition of 5 μΐ of Stop mix consisting of 65 mM HEPES (pH7.2), 35.5 mM EDTA, 0.227% Coatin Reagent 3 (Caliper/PerkinElmer), and 0.003%) Tween. Phosphorylated and unphosphorylated substrate was detected by a Caliper LC3000 reader (Caliper/PerkinElmer) in the presence of separation buffer consisting of 100 mM HEPES (pH7.2), 15.8 mM EDTA, 0.1% Coatin Reagent 3 (Caliper/PerkinElmer), 0.015% Brij-35, 5% DMSO, and 5.6 mM MgCl ₂ . CDK9 enzyme was acquired from Carna Biosciences (Catalogue number 04-110), the CDK9 peptide substrate was acquired from Intonation (Boston, MA; Custom-made).

IC50 values were calculated using standard curve fitting methods, with the maximum signal being defined as the turnover from the inhibited reaction at 83.3 mM EDTA and the minimum signal being defined as the turnover from the reaction at 0.83% DMSO.

Approximately 66 compounds of the Examples were tested and found to have ICso's against CDK9 in the range of 0.6 μΜ to greater than 30 μΜ. The compounds of the Examples, where tested, are at least 364 fold, and generally at least 2000 fold, more selective for ERK2 over CDK9. Example 1 of the present application was found to have an IC50 against CDK9 of 5.61 μΜ and is therefore at least 14025 fold more selective for ER 2 over CDK9 when Workflow 1 ERK2 Enzyme assay as described herein was used to determine the IC50 against ER 2. Aurora A Kinase activity assay

The compounds were solubilized at 30mM in 100% DMSO (Sigma- Aldrich;

reference: 472 301; purity >99.9%) in glass tubes (supplier: VWR; reference :212-0028 borosilicate glass size 75x12 mm) using a 30-seconds sequence with a Covaris S2 (acoustic system) (Manufacturer: Covaris Inc). Each compound at 30 mM was then transferred from tubes to an ABgene 96-well plate (supplier: DUTSCHER DOMINIQUE; reference: AB1127 (SP-0649)) with a Genesis robot (manufacturer: Tecan). The compounds were then serially diluted in columns with a Velocity robot (manufacturer: Agilent) using 100% DMSO to obtain an intermediate 100-fold concentrated dilution plate of the 8 concentrations (lxlO ⁶ , lxlO ^"5 , 3xl0 ^"5 , lxlO ^"4 , 3xl0 ^"4 , lxlO ^"3 , 3xl0 ^"3 and lxlO ^"2 M). Each well was then further diluted in distilled water to a 5-fold concentrated solution (5χ1θ 5xl0 ^"7 , 1.5xl0 ^"6 , 5xl0 ^"6 , 1.5xl0 ^"5 , 5xl0 ^"5 , 1.5xl0 ^"4 and 5xl0 ^"4 M).

Assay volume was 10 μΐ. Human Aurora A protein was supplied by Millipore (ref 14-511). The Aurora A assay was performed in TR-FRET-Lance using an assay kit from PerkinElmer (TRF0203 / TRF0110. 2 μΐ of the test compound 5-fold concentrated solution was transferred with a biomek FX2 robot (Beckman Coulter) from the ABgene 96-well plate to a 384-well white low volume Greiner assay plate (Greiner reference 781075) already containing the assay reference compound and the positive and negative controls. Then, the following solutions were added to initiate the enzymatic reaction: 4 μΐ of 0^g/ml Aurora A protein in assay buffer consisting of 40 mM HEPES/Tris (pH 7.4), 1.6 mM DTT, 0.8 mM EGTA/Tris, 0.008% v/v Tween20 and 8 mM MgCl ₂ . For negative controls, protein was omitted from the assay buffer. 4 μΐ of mix substrate/ ATP solution consisting of 25μΜ ATP (Sigma A2383) and 250nM substrate Ulight-RRRSLLE (PLK) (Perkin Elmer TRFOl 10) in assay buffer. Final testing concentrations for the test compounds was lxlO ^"8 , lxlO ^"7 , 3xl0 ^"7 , lxlO ^"6 , 3xl0 ^"6 , lxlO ^"5 , 3xl0 ^"5 and lxlO ^"5 M, for ATP was 10 μΜ (Κ _π1 ΑΤΡ=5.3μΜ) and for the substrate was ΙΟΟηΜ (K _m subs=170nM). Final DMSO was 1% at each testing concentration. The assay reaction was allowed to proceed for 15 min at room temperature before stopping the reaction by the addition of 5 μΐ of 40 mM EDTA with a Flex drop. Following at 5 minutes at room temperature, 5 μΐ of revelation solution consisting of 4 nM anti-phospho-PLK antibody labeled with europium chelate was added. After 60 min, the fluorescence transfer was measured at lex=337 nm, l _em =620 nm and lem=665 nm using a microplate reader (Envision, Perkin Elmer). The enzyme activity was determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio).

The results were expressed as a percent inhibition of the control enzyme activity. The standard inhibitory reference compound was staurosporine, which was tested in each experiment at several concentrations to obtain an inhibition curve from which its IC50 value was calculated.

Example 1 of the present application was found to have an IC50 against Aurora A kinase of 0.77 μΜ and is therefore is at least 1925 fold more selective for ERK2 over Aurora A kinase when Workflow 1 ERK2 Enzyme assay as described herein was used to determine the IC50 against ER 2. Example 20 of the present application was found to have an IC50 against Aurora A kinase of 1.03 μΜ and is therefore is at least 2575 fold more selective for ERK2 over Aurora A kinase when Workflow 1 ERK2 Enzyme assay as described herein was used to determine the IC50 against ERK2. Example 73 of the present application was found to have an IC50 against Aurora A kinase of 2.28 μΜ and is therefore is at least 7600 fold more selective for ERK2 over Aurora A kinase when Workflow 1 ER 2 Enzyme assay as described herein was used to determine the IC50 against ERK2.

Combination studies - Tumour Growth Inhibition

Materials and Methods

A549 is a human non small cell lung cancer line carrying an oncogenic mutation in the KRAS gene (G12S). Female nude mice (Harlan, UK) were implanted subcutaneously (s.c.) on the left flank, with 5xl0 ⁶ A549 cells (ATCC) per mouse.

Tumour growth was monitored by twice weekly calliper measurement and volumes calculated using elliptical formula (pi/6 x width x width x length). Once tumours had reached a volume of ~200-300mm ³ animals were randomised into groups of 7-11 and were treated with a continuous combination schedule of selumetinib (ARRY-142886) 25mg/kg BiD and Example 1 50mg/kg QD (four hours after first selumetib (ARRY-142886) dose), both were dosed by peroral route. Tumour volumes were measured twice weekly after dosing commenced.

Selumetinib (ARRY-142886) was formulated in HPMC/Tween (0.5% Methocel [hydroxypropyl methocellulose] / 0.1% Polysorbate 80), the suspension was ball milled over night. Example 1 was formulated in 10% DMSO, 90% of a 40% kleptose solution (Kleptose is sourced from Roquette -Pharma [Trademarked] Hydroxypropyl

betacyclodextrin - suitable for in vivo use and formulations).

Tumour Growth Inhibition by Example 1 in Combination with MEK inhibitor (selumetinib (ARRY-142886))

Studies were performed in the A549 xenograft model. Selumetinib

(ARRY-142886) was dosed twice daily (BiD) 8 hours apart and Example 1 was dosed once daily (QD) 4 hours after the first selumetinib dose. Both compounds were dosed continuously for 3 weeks. Both vehicles were dosed in the vehicle group. Both selumetinib (ARRY-142886) and Example 1 reduced tumour growth relative to vehicle only control (shown in Figure 1). The combination of selumetinib (ARRY-142886) plus Example 1 resulted in a further reduction in tumour growth, with evidence of regression in some animals.

Combination Studies - Cell growth Inhibition

Cell lines and treatments

A549 is a human non small cell lung cancer line carrying an oncogenic mutation in the KRAS gene (G12S). H2122 is a human non small cell lung cancer line carrying an oncogenic mutation in the KRAS gene (G12C). H2009 is a human non small cell lung cancer line carrying an oncogenic mutation in the KRAS gene (G12A). HCT116 is a human colorectal cancer line carrying an oncogenic mutation in the KRAS (G13D) gene. Calu6 is a human non small cell lung cancer line carrying mutation in the KRAS (G13K) gene. All cell lines were obtained from the American Type Culture Collection.

All cell line were maintained at 37°C and 5% C0 ₂ in a humidified atmosphere and grown in RPMI-1640 growth media supplemented with 10% FBS and 2mmol/L glutamine. The identity of all cell lines was confirmed using short tandem repeat analysis as described previously (Davies BR, Greenwood H, Dudley P, et ah Preclinical pharmacology of AZD5363, an inhibitor of AKT: Pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther 11(4):873-87, 2012). Compounds were dissolved in DMSO to a concentration of 10 mmol/L and stored under nitrogen. Determination of cell growth

Cells were seeded in 384-well black, clear bottomed plates (Greiner Bio-One, Stonehouse, UK) at 1,000 to 2,000 cells per well, cultured for 18-24 hours and treated with increasing concentrations of Example 1 and Selumetinib (ARRY-142886) (0 - 10 μιηοΙ/L) in a 6x6 dosing matrix. After 5 days of treatment, live cell number was determined using a Sytox Green endpoint as described previously (Davies BR, Greenwood H, Dudley P, et al: Preclinical pharmacology of AZD5363, an inhibitor of AKT: Pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther 11(4):873-87, 2012). Briefly, Sytox Green nucleic acid dye (Invitrogen) diluted in TBS-EDTA buffer was added to cells at a final concentration of 0.13 μιηοΙ/L and the number of dead cells detected using an Accumen Explorer (TTP Labtech, Melbourn, UK). Cells were then permeabilised by the overnight addition of saponin (0.03% final concentration, diluted in TBS-EDTA buffer) and a total cell count measured. The live cell count was then determined by subtracting the number of dead cells per well from the total number of cells. Pre-dose measurements were made to indicate the number of live cells at the start of the experiment and thus an indication of whether the treatment regimen had resulted in cell death. The data is presented as % growth using the NCI formulas as follows; [(Ti-Tz)/(C-Tz)] x 100 for values for which Ti>/=Tz and [(Ti-Tz)/Tz] x 100 for concentrations for which Ti<Tz where, Tz represents the number of live cells at time zero, C represents the control growth and Ti represents the number of live cells in the presence of each drug regimen. This formula gives a growth percentage from 0% to 200%. 0% to 100% scores are for anti-proliferation, 100% to 200% are for cell killing.

Analysis of combination activity

Combination activity (synergism), across the 6x6 dose matrix, was analysed in Genedata Screenerl2 (Genedata, Basel, Switzerland) using the Loewe dose-additivity model as described previously (Lehar J, Krueger AS, Avery W, et al: Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat Biotechnol

27(7):659-66, 2009 and Rickles RJ, Tarn WF, Giordano TP,3rd, et al: Adenosine A2A and beta-2 adrenergic receptor agonists: Novel selective and synergistic multiple myeloma targets discovered through systematic combination screening. Mol Cancer Ther

11(7):1432-42, 2012). This model of additivity provides a null-reference that is predicted by the expected response if the two agents were the same drug. The 3 -dimensional model surface, predicted from the two single-agent response curves, is subtracted from the experimentally-derived 3 -dimensional dose effect surface to generate a difference volume. This excess matrix volume can be integrated to generate a synergy score. A synergy score cutoff >5 was used to identify combinations of interest in the initial high-throughput screen.

The results (shown in Figures 2-16) demonstrate that Example 1 can inhibit the growth of a panel of cancer cell lines with KRAS mutations as a monotherapy and this effect is synergistically enhanced by treatment with selumetinib. Synergy scores for each cell line are 8 (A549), 22 (H2122), 12 (H2009), 20.5 (HCT116) and 6 (Calu6). The synergy scores above may be a result from a single experiment or an average of two or more independent experiments.

According to a further aspect of the disclosure there is provided a pharmaceutical composition, which comprises a compound of the Formula (I), or a

pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically acceptable diluent or carrier.

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents, granulating and disintegrating agents, binding agents, lubricating agents, preservative agents and antioxidants. A further suitable pharmaceutically acceptable excipient may be a chelating agent. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.

Compositions for oral use may alternatively be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil.

Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, dispersing or wetting agents. The aqueous suspensions may also contain one or more preservatives, anti-oxidants, colouring agents, flavouring agents, and/or sweetening agents.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil or in a mineral oil. The oily suspensions may also contain a thickening agent. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil or a mineral oil or a mixture of any of these. The emulsions may also contain sweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents, and may also contain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent system.

Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient. Dry powder inhalers may also be suitable.

For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, oral administration to humans will generally require, for example, from 1 mg to 2 g of active agent (more suitably from lOOmg to 2g, for example from 250 mg to 1.8g, such as from 500mg to 1.8g, particularly from 500mg to 1.5g, conveniently from 500mg to lg) to be administered compounded with an appropriate and convenient amount of excipients which may vary from about 3 to about 98 percent by weight of the total composition. It will be understood that, if a large dosage is required, multiple dosage forms may be required, for example two or more tablets or capsules, with the dose of active ingredient divided conveniently between them. Typically, unit dosage forms will contain about 10 mg to 0.5 g of a compound of this invention, although a unit dosage form may contain up to lg. Conveniently, a single solid dosage form may contain between 1 and 300mg of active ingredient.

The size of the dose for therapeutic or prophylactic purposes of compounds of the present invention will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

In using compounds of the present invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 1 mg/kg to 100 mg/kg body weight is received, given if required in divided doses. In general, lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 1 mg/kg to 25 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 1 mg/kg to 25 mg/kg body weight will be used. Oral administration is however preferred, particularly in tablet form.

In one aspect of the invention, compounds of the present invention or

pharmaceutically acceptable salts thereof, are administered as tablets comprising lOmg to 500mg of the compound of Formula (I) (or a pharmaceutically acceptable salt thereof), wherein one or more tablets are administered as required to achieve the desired dose.

As stated above, it is known that signalling through ERK causes tumourigenesis by one or more of the effects of mediating proliferation of cancer and other cells, mediating angiogenic events and mediating the motility, migration and invasiveness of cancer cells. We have found that the compounds of the present invention possess potent anti-tumour activity which it is believed is obtained by way of inhibition of ERK that is involved in the signal transduction steps which lead to the proliferation and survival of tumour cells and the invasiveness and migratory ability of metastasising tumour cells. Accordingly, the compounds of the present invention may be of value as anti -tumour agents, in particular as selective inhibitors of the proliferation, survival, motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of tumour growth and survival and to inhibition of metastatic tumour growth. Particularly, the compounds of the present invention may be of value as anti-proliferative and anti -invasive agents in the containment and/or treatment of solid tumour disease. Particularly, the compounds of the present invention may be useful in the prevention or treatment of those tumours which are sensitive to inhibition of ERK and that are involved in the signal transduction steps which lead to the proliferation and survival of tumour cells and the migratory ability and invasiveness of metastasising tumour cells. Further, the compounds of the present invention may be useful in the prevention or treatment of those tumours which are mediated alone or in part by inhibition of ERK, i.e. the compounds may be used to produce an ERK inhibitory effect in a warm-blooded animal in need of such treatment.

According to a further aspect there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use as a medicament in a warm-blooded animal such as man.

According to a further aspect, there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.

According to a further aspect there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and/or treatment of solid tumour disease.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for the production of an anti-proliferative effect in a warm-blooded animal such as man.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the

manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in a warm-blooded animal such as man as an anti- invasive agent in the containment and/or treatment of solid tumour disease.

According to a further aspect there is provided a method for producing an antiproliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a method for producing an anti- invasive effect by the containment and/or treatment of solid tumour disease in a warmblooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect, there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the prevention or treatment of cancer in a warm-blooded animal such as man.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of cancer in a warm-blooded animal such as man.

According to a further aspect there is provided a method for the prevention or treatment of cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect, there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the

manufacture of a medicament for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.

According to a further aspect there is provided a method for the prevention or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

The phrase "effective amount" or "therapeutically-effective amount" means an amount that (i) treats the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition or disorder, (iii) delays or prevents the onset of one or more symptoms of the particular disease, condition or disorder described herein. In the case of cancer, the effective amount may reduce the number of cancer cells; reduce the tumour size; inhibit (eg slow to some extent and preferably stop) infiltration of the cancer cells into peripheral organs; inhibit tumour metastasis; inhibit to some extent tumour growth; and/or relieve to some extent one or more of the symptoms associated with cancer. For cancer therapy, efficacy can be measure by assessing, for example the time to disease progression (TTP) and/or assessing the response rate (RR).

According to a further aspect there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the prevention or treatment of a hyperproliferative disease or disorder modulated by RAS/RAF/MEK/ERK kinases.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the

manufacture of a medicament for use in the prevention or treatment of a hyperproliferative disease or disorder modulated by RAS/RAF/MEK/ERK kinases.

According to a further aspect there is provided a method for the prevention or treatment of a hyperproliferative disease or disorder modulated by RAS/RAF/MEK/ERK kinases which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the prevention or treatment of a hyperproliferative disease or disorder mediated by ERK.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the

manufacture of a medicament for use in the prevention or treatment of a hyperproliferative disease or disorder mediated by ERK. According to a further aspect there is provided a method for the prevention or treatment of a hyperproliferative disease or disorder mediated by ERK which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the prevention or treatment of those tumours which are sensitive to inhibition of ERK.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the

manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of ERK.

According to a further aspect there is provided a method for the prevention or treatment of those tumours which are sensitive to inhibition of ERK which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in providing an inhibitory effect on ERK.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing an inhibitory effect on ERK.

According to a further aspect there is also provided a method for providing an inhibitory effect on ERK which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in providing a selective inhibitory effect on ERK2.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the

manufacture of a medicament for use in providing a selective inhibitory effect on ERK2.

According to a further aspect there is also provided a method for providing a selective inhibitory effect on ERK2 which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

Compounds of Formula (I) may be effective in treating any cancer where the RAS/RAF/MEK/ERK kinase pathway is activated. Examples of cancers which have been reported to have such activation include acute myelogenous leukemia (AML), chronic myelomonocyic leukemia, multiple myeloma, chronic myelogenous leukemia, colorectal cancer (CRC), breast cancer, bladder cancer, head and neck cancer, brain cancer, glioblastoma, neuroblastoma, Non-Hodgkins lymphoma, pancreatic cancer, ovarian cancer, testicular cancer, thyroid cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, melanoma, neurofibromatosis type 1 (NF1), biliary tract.

In one aspect, compounds may be effective in treating a cancer selected from NSCLC, pancreatic, CRC, melanoma, uveal melanoma, paediatric NF1, differentiated thyroid and biliary tract cancer.

In one aspect, compounds may be effective in treating KRAS or BRAF mutant cancers.

In one aspect, compounds may be effective in treating MAPK pathway dependent cancers such as NSCLC, pancreatic and CRC; in some embodiments such cancers are KRAS mutant cancers as described hereinafter.

In another aspect, compounds may be effective in treating BRAF mutant melanoma.

In a further aspect, compounds may be effective in treating a cancer selected from NRAS mutant melanoma, uveal melanoma, paediatric NF1, differentiated thyroid and biliary tract cancer.

According to a further aspect there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of NSCLC, pancreatic, CRC, melanoma, uveal melanoma, paediatric NF1, differentiated thyroid and biliary tract cancers.

According to a further aspect there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of NSCLC, pancreatic and CRC. According to a further aspect there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of BRAF mutant melanoma.

According to a further aspect there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of NRAS mutant melanoma, uveal melanoma, paediatric NF1, differentiated thyroid and biliary tract cancer.

According to a further aspect there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of a cancer mediated by ERK, wherein the cancer has developed resistance to one or more other MAPK pathway inhibitors.

According to a further aspect there is provided a method for treating a cancer selected from NSCLC, pancreatic, CRC, melanoma, uveal melanoma, paediatric NF1, differentiated thyroid and biliary tract cancers, which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a method for treating a cancer selected from NSCLC, pancreatic and CRC, which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a method for treating BRAF mutant melanoma, which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a method for treating a cancer selected from NRAS mutant melanoma, uveal melanoma, paediatric NF1, differentiated thyroid and biliary tract cancer, which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further aspect there is provided a method for treating a cancer mediated by ERK, wherein the cancer has developed resistance to one or more other MAPK pathway inhibitors, which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore. According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the

manufacture of a medicament for use in the treatment of a cancer selected from NSCLC, pancreatic, CRC, melanoma, uveal melanoma, paediatric NF1, differentiated thyroid and biliary tract cancers.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the

manufacture of a medicament for use in the treatment of a cancer selected from NSCLC, pancreatic and CRC.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the

manufacture of a medicament for use in the treatment of BRAF mutant melanoma.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the

manufacture of a medicament for use in the treatment of NRAS mutant melanoma, uveal melanoma, paediatric NF1, differentiated thyroid and biliary tract cancer.

According to a further aspect there is provided the use of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the

manufacture of a medicament for use in the treatment of a cancer mediated by ERK, wherein the cancer has developed resistance to one or more other MAPK pathway inhibitors.

As stated hereinbefore, the in-vivo effects of a compound of the Formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I).

In the above compositions, methods and uses, particular compounds of Formula (I) are the compounds of the Examples, or pharmaceutically acceptable salts thereof. Further illustrative compounds of Formula (I) for use in the above compositions, methods and uses are:

(3 R)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(3 S)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one; (3 S)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((2- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(5)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((2- methyl-2H-l,2,3-triazol-4-yl)methyl)-3,4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one;

7-(5-Methyl-2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2- yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one; and

(3 S)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one.

A further illustrative Example of a compound of formula (I) for use in the above compositions, methods and uses is (3R)-3-Methyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3, 4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one, or a pharmaceutically-acceptable salt thereof.

The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the invention, conventional surgery or

radiotherapy or chemotherapy. In certain embodiments, a compound of formula (I) is combined with another compound which has anti-hyperproliferative properties or that is useful in treating a hyperproliferative disorder. The additional compound may suitably have complementary activites to the compound of formula (I) such that they do not adversely affect each other. In some aspects such combination therapy may prevent or delay inherent or acquired resistance attributable to activation of the RAS/RAF/MEK/ERK pathway observed with MEK inhibition and to prevent or delay inherent or acquired resistance mediated via RAS pathway activation.

In addition to providing improved treatment for a given hyperproliferative disorder, administration of certain combinations may improve the quality of life of a patient compared to the quality of life experienced by the same patient receiving a different treatment. For example, administration of a combination to a patient may provide an improved quality of life compared to the quality of life the same patient would experience if they received only one of the individual agents as therapy. For example, a combined therapy may lower the dose of the therapeutic agents required. The combination may also cause reduced tumour burden and thereby reduce the associated adverse events. Accordingly, in one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an additional anti-tumour substance for the conjoint treatment of cancer.

The anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents :-

(i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii) antihormonal agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;

(iii) inhibitors of growth factor function and their downstream signalling pathways: included are Ab modulators of any growth factor or growth factor receptor targets, reviewed by Stern et al. Critical Reviews in Oncology/Haematology, 2005, 54, ppl 1-29); also included are small molecule inhibitors of such targets, for example kinase inhibitors - examples include the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-EGFR antibody cetuximab [Erbitux, C225] and tyrosine kinase inhibitors including inhibitors of the erbB receptor family, such as epidermal growth factor family receptor (EGFR/erbBl) tyrosine kinase inhibitors such as gefitinib or erlotinib, erbB2 tyrosine kinase inhibitors such as lapatinib, and mixed erbl/2 inhibitors such as afatanib; similar strategies are available for other classes of growth factors and their receptors, for example inhibitors of the hepatocyte growth factor family or their receptors including c-met and ron; inhibitors of the insulin and insulin growth factor family or their receptors (IGFR, IR) inhibitors of the platelet-derived growth factor family or their receptors (PDGFR), and inhibitors of signalling mediated by other receptor tyrosine kinases such as c-kit, AnLK, and CSF-1R;

also included are modulators which target signalling proteins in the wider PI3 -kinase signalling pathway, for example, inhibitors of other PI3-kinase isoforms such as PI3K- β, and ser / thr kinases such as AKT, mTOR, PDK, SGK, PI4K or PIP5K;

also included are inhibitors of serine/threonine kinases not listed above, for example raf inhibitors such as vemurafenib, MEK inhibitors such as selumetinib (AZD6244,

ARRY-142886), cobimetinib or GDC-0623 (see for example WO2015/0832840), Abl inhibitors such as imatinib or nilotinib, Btk inhibitors such as ibrutinib, Syk inhibitors such as fostamatinib, aurora kinase inhibitors (for example AZD1152), inhibitors of other ser/thr kinases such as JAKs, STATs and IRAK4, and cyclin dependent kinase inhibitors;

iv) modulators of DNA damage signalling pathways, for example PARP inhibitors (e.g. Olaparib), ATR inhibitors or ATM inhibitors;

v) modulators of apoptotic and cell death pathways such as Bel family modulators (e.g. ABT-263 / Navitoclax, ABT-199);

(vi) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as sorafenib, axitinib, pazopanib, sunitinib and vandetanib (and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ανβ3 function and angiostatin)];

(vii) vascular damaging agents, such as Combretastatin A4;

(viii) anti-invasion agents, for example c-Src kinase family inhibitors like (dasatinib, L Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase]; (ix) immunotherapy approaches, including for example ex -vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte -macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine -transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. Specific examples include

monoclonal antibodies targeting PD-1 (e.g. BMS-936558 . PDL-1 or CTLA4 (e.g.

ipilimumab and tremelimumab);

(x) Antisense or RNAi based therapies, for example those which are directed to the targets listed.

(xi) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy.

According to this aspect there is provided a combination suitable for use in the treatment of cancer comprising a compound of Formula (I) as defined hereinbefore or a pharmaceutically acceptable salt thereof and another anti-tumour agent, in particular any one of the anti tumour agents listed under (i) - (xi) above. In particular, the anti-tumour agent listed under (i)-(xi) above is the standard of care for the specific cancer to be treated; the person skilled in the art will understand the meaning of "standard of care".

Therefore in a further aspect there is provided a compound of Formula (I) or a

pharmaceutically acceptable salt thereof in combination with another anti -tumour agent, in particular an anti-tumour agent selected from one listed under (i) - (xi) herein above.

According to a further aspect there is provided a pharmaceutical composition which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) - (xi) herein above, in association with a pharmaceutically acceptable diluent or carrier.

According to a further aspect there is provided a pharmaceutical composition which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) - (xi) herein above, in association with a pharmaceutically acceptable diluent or carrier for use in treating cancer.

According to another feature there is provided the use of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti- tumour agent selected from one listed under (i) - (xi) herein above, in the manufacture of a medicament for use in cancer in a warm-blooded animal, such as man.

According to another feature, there is provided a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti -tumour agent selected from one listed under (i) - (xi) herein above.

In a further aspect there is provided a compound of Formula (I) or a

pharmaceutically acceptable salt thereof in combination with another anti-tumour agent, in particular an anti-tumour agent selected from one listed under (i) above.

In a further aspect there is provided a combination suitable for use in the treatment of cancer comprising a compound of Formula (I) as defined hereinbefore or a

pharmaceutically acceptable salt thereof and any one of the anti tumour agents listed under (i) above.

According to a further aspect there is provided a pharmaceutical composition which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) herein above, in association with a pharmaceutically acceptable diluent or carrier.

According to a further aspect there is provided a pharmaceutical composition which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) herein above, in association with a pharmaceutically acceptable diluent or carrier for use in treating cancer.

According to another feature there is provided the use of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti- tumour agent selected from one listed under (i) herein above, in the manufacture of a medicament for use in cancer in a warm-blooded animal, such as man.

According to another feature, there is provided a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti -tumour agent selected from one listed under (i) herein above.

In a further aspect there is provided a compound of Formula (I) or a

pharmaceutically acceptable salt thereof in combination with another anti -tumour agent, in particular an anti-tumour agent selected from one listed under (iii) above.

In a further aspect there is provided a combination suitable for use in the treatment of cancer comprising a compound of Formula (I) as defined hereinbefore or a

pharmaceutically acceptable salt thereof and any one of the anti tumour agents listed under (iii) above.

According to a further aspect there is provided a pharmaceutical composition which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (iii) herein above, in association with a pharmaceutically acceptable diluent or carrier.

According to a further aspect there is provided a pharmaceutical composition which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (iii) herein above, in association with a pharmaceutically acceptable diluent or carrier for use in treating cancer.

According to another feature there is provided the use of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti- tumour agent selected from one listed under (iii) herein above, in the manufacture of a medicament for use in cancer in a warm-blooded animal, such as man.

According to another feature, there is provided a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (iii) herein above.

In one aspect, suitable examples of anti tumour agents listed in (iii) above are those agents which also act on MAPK kinsases, particularly on the RAS-RAF-MEK-ER signaling cascade such as MEK inhibitors.

In a further aspect there is provided a combination suitable for use in the treatment of cancer comprising a compound of Formula (I) as defined hereinbefore or a pharmaceutically acceptable salt thereof and a MEK inhibitor, such as selumetinib

(ARRY-142886).

In one aspect, the above combination of the compound of formula (I) and

selumetinib (ARRY-142886) is suitable for use in the treatment of any cancer dependent on the MAPK pathway, such as NSCLC, pancreatic or CR cancer, optionally in

combination with standard of care therapy.

The combination of a compound of Formula (I) and an anti-tumour agent listedin (iii) above, particularly another agent acting on MAPK kinases, particularly on the RAS- RAF-MEK-ERK signaling cascade such as MEK inhibitors / may be particularly useful in treating tumours with a higher prevalence of mutation in KRAS or BRAF.

Particular combinations of the invention comprise any one of the compounds of the Examples herein (or a pharmaceutically acceptable salt thereof) and a MEK inhibitor such as selumetinib (ARRY-142886) as described hereinabove. Further illustrative examples are individual combinations of a MEK inhibitor such as selumetinib (ARRY-142886) and a compound selected from:

(3R)-3-Methyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5-yl)amino )pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(3 S)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(3 S)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(5)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((2- methyl-2H-l,2,3-triazol-4-yl)methyl)-3,4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one;

7-(5-Methyl-2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2- yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one; and

(3 S)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6- methylpyrimidin-4-yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazi n-l(2H)-one; one or a pharmaceutically-acceptable salt thereof.

A further illustrative example is a combination of selumetinib (ARRY-142886) and (3 R)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one or a

pharmaceutically-acceptable salt thereof. In all of the above combinations, it will be understood that the combination may also be dosed with standard of care treatment, as understood by the skilled person, such as other treatments from (i) to (xi) hereinbefore. In other aspects, suitably the standard of care may be selected from (i) above.

Therefore in a further aspect of the invention, there is provided a triple combination suitable for use in the treatment of cancer

a) a compound of formula (I) or a pharmaceutically-acceptable salt thereof;

b) a compound selected from (iii) above (such as another compound acting on MAPK kinases) or a pharmaceutically-acceptable salt thereof; and

c) standard of care therapy for the cancer to be treated.

Suitably standard of care therapy may be dosed according to its usual dosing regimen, as understood by the skilled person.

According to a further aspect there is provided a kit comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti- tumour agent selected from one listed under (i) - (xi) herein above.

According to a further aspect there is provided a kit comprising:

a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof in a first unit dosage form;

b) an anti-tumour agent selected from one listed under (i) - (xi) herein above in a second unit dosage form; and

c) container means for containing said first and second dosage forms.

According to a further aspect there is provided a kit comprising:

a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof in a first unit dosage form;

b) an anti-tumour agent selected from one listed under (i) - (xi) herein above in a second unit dosage form;

c) container means for containing said first and second dosage forms; and optionally d) instructions for use.

In the above kits, particular compounds of Formula (I) are the compounds of the Examples, or pharmaceutically acceptable salts thereof, for example a compound selected from: (3R)-3-Methyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5^

methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(3 S)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one;

(3 S)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one;

(5)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((2- methyl-2H-l,2,3-triazol-4-yl)methyl)-3,4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one;

7-(5-Methyl-2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2- yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one; and

(3 S)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6- methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one.

A further illustrative compound of the formula (I) for use in the kits described above is {3R)-3-Methyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5-yl)amino )pyrimidin-4-yl)- 2-((6-methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[l,2-a]py razin-l(2H)-one, or a pharmaceutically-acceptable salt thereof.

Herein, where the term "combination" is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention "combination" refers to simultaneous administration. In another aspect of the invention "combination" refers to separate administration. In a further aspect of the invention "combination" refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect.

Although the compounds of the Formula (I) are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit ER . Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.

Personalised Healthcare

Another aspect of the present invention is based on identifying a link between the status of the gene encoding KRAS and susceptibility to treatment with a compound of Formula (I). This therefore provides opportunities, methods and tools for selecting patients for treatment with a compound of Formula (I), particularly cancer patients, and/or avoiding treatment of patients less likely to respond therapeutically to the treatment thus avoiding unnecessary treatment and any side effects that may be associated with such ineffective treatment.

The present invention relates to patient selection tools and methods (including personalised medicine). The selection is based on whether the tumour cells to be treated possess wild-type or mutant KRAS gene. The KRAS gene status can therefore be used as a biomarker of susceptibility to treatment with an ERK inhibitor.

There is a clear need for biomarkers that will enrich for or select patients whose tumours will respond to treatment with an ERK inhibitor, such as a compound of Formula (I). Patient selection biomarkers that identify the patients most likely to respond to an agent are ideal in the treatment of cancer, since they reduce the unnecessary treatment of patients with non-responding tumours to the potential side effects of such agents.

A biomarker can be described as "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention". A biomarker is any identifiable and measurable indicator associated with a particular condition or disease where there is a correlation between the presence or level of the biomarker and some aspect of the condition or disease (including the presence of, the level or changing level of, the type of, the stage of, the susceptibility to the condition or disease, or the responsiveness to a drug used for treating the condition or disease). The correlation may be qualitative, quantitative, or both qualitative and quantitative. Typically a biomarker is a compound, compound fragment or group of compounds. Such compounds may be any compounds found in or produced by an organism, including proteins (and peptides), nucleic acids and other compounds.

Biomarkers may have a predictive power, and as such may be used to predict or detect the presence, level, type or stage of particular conditions or diseases (including the presence or level of particular microorganisms or toxins), the susceptibility (including genetic susceptibility) to particular conditions or diseases, or the response to particular treatments (including drug treatments). It is thought that biomarkers will play an increasingly important role in the future of drug discovery and development, by improving the efficiency of research and development programs. Biomarkers can be used as diagnostic agents, monitors of disease progression, monitors of treatment and predictors of clinical outcome. For example, various biomarker research projects are attempting to identify markers of specific cancers and of specific cardiovascular and immunological diseases. It is believed that the development of new validated biomarkers will lead both to significant reductions in healthcare and drug development costs and to significant improvements in treatment for a wide variety of diseases and conditions.

In order to optimally design clinical trials and to gain the most information from these trials, a biomarker may be required. The marker may be measurable in surrogate and tumour tissues. Ideally these markers will also correlate with efficacy and thus could ultimately be used for patient selection.

Thus, the technical problem underlying this aspect of the present invention is the identification of means for stratification of patients for treatment with a compound of Formula (I). The technical problem is solved by provision of the embodiments

characterized in the claims and/or description herein.

The invention provides a method of determining sensitivity of cells to a compound of Formula (I). The method comprises determining the status of KRAS gene in said cells.

The cells are identified as likely to be sensitive to a compound of Formula I if the cells possess a mutated KRAS gene. Those patients with a mutated KRAS gene are therefore predicted to be particularly susceptible to treatment with a compound of Formula (I). A cell is defined as sensitive to a compound of Formula (I) if it inhibits the increase in cell number in a cell growth assay (either through inhibition of cell proliferation and /or through increased cell death). Methods of the invention are useful for predicting which cells are more likely to respond to a compound of Formula (I) by growth inhibition.

The present invention is further based, in part, on methods that can be used to determine a patient's responsiveness to a compound of Formula (I) including determining whether to administer a compound of Formula (I). Specifically the methods of the present invention include the determination of the gene status of KRAS. The presence of a mutated KRAS gene indicates that the tumour cells are more likely to respond by growth inhibition when contacted with a compound of Formula (I). The KRAS gene status can therefore be used to select patients for treatment with a compound of Formula (I). A sample "representative of the tumour" can be the actual tumour sample isolated, or may be a sample that has been further processed, e.g. a sample of PCR amplified nucleic acid from the tumour sample.

Definitions:

In this Personalised Healthcare section:

"Allele" refers to a particular form of a genetic locus, distinguished from other forms by its particular nucleotide or amino acid sequence.

"Amplification reactions" are nucleic acid reactions which result in specific amplification of target nucleic acids over non-target nucleic acids. The polymerase chain reaction (PCR) is a well known amplification reaction.

"Cancer" is used herein to refer to neoplastic growth arising from cellular transformation to a neoplastic phenotype. Such cellular transformation often involves genetic mutation.

"Gene" is a segment of DNA that contains all the information for the regulated biosynthesis of an RNA product, including a promoter, exons, introns, and other sequence elements which may be located within 5 ' or 3 ' flanking regions (not within the transcribed portions of the gene) that control expression.

"Gene status" refers to whether the gene is wild type or not (i.e. mutant).

"Label" refers to a composition capable of producing a detectable signal indicative of the presence of the target polynucleotide in an assay sample. Suitable labels include radioisotopes, nucleotide chromophores, enzymes, substrates, fluorescent molecules, chemiluminescent moieties, magnetic particles, bioluminescent moieties, and the like. As such, a label is any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means.

"Non-synonymous variation" refers to a variation (variance) in or overlapping the coding sequence of a gene that result in the production of a distinct (altered) polypeptide sequence. These variations may or may not affect protein function and include missense variants (resulting in substitution of one amino acid for another), nonsense variants (resulting in a truncated polypeptide due to generation of a premature stop codon) and insertion/deletion variants.

"Synonymous variation" refers to a variation (variance) in the coding sequence of a gene that does not affect sequence of the encoded polypeptide. These variations may affect protein function indirectly (for example by altering expression of the gene), but, in the absence of evidence to the contrary, are generally assumed to be innocuous.

"Nucleic acid" refers to single stranded or double stranded DNA and RNA molecules including natural nucleic acids found in nature and/or modified, artificial nucleic acids having modified backbones or bases, as are known in the art.

"Primer" refers to a single stranded DNA oligonucleotide sequence capable of acting as a point of initiation for synthesis of a primer extension product which is complementary to the nucleic acid strand to be copied. The length and sequence of the primer must be such that they are able to prime the synthesis of extension products. A typical primer contains at least about 7 nucleotides in length of a sequence substantially complementary to the target sequence, but somewhat longer primers are preferred. Usually primers contain about 15-26 nucleotides, but longer or shorter primers may also be employed.

"Polymorphic site" is a position within a locus at which at least two alternative sequences are found in a population.

"Polymorphism" refers to the sequence variation observed in an individual at a polymorphic site. Polymorphisms include nucleotide substitutions, insertions, deletions and microsatellites and may, but need not, result in detectable differences in gene expression or protein function. In the absence of evidence of an effect on expression or protein function, common polymorphisms, including non-synonomous variants, are generally considered to be included in the definition of wild-type gene sequence. A catalog of human polymorphisms and associated annotation, including validation, observed frequencies, and disease association, is maintained by NCBI (dbSNP:

http ://www.ncbi.nlm.nih. ov/proj ects/SNP/) . Please note that the term "polymorphism" when used in the context of gene sequences should not be confused with the term

"polymorphism" when used in the context of solid state form of a compound, that is the crystalline or amorphous nature of a compound. The skilled person will understand the intended meaning by its context.

"Probe" refers to single stranded sequence-specific oligonucleotides which have a sequence that is exactly complementary to the target sequence of the allele to be detected.

"Response" is defined by measurements taken according to Response Evaluation Criteria in Solid Tumours (RECIST) involving the classification of patients into two main groups: those that show a partial response or stable disease and those that show signs of progressive disease.

"Stringent hybridisation conditions" refers to an overnight incubation at 42°C in a solution comprising 50% formamide, 5x SSC (750 mM NaCI, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5x Denhardt's solution, 10% dextran sulphate, and 20 pg/ml denatured, sheared salmon sperm DNA, followed by washing the filters in O.lx SSC at about 65°C.

"Survival" encompasses a patients' overall survival and progression-free survival.

"Overall survival" (OS) is defined as the time from the initiation of drug administration to death from any cause. "Progression-free survival" (PFS) is defined as the time from the initiation of drug administration to first appearance of progressive disease or death from any cause.

According to one aspect, the invention provides a method for selecting a cancer patient suitable for treatment with a compound of Formula (I), the method comprising;

(a) testing a cancer patient to determine whether the KRAS gene in the patient's tumour is wild type or mutant; and selecting a patient for treatment with a compound of Formula (I) based thereon.

In one embodiment, the status of the KRAS gene in a patient's tumour is determining from a biological sample obtained from said patient In one embodiment the biological sample is a tumour cell containing sample. In one embodiment the biological sample is one that contains tumour DNA, such as a blood sample. According to one aspect of the invention there is provided a method for selecting a patient for treatment with a compound of Formula (I), the method comprising obtaining a sample from a patient that comprises tumour cells or nucleic acid from the tumour cell; determining whether the KRAS gene in the patient's tumour cells is wild type or mutant; and selecting a patient for treatment with a compound of Formula (I) based thereon.

The method may include or exclude the actual patient sample isolation step. Thus, according to one aspect of the invention there is provided a method for selecting a patient for treatment with a compound of Formula (I), the method comprising determining whether the KRAS gene in a tumour cell or nucleic acid containing sample previously isolated from the patient is wild type or mutant; and selecting a patient for treatment with a compound of Formula (I) based thereon. In one embodiment, the patient is selected for treatment with a compound of Formula (I) if the tumour cell has a mutant KRAS gene.

According to another aspect of the invention there is provided a method for predicting a patient's responsiveness to a compound of Formula (I), the method comprising determining whether the KRAS gene in the patient's tumour cells is wild type or mutant and based thereon, predicting a patient's responsiveness to treatment with a compound of Formula (I).

According to another aspect of the invention there is provided a method for determining the likelihood of effectiveness of treatment with a compound of formula I in a human patient affected with cancer comprising: determining whether the KRAS gene(s) in the patient's tumour cells is wild type or mutant and based thereon, predicting a patient's responsiveness to treatment with a compound of Formula (I).

For the purpose of this invention, a gene status of wild-type is meant to indicate normal or appropriate expression of the gene and normal function of the encoded protein. In contrast, mutant status is meant to indicate abnormal or inappropriate gene expression, or expression of a protein with altered function, consistent with the known roles of mutant KRAS in cancer (as described herein). Any number of genetic or epigenetic alterations, including but not limited to mutation, amplification, deletion, genomic rearrangement, or changes in methylation profile, may result in a mutant status. However, if such alterations nevertheless result in appropriate expression of the normal protein, or a functionally equivalent variant, then the gene status is regarded as wild-type. Examples of variants that typically would not result in a functional mutant gene status include synonomous coding variants and common polymorphisms (synonymous or non-synonymous). As discussed below, gene status can be assessed by a functional assay, or it may be inferred from the nature of detected deviations from a reference sequence.

In certain embodiments the wild-type or mutant status of the KRAS gene is determined by the presence or absence of non-synonymous nucleic acid variations in the genes. Observed non-synonymous variations corresponding to known common polymorphisms with no annotated functional effects do not contribute to a gene status of mutant.

KRAS Gene bank accession details: KRAS NM 004985. It will be apparent that the gene and mRNA sequences disclosed for KRAS and the KRAS protein sequence are each a representative sequence. In normal individuals there are two copies of each gene, a maternal and paternal copy, which will likely have some sequence differences, moreover within a population there will exist numerous allelic variants of the gene sequence. Other sequences regarded as wild type include those that possess one or more synonymous changes to the nucleic acid sequence (which changes do not alter the encoded protein sequence), non-synonymous common polymorphisms (e.g. germ-line polymorphisms) which alter the protein sequence but do not affect protein function, and intronic non-splice-site sequence changes.

According to another aspect of the invention there is provided a method for determining the likelihood of effectiveness of treatment with a compound of Formula (I) in a human patient affected with cancer comprising: detecting the presence or absence of at least one non-synonymous nucleic acid variance in the KRAS gene of said patient relative to the wild type gene, wherein the presence of at least one somatic non-synonymous nucleic acid variance in the KRAS gene indicates that treatment with the compound of Formula (I) is likely to be effective.

According to another aspect of the invention there is provided a method for assessing the susceptibility of an individual to treatment with a compound of Formula (I), which method comprises:

(i) determining the non-synonymous mutation status of the KRAS gene in tumour cell nucleic acid from the individual; and,

(ii) determining the likely susceptibility of the individual to treatment with a compound of Formula (I) by reference to the non-synonymous mutation status of the KRAS gene in the tumour cells.

There are numerous techniques available to the person skilled in the art to determine the gene status of KRAS. The gene status can be determined by determination of the nucleic acid sequence. This could be via direct sequencing of the full-length gene or analysis of specific sites within the gene, e.g. commonly mutated sites.

An alternative means for determining whether or not the KRAS gene is wild type or mutant is to assess the function of the transcribed gene. Functional mutation of this KRAS gene produces a protein that has impaired GTP hydrolysis capability. Mutant KRAS persists in an active, GTP-bound state, leading to constitutive and deregulated stimulation of downstream signalling of the pathway in cells, including but not limited to activation of Raf, PI3K and Ral pathways.

The assays to assess the functional status of KRAS variants when expressed in cells include but are not limited to:

(i) increased binding to the Ras binding domain (RBD) of Rafl

(ii) increased levels of phosphorylated ERK1/2, MEK1/2, or Akt;

(iii) increased focus and colony formation of NIH-3T3 cells transfected with the variant of KRAS

Samples

The patient's sample to be tested for the gene status can be any tumour tissue, tumour-cell containing or tumour nucleic acid containing sample obtained or obtainable from the individual. The test sample is conveniently a sample of blood, mouth swab, biopsy, or other body fluid or tissue obtained from an individual. Particular examples include: circulating tumour cells, circulating DNA in the plasma or serum, cells isolated from the ascites fluid of ovarian cancer patients, lung sputum for patients with tumours within the lung, a fine needle aspirate from a breast cancer patient, urine, peripheral blood, a cell scraping, a hair follicle, a skin punch or a buccal sample.

It will be appreciated that the test sample may equally be a nucleic acid sequence corresponding to the sequence in the test sample, that is to say that all or a part of the region in the sample nucleic acid may firstly be amplified using any convenient technique e.g. polymerase chain reaction (PCR), before analysis. The nucleic acid may be genomic DNA or fractionated or whole cell RNA. In particular embodiments the RNA is whole cell RNA and is used directly as the template for labelling a first strand cDNA using random primers or poly A primers. The nucleic acid or protein in the test sample may be extracted from the sample according to standard methodologies (see Green & Sambrook, Eds., Molecular Cloning: A Laboratory Manual, (2012, 4th edition, Vol. 1-3, ISBN

9781936113422), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).

The diagnostic methods of the invention can be undertaken using a sample previously taken from the individual or patient. Such samples may be preserved by freezing or fixed and embedded in formalin-paraffin or other media. Alternatively, a fresh tumour cell containing sample may be obtained and used. The methods of the invention can be applied using cells from any tumour. Suitable tumours for treatment with a compound of Formula (I) have been described hereinbefore.

Methods for Detection of Nucleic Acids

The detection of mutant KRAS nucleic acids can be employed, in the context of the present invention, to predict the response to drug treatment. Since mutations in these genes occur at the DNA level, the methods of the invention can be based on detection of mutations or variances in genomic DNA, as well as transcripts and proteins themselves. It can be desirable to confirm mutations in genomic DNA by analysis of transcripts and/or polypeptides, in order to ensure that the detected mutation is indeed expressed in the subject.

It will be apparent to the person skilled in the art that there are a large number of analytical procedures which may be used to detect the presence or absence of variant nucleotides at one or more positions in a gene. In general, the detection of allelic variation requires a mutation discrimination technique, optionally an amplification reaction (such as one based on polymerase chain reaction) and optionally a signal generation system. There are a multitude of mutation detection techniques available in the art and these may be used in combination with a signal generation system, of which there are numerous available in the art. Many methods for the detection of allelic variation are reviewed by Nollau et al., Clin. Chem., 1997, 43, 1114-1120; Anderson SM. Expert Rev Mol Diagn., 2011, 11, 635- 642; Meyerson M. et al, Nat Rev Genet., 2010, H, 685-696; and in standard textbooks, for example "Laboratory Protocols for Mutation Detection", Ed. by U. Landegren, Oxford University Press, 1996 and "PCR", 2 ^nd Edition by Newton & Graham, BIOS Scientific Publishers Limited, 1997.

As noted above, determining the presence or absence of a particular variance or plurality of variances in the KRAS gene in a patient with cancer can be performed in a variety of ways. Such tests are commonly performed using DNA or RNA collected from biological samples, e.g., tissue biopsies, urine, stool, sputum, blood, cells, tissue scrapings, breast aspirates or other cellular materials, and can be performed by a variety of methods including, but not limited to, PCR, hybridization with allele-specific probes, enzymatic mutation detection, chemical cleavage of mismatches, mass spectrometry or DNA sequencing, including minisequencing. Suitable mutation detection techniques include amplification refractory mutation system (ARMS™), amplification refractory mutation system linear extension (ALEX™), competitive oligonucleotide priming system (COPS), Taqman, Molecular Beacons, restriction fragment length polymorphism (RFLP), and restriction site based PCR and fluorescence resonance energy transfer (FRET) techniques.

In particular embodiments the method employed for determining the nucleotide(s) within a biomarker gene is selected from: allele-specific amplification (allele specific PCR) - such as amplification refractory mutation system (ARMS), sequencing, allelic discrimination assay, hybridisation, restriction fragment length polymorphism (RFLP) or oligonucleotide ligation assay (OLA).

Generation of nucleic acids for analysis from samples generally requires nucleic acid amplification. Many amplification methods rely on an enzymatic chain reaction (such as a polymerase chain reaction, a ligase chain reaction, or a self-sustained sequence replication) or from the replication of all or part of the vector into which it has been cloned. Preferably, the amplification according to the invention is an exponential amplification, as exhibited by for example the polymerase chain reaction.

Many target and signal amplification methods have been described in the literature, for example, general reviews of these methods in Landegren, U. , et al, Science, 1988 242, 229-237 and Lewis, R., Genetic Engineering News 1990, 10, 54-55. These amplification methods can be used in the methods of our invention, and include polymerase chain reaction (PCR), PCR in situ, ligase amplification reaction (LAR), ligase hybridisation, QP bacteriophage replicase, transcription-based amplification system (TAS), genomic amplification with transcript sequencing (GAWTS), nucleic acid sequence-based amplification (NASBA) and in situ hybridisation. Primers suitable for use in various amplification techniques can be prepared according to methods known in the art.

Polymerase Chain Reaction (PCR) PCR is a nucleic acid amplification method described inter alia in U.S. Pat. Nos. 4,683,195 and 4,683,202. PCR consists of repeated cycles of DNA polymerase generated primer extension reactions. The target DNA is heat denatured and two oligonucleotides, which bracket the target sequence on opposite strands of the DNA to be amplified, are hybridised. These oligonucleotides become primers for use with DNA polymerase. The DNA is copied by primer extension to make a second copy of both strands. By repeating the cycle of heat denaturation, primer hybridisation and extension, the target DNA can be amplified a million fold or more in about two to four hours. PCR is a molecular biology tool, which must be used in conjunction with a detection technique to determine the results of amplification. An advantage of PCR is that it increases sensitivity by amplifying the amount of target DNA by 1 million to 1 billion fold in approximately 4 hours. PCR can be used to amplify any known nucleic acid in a diagnostic context (Mok et al, Gvnaecologic Oncology, 1994, 52: 247-252,).

An allele specific amplification technique such as Amplification Refractory Mutation System (ARMS™) (Newton et al, Nucleic Acids Res., 1989, 17, 2503-2516) can also be used to detect single base mutations. Under the appropriate PCR amplification conditions a single base mismatch located at the 3 '-end of the primer is sufficient for preferential amplification of the perfectly matched allele (Newton et al, 1989, supra), allowing the discrimination of closely related species. The basis of an amplification system using the primers described above is that oligonucleotides with a mismatched 3'-residue will not function as primers in the PCR under appropriate conditions. This amplification system allows genotyping solely by inspection of reaction mixtures after agarose gel electrophoresis.

Analysis of amplification products can be performed using any method capable of separating the amplification products according to their size, including automated and manual gel electrophoresis, mass spectrometry, and the like.

The methods of nucleic acid isolation, amplification and analysis are routine for one skilled in the art and examples of protocols can be found, for example, Green & Sambrook, Eds., Molecular Cloning: A Laboratory Manual, (2012, 4th edition, Vol. 1-3, ISBN 9781936113422), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.) Particularly useful protocol source for methods used in PCR amplification is PCR (Basics: From Background to Bench) by M. J. McPherson, S. G. Mailer, R. Beynon, C. Howe, Springer Verlag; 1st edition (October 15, 2000), ISBN: 0387916008.

According to another aspect of the invention there is provided the use of a compound of Formula (I) to treat a cancer patient whose tumour cells have been identified as possessing a mutant KRAS gene.

According to another aspect of the invention there is provided a compound of Formula (I) for treating cancers with tumour cells identified as harbouring mutant KRAS gene. In still further embodiments, the invention relates to pharmaceutical composition comprising a compound of Formula (I) for use in the prevention and treatment of cancer with tumour cells identified as harbouring a mutant KRAS gene.

For all the aspects above, mutant forms of KRAS determined/identified are at all positions across the gene.

In further aspects, compounds of the invention may also be useful in treating BRAF mutant cancers. The information provided above within this personalised Healthcare section for KRAS mutant cancers may analogously be applied to BRAF resistant cancers, other than Gene Bank Accession details. BRAF gene bank accession details:

BRAF NM 004333.

Description of figure

Figure 1 shows Tumour Growth Inhibition by Example 1 in combination with selumetinib (ARRY-142886) in A549 xenograft model.

Figure 2: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) A549 cell line by Example 1 in combination with selumetinib (ARRY-142886). Dose matrix representing percent growth inhibition values taken from the fitted dose response curves.

Figure 3: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) A549 cell line by Example 1 in combination with selumetinib (ARRY-142886). Loewe model of additivity calculated from the monotherapy dose response curves.

Figure 4: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) A549 cell line by Example 1 in combination with selumetinib (ARRY-142886). Excess heatmap (synergy) calculated by subtracting the Loewe model of additivity data from the fitted data.

Figure 5: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) H2122 cell line by Example 1 in combination with selumetinib (ARRY-142886). Dose matrix representing percent growth inhibition values taken from the fitted dose response curves.

Figure 6: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) H2122 cell line by Example 1 in combination with selumetinib (ARRY-142886). Loewe model of additivity calculated from the monotherapy dose response curves. Figure 7: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) H2122 cell line by Example 1 in combination with selumetinib (ARRY-142886). Excess heatmap (synergy) calculated by subtracting the Loewe model of additivity data from the fitted data.

Figure 8: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) H2009 cell line by Example 1 in combination with selumetinib (ARRY-142886). Dose matrix representing percent growth inhibition values taken from the fitted dose response curves.

Figure 9: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) H2009 cell line by Example 1 in combination with selumetinib (ARRY-142886). Loewe model of additivity calculated from the monotherapy dose response curves.

Figure 10: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer

(NSCLC) H2009 cell line by Example 1 in combination with selumetinib (ARRY-142886). Excess heatmap (synergy) calculated by subtracting the Loewe model of additivity data from the fitted data.

Figure 11 : Cell Growth Inhibition in KRAS-mutant Colorectal Cancer (CRC) HCT116 cell line by Example 1 in combination with selumetinib (ARRY-142886). Dose matrix representing percent growth inhibition values taken from the fitted dose response curves. Figure 12: Cell Growth Inhibition in KRAS-mutant Colorectal Cancer (CRC) HCT116 cell line by Example 1 in combination with selumetinib (ARRY-142886). Loewe model of additivity calculated from the monotherapy dose response curves.

Figure 13: Cell Growth Inhibition in KRAS-mutant Colorectal Cancer (CRC) HCT116 cell line by Example 1 in combination with selumetinib (ARRY-142886). Excess heatmap (synergy) calculated by subtracting the Loewe model of additivity data from the fitted data. Figure 14: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer

(NSCLC) Calu6 cell line by Example 1 in combination with selumetinib (ARRY-142886). Dose matrix representing percent growth inhibition values taken from the fitted dose response curves.

Figure 15: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer

(NSCLC) Calu6 cell line by Example 1 in combination with selumetinib (ARRY-142886). Loewe model of additivity calculated from the monotherapy dose response curves. Figure 16: Cell Growth Inhibition in KRAS-mutant Non-Small Cell Lung Cancer

(NSCLC) Calu6 cell line by Example 1 in combination with selumetinib (ARRY-142886). Excess heatmap (synergy) calculated by subtracting the Loewe model of additivity data from the fitted data.

Examples

The invention will now be illustrated in the following Examples in which, generally:

(i) operations were carried out at ambient temperature, i.e. in the range 17 to 25 °C and under an atmosphere of an inert gas such as nitrogen unless otherwise stated;

(ii) evaporations were carried out by rotary evaporation or utilising Genevac equipment or Biotage vlO evaporator in vacuo and work-up procedures were carried out after removal of residual solids by filtration;

(iii) flash chromatography purifications were performed on an

automated Teledyne Isco CombiFlash® Rf or Teledyne Isco CombiFlash®

Companion® using prepacked RediSep Rf Gold™ Silica Columns (20-40 μιη, spherical particles), GraceResolv™ Cartridges (Davisil® silica) or Silicycle cartridges (40 - 63 μιη).

(iv) preparative chromatography was performed on a Gilson prep HPLC instrument with UV collection;

(v) chiral preparative chromatography was performed on a Gilson instrument with UV collection (233 injector / fraction collector, 333 & 334 pumps, 155 UV detector), or an Interchim PuriFlash 4250-250 system or a Novasep LC50 system with Knauer K2501 UV detector;

(vi) yields, where present, are not necessarily the maximum attainable;

(vii) in general, the structures of end-products of the Formula I were confirmed by nuclear magnetic resonance (NMR) spectroscopy; NMR chemical shift values were measured on the delta scale [proton magnetic resonance spectra were determined using a Bruker Avance 500 (500 MHz) or Bruker Avance 400 (400 MHz) instrument];

measurements were taken at ambient temperature unless otherwise specified; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublet; dt, doublet of triplets; bs, broad signal (viii) in general, end-products of the Formula I were also characterised by mass spectroscopy following liquid chromatography (LCMS or UPLC); UPLC was carried out using a Waters UPLC fitted with Waters SQ mass spectrometer (Column temp 40, UV = 220-300nm, Mass Spec = ESI with positive/negative switching) at a flow rate of lml/min using a solvent system of 97% A + 3% B to 3% A to 97% B over 1.50mins (total runtime with equilibration back to starting conditions etc 1.70min), where A = 0.1% formic acid in water (for acid work) or 0.1% ammonia in water (for base work) B = acetonitrile. For acid analysis the column used was Waters Acquity HSS T3 1.8μιη 2.1 x50 mm, for base analysis the column used was Waters Acquity BEH 1.7μιη 2.1x50mm; LCMS was carried out using a Waters Alliance HT (2795) fitted with a Waters ZQ ESCi mass spectrometer and a Phenomenex Gemini -NX (50x2. lmm 5μιη) column at a flow rate of 1.lml/min 95 %A to 95 %B over 4 min with a 0.5 min hold. The modifier is kept at a constant 5% C (50:50 acetonitrile: water 0.1% formic acid) or D (50:50 acetonitrile: water 0.1% ammonium hydroxide (0.88 SG) depending on whether it is an acidic or basic method.

(ix) ion exchange purification was generally performed using a SCX-2 (Biotage, Propylsulfonic acid functionalized silica. Manufactured using a trifunctional silane. Non end-capped) cartridge.

(x) intermediate purity was assessed by thin layer chromatographic, mass spectral, HPLC (high performance liquid chromatography) and/or NMR analysis;

(xi) the following abbreviations have been used:- aq. Aqueous

AlMe ₃ trimethyl aluminium

Boc tert-Butoxycarbonyl

n-BuLi n-butyl lithium

tBuOH tert-butanol

CDC1 deutero-chloroform

Cone. Concentrated

Cs ₂ C0 ₃ cesium carbonate

DCM dichloromethane

DEA diethylamine

DIPEA diisopropylethylamine DMA N,N-dimethylacetamide

DMAP dimethylaminopyridine

DMF dimethyl fo rm am ide

DMSO dimethyl sulphoxide (when used in NMR experiment DMSO is D ₆ -DMSO)

EtOH ethanol

EtOAc ethyl acetate

MeOH methanol

MeLi methyl lithium

Na ₂ S0 ₄ sodium sulfate

RM reaction mixture

rt/RT room temperature

sat. saturated

sol. Solution

SM starting material

THF tetrahydrofuran

Tos tosyl

3rd Generation BrettPhos precatalyst is [(2-Di-cyclohexylphosphino-3,6-dimethoxy- 2',4',6'- triisopropyl-1 , 1 '-biphenyl)-2-(2'-amino-l , 1 ' -biphenyl)]palladium(II)

methanesulfonate

Example 1

(3R)-3-Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6- methylp yridin-2- yl)methyl)-3 ,4-dihydrop yrrolo Γ 1 ,2-alpyrazin- 1 (2H)- one

(3R)-7-(2-Chloro-5-methylpyrimidin-4-yl)-3-methyl-2-((6-meth ylpyridin-2-yl)methyl)- 3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (133 mg, 0.35 mmol), 1 -methyl- lH-pyrazol- 5-amine (37.2 mg, 0.38 mmol) and cesium carbonate (250 mg, 0.77 mmol) were suspended in tert-butanol (3 mL) and de-gassed for 5 minutes, then BrettPhos 3rd generation pre- catalyst (15.79 mg, 0.02 mmol) was added. The reaction was heated to 83 °C for 2 hours. The reaction mixture was diluted with EtOAc (30 mL), and washed with brine (30 mL). The aqueous layer was extracted with DCM (2 x 30 mL) then combined organics were evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0.5 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (3R)-3-methyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3, 4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one (118 mg, 77 %) as a yellow solid. ^! H NMR (400 MHz, DMSO, 30 °C) 1.15 (3H, d), 2.32 (3H, s), 2.46 (3H, s), 3.68 (3H, s), 3.96 (1H, dt), 4.20 (1H, dd), 4.29 (1H, d), 4.36 (1H, dd), 5.13 (1H, d), 6.26 (1H, d), 7.15 (2H, dd), 7.25 (1H, d), 7.32 (1H, d), 7.61 - 7.68 (2H, m), 8.23 (1H, s), 9.06 (1H, s). m/z: ES+ [M+H]+ 443

A methanesulfonic acid salt of this compound may be made as follows:

A sample of (3R)-3-methyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5-yl)amino )pyrimidin-4- yl)-2-((6-methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one (3.5 g) was dissolved in DCM followed by addition of 0.5 M HC1. The organic layer was separated and discarded. The acidic layer was neutralised with sodium hydrogen carbonate, then extracted with DCM. The organic extract was dried (Na ₂ S04), filtered and evaporated to dryness.

This was dissolved with acetone (60 mL) and a solution of methanesulfonic acid (0.565 mL, 8.70 mmol) in acetone (40 mL) was added to the stirring mixture, to precipitate a solid. The mixture was refluxed (not all of the solids dissolved) then allowed to cool and the solid filtered to give (3R)-3-methyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3, 4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one (2.70 g, 55.5 %) as the methane sulphonic acid salt, NMR analysis suggest this to be a 1 : 1.8 ratio of substrate to methanesulfonic acid. tert-Butyl (4R)-4-methyl-2-oxido-oxathiazolidin-2-ium-3-carboxylate

To a solution of lH-imidazole (155 g, 2282.77 mmol) and triethylamine (182 ml, 1312.59 mmol) in dichloromethane (2097 ml) at -50°C was added thionyl chloride (47.9 ml, 656.30 mmol) dropwise (exothermic, keeping T < -40°C). The mixture was stirred for 5 minutes while cooling to -60C and a solution of (R)-tert-butyl l-hydroxypropan-2-ylcarbamate (Sigma-Aldrich) (100 g, 570.69 mmol) in dichloromethane (2097 ml) was added dropwise over 6 hours (dropping funnel). Stirred while warming to RT overnight. Water was added (2000 mL) and the phases separated. The aqueous was further extracted into

dichloromethane (1000 mL). The combined organics were washed with water (800 mL), saturated brine (500 mL), dried over MgS0 ₄ , filtered and concentrated in vacuo to give tert-butyl (4R)-4-methyl-2-oxido-oxathiazolidin-2-ium-3-carboxylate (126 g, 569 mmol, 100 %) as a pale oil.

(4R)-4-Methyl-2,2-dioxo-oxathiazolidine-3-carboxylate

Ruthenium(III) chloride hydrate (0.087 g, 0.39 mmol) was added to a stirred mixture of tert-butyl (4R)-4-methyl-2-oxido-oxathiazolidin-2-ium-3-carboxylate (126 g, 552.35 mmol) in acetonitrile (1088 ml) and water (586 ml) at room temperature, followed by portionwise addition of sodium periodate (130 g, 607.58 mmol). Endothermic initially to 12°C (dissolution of periodate) then significant exotherm to 27 °C as a white solid was precipitated. This exotherm was controlled with external cooling. The biphasic mixture was stirred at room temperature for 2.5 hours. The mixture was diluted into water (1000 mL) and extracted into (3 x 1000 mL) ethyl acetate. The combined organics were washed with water, brine, dried over MgS0 ₄ , filtered and concentrated in vacuo to give tert-butyl (4R)-4-methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (112 g, 85 %) as a white solid. ¾ NMR (400 MHz, CDCb, 30 °C) 4.59 (1H, dd), 4.35 (1H, pd), 4.12 (1H, dd), 1.49 (9H, s), 1.44 (3H, d).

1 -tert-Butyl 2-methyl 4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-pyrrole- 1 ,2- dicarboxylate

4,4,4 ^* ,4 ^* ,5,5,5 ^* ,5 ^* -Octamethyl-2,2 ^, -bi(l,3,2-dioxaborolane) (59.2 g, 233.08 mmol), (1,5- cyclooctadiene)(methoxy) iridium (I) dimer (1.177 g, 1.78 mmol) and 4,4'-di-tert-butyl- 2,2'-bipyridine (0.953 g, 3.55 mmol) were placed in a 500 mL three-necked flask, which was purged with nitrogen. Degassed MTBE (500 mL) was added and the mixture was stirred and sonicated until a clear brown solution was obtained. 1 -tert-butyl 2-methyl 1H- pyrrole-l,2-dicarboxylate (Sigma Aldrich) (50 g, 221.98 mmol) was added and flushed with nitrogen. The solution was heated in a microwave reactor at 80 °C for 20 minutes. The mixtures were combined and evaporated. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% DCM in heptane to afford 1 -tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-l , 3, 2-dioxaborolan-2-yl)-l H-pyrrole- 1 ,2-dicarboxylate (59.3g, 76%) as a white crystalline solid. 1 -tert-Butyl 2-methyl 4-(2-chloro-5-methylpyrimidin-4-v0- 1 H-pyrrole- 1 ,2-dicarboxylate

Pd(PPli3)4 (0.982 g, 0.85 mmol) was added to a de-gassed solution of 2,4-dichloro-5- methylpyrimidine (Sigma-Aldrich) (4.62 g, 28.33 mmol), 1-tert-butyl 2-methyl 4-(4,4,5,5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)-l H-pyrrole- 1 ,2-dicarboxylate (9.95 g, 28.33 mmol) and potassium phosphate (18.04 g, 84.99 mmol) in dioxane (120 ml) and water (30 ml) at 22 °C under nitrogen. The resulting solution was stirred at 80 °C for 4 hours. The reaction mixture was concentrated and diluted with EtOAc (150 mL), and brine (100 mL). The layers were partitioned, then the aqueous extracted with further EtOAC (2 x 150 mL). Combined organics were evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution solvent 5-50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 1-tert-butyl 2-methyl 4-(2-chloro-5- methylpyrimidin-4-yl)-l H-pyrrole- 1 ,2-dicarboxylate (6.36 g, 63.8 %) as a white solid. ^ NMR ^OO MHz, DMSO, 30 °C) 1.56 (9H, s), 2.41 - 2.47 (3H, m), 3.83 (3H, s), 7.39 (1H, d), 8.01 (1H, d), 8.61 (1H, d). m/z: ES+ [M-Boc] 252

Meth l 4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate

Hydrogen chloride (4M in dioxane) (43.6 mL, 174.25 mmol) was added to 1-tert-butyl 2- methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrole-l,2-dicarboxy late (6.13 g, 17.43 mmol) in methanol (40 mL) at 22 °C. The resulting mixture was stirred at 22 °C for 18 hours. The solid was collected by filtration, washed with diethyl ether, and air dried to yield methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate (4.21 g, 96 %) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 2.40 (3H, s), 3.79 (3H, s),

7.37 (1H, d), 7.70 (1H, d), 8.46 (1H, s). m/z: ES+ [M+H]+ 252

(R)-Methyl l-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2-chloro-5-methy lpyrimidin-4- yP- 1 H-pyrrole-2-carboxylate

(R)-tert-Butyl 4-methyl-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (2.206 g,

9.30 mmol) was added to methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrole-2- carboxylate (1.8 g, 7.15 mmol), potassium carbonate (8.90 g, 64.37 mmol) and

1,4,7,10,13,16-hexaoxacyclooctadecane (0.473 g, 1.79 mmol) in 1,4-dioxane (100 mL) at 22 °C under nitrogen. The resulting suspension was stirred at 50 °C for 20 hours. The reaction mixture was diluted with EtOAc (200 mL), and washed with water. The organic layer was washed with brine (150 mL), then was dried over Na2S04, filtered and evaporated to afford (R)-methyl l-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2-chloro-5- methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate (4.85 g, 166 %) as a white solid.

lH NMR (400 MHz, DMSO, 30 °C) 1.08 (3H, d), 1.16 (9H, s), 2.42 (3H, s), 3.80 (3H, s), 3.83 - 4.02 (2H, m), 4.60 (1H, dd), 6.77 (1H, d), 7.43 (1H, s), 7.81 (1H, s), 8.51 (1H, s). m/z: ES+ [M+H]+ 409. (R)-Methyl l-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyr role-2- carboxylate

Hydrogen chloride, 4.0M in dioxane (17.79 mL, 71.17 mmol) was added to (R)-methyl 1- (2-((tert-butoxycarbonyl)amino)propyl)-4-(2-chloro-5 -methylpyrimidin-4-yl)- 1 H-pyrrole- 2-carboxylate (4.85, 7.12 mmol) in DCM (50 mL) at 22 °C. The resulting mixture was stirred at 22 °C for 2 hours. The mixture was filtered and solids were treated with sodium carbonate solution (150 mL). The solution was extracted with DCM (3 x 150 mL). The combined organic extracts were evaporated to afford (R)-methyl l-(2-aminopropyl)-4-(2- chloro-5-methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate (1.99 g, 91 %) as a white solid. 'H NMR (400 MHz, DMSO, 30 °C) 0.95 (3H, d), 1.39 (2H, s), 2.42 (3H, s), 3.08 (1H, h), 3.78 (3H, s), 4.11 (1H, dd), 4.34 (1H, dd), 7.46 (1H, d), 7.92 (1H, d), 8.50 (1H, s). m/z: ES+ [M+H]+ 309.

(3R)-7-(2-Chloro-5-methylpyrimidin-4-yl)-3-methyl-3^-dihv dropyrrolori,2-a1pyrazin- l(2H -one

Ammonia, 7.0M in methanol (92 mL, 644.51 mmol) was added to (R)-methyl l-(2- aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrole- 2-carboxylate (1.99 g, 6.45 mmol) in DCM (20 mL) at 22 °C. The resulting mixture was stirred at 22 °C for 20 hours. The resulting suspension was concentrated to yield (R)-7-(2-chloro-5-methylpyrimidin-4- yl)-3-methyl-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (1.89 g, 106 %) as a yellow solid. ^! H NMR (400 MHz, DMSO, 30 °C) 1.20 (3H, d), 2.42 (3H, s), 3.83 - 3.93 (2H, m), 4.25 - 4.35 (1H, m), 7.23 (1H, d), 7.81 (1H, d), 7.92 (1H, s), 8.49 (1H, s). m/z: ES+

[M+H]+ 277.

(3R)-7-(2-Chloro-5-methylpyrimidin-4-yl)-3-methyl-2-((6-m ethylpyridin-2-v

3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one

Sodium hydride (20 mg, 0.50 mmol) was added to (R)-7-(2-chloro-5-methylpyrimidin-4- yl)-3-methyl-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (125 mg, 0.45 mmol) in DMF (3 mL) at 22 °C under nitrogen. The resulting suspension was stirred at RT for 30 minutes Sodium hydride (20 mg, 0.50 mmol) was added to 2-(chloromethyl)-6-methylpyridine hydrochloride (88 mg, 0.50 mmol) and the resulting solution stirred at RT for 10 minutes, then added to the main reaction mixture. The resulting solution was stirred at 22 °C for 18 hours. The reaction mixture was quenched with saturated NH ₄ C1 (20 mL) and then the mixture extracted with DCM (2 x 20 mL) and evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0.5 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford (R)-7-(2- chloro-5 -methylpyrimidin-4-yl)-3 -methyl-2-((6-methylpyridin-2-yl)methyl)-3 ,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (135 mg, 78 %) as a white solid. ¾ NMR (400 MHz, DMSO, 30 °C) 1.15 (3H, d), 2.41 - 2.45 (3H, m), 2.46 (3H, s), 3.98 (1H, ddd), 4.23 (1H, dd), 4.30 (1H, d), 4.38 (1H, dd), 5.13 (1H, d), 7.09 - 7.19 (2H, m), 7.28 (1H, d), 7.64 (1H, t), 7.86 (1H, d), 8.50 (1H, d). m/z: ES+ [M+H]+ 382. Example 2

(3 S)-3-Methyl-7-(5 -methyl -2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6- meth lpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-alpyrazin- 1 (2H)- one

(3S)-7-(2-Chloro-5-methylpyrimidin-4-yl)-3-methyl-2-((6-meth ylpyridin-2-yl)methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (89 mg, 0.21 mmol), 1 -methyl- lH-pyrazol-5- amine (23.90 mg, 0.25 mmol) and cesium carbonate (147 mg, 0.45 mmol) were suspended in tert-butanol (3 mL) and de-gassed for 5 minutes, then BrettPhos 3rd generation pre- catalyst (9.30 mg, 10.26 μιηοΐ) was added. The reaction was sealed in a microwave tube and heated to 100 °C in the microwave for 1 hour. The reaction mixture was diluted with DCM (30 mL), and washed with brine (30 mL). The aqueous layer was extracted with DCM (2 x 30 mL) then combined organics were evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0.5 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (S)-3-methyl-7-(5- methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2- yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (76 mg, 84 %) as a white solid. ^! H

NMR (400 MHz, DMSO, 30 °C) 1.15 (3H, d), 2.32 (3H, s), 2.46 (3H, s), 3.68 (3H, s), 3.94 - 3.98 (1H, m), 4.20 (1H, dd), 4.29 (1H, d), 4.36 (1H, dd), 5.13 (1H, d), 6.26 (1H, d), 7.15 (2H, dd), 7.25 (1H, d), 7.32 (1H, d), 7.61 - 7.67 (2H, m), 8.23 (1H, s), 9.06 (1H, s). m/z: ES+ [M+H]+ 443. tert-Butyl (4S)-4-methyl-2-oxido-oxathiazolidin-2-ium-3-carboxylate

To a solution of lH-imidazole (106 g, 1553.20 mmol) and triethylamine (124 ml, 893.09 mmol) in anhydrous dichloromethane (1427 ml) at -55 °C was added thionyl chloride (32.6 ml, 446.54 mmol) dropwise (exothermic, keeping T < -40 °C). The mixture was stirred for 5 minutes while cooling to -60 °C and a solution of (S)-tert-butyl 1- hydroxypropan-2-ylcarbamate (Sigma-Aldrich) (68.04 g, 388.30 mmol) in anhydrous dichloromethane (1427 mL) was added dropwise over 3.5 hours (dropping funnel). Stirred while warming to RT overnight. Water was added (750 mL) and the phases separated. The aqueous was further extracted into dichloromethane (500 mL). The combined organics were washed with water (250 mL), saturated brine (250 mL), dried over MgS0 ₄ , filtered and concentrated in vacuo to give tert-butyl (4S)-4-methyl-2-oxido-oxathiazolidin-2-ium- 3-carboxylate (87.3 g, 395 mmol, 100 %) as a pale oil. ^! H NMR (400 MHz, CDCb, 30 °C) 1.50 (3H, d), 4.29 (1H, d), 4.68 (1H, t), 4.77 (1H, dd).

(4S -tert-Butyl 4-methyl- 1 ,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

Ruthenium(III) chloride hydrate (0.062 g, 0.28 mmol) was added to a stirred mixture of tert-butyl (4S)-4-methyl-2-oxido-oxathiazolidin-2-ium-3-carboxylate (87.36 g, 394.80 mmol) in acetonitrile (778 ml) and water (419 ml) at 15 °C, followed by portionwise addition of sodium periodate (93 g, 434.29 mmol). The biphasic mixture was stirred at 20 °C for 1 hour. Water (600 mL) was added and the mixture extracted into ethyl acetate (3 x 600 mL). The combined organics were washed with water (500 mL), brine (250 mL), dried over MgS0 ₄ , filtered and concentrated in vacuo to give (S)-tert-butyl 4-methyl- 1,2,3 - oxathiazolidine-3-carboxylate 2,2-dioxide (84.3 g, 355 mmol, 90 %) as an off-white solid.

¾ NMR (400 MHz, CDCb, 30 °C) 1.51 (3H, d), 1.55 (9H, s), 4.19 (1H, dd), 4.37 - 4.46 (1H, m), 4.66 (1H, dd). (S)-M ethyl l-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2-chloro-5-methy l yrimidin-4- vD- 1 H-pyrrole-2-carboxylate

(S)-tert-Butyl 4-methyl-l ,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.501 g, 2.11 mmol) was added to methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrole-2- carboxylate (0.43 g, 1.62 mmol), potassium carbonate (2.019 g, 14.61 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (0.107 g, 0.41 mmol) in 1,4-dioxane (20 mL) at 22 °C under nitrogen. The resulting suspension was stirred at 50 °C for 20 hours. The mixture was diluted with water (50 mL) and the product extracted with EtOAc (3 x 70 mL). Organics were dried (Na ₂ S04) and concentrated to yield (S)-methyl l-(2-((tert- butoxycarbonyl)amino)propyl)-4-(2-chloro-5 -methylpyrimidin-4-yl)- 1 H-pyrrole-2- carboxylate (0.648 g, 98 %) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 1.08 (3H, d), 1.16 (9H, s), 2.42 (3H, s), 3.80 (3H, s), 3.84 - 4.01 (2H, m), 4.60 (1H, dd), 6.77 (1H, d), 7.43 (1H, s), 7.81 (1H, s), 8.51 (1H, s). m/z: ES+ [M+H]+ 409.

(S)-M ethyl l-(2-aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyr role-2- carboxylate

NH ₂ Hydrogen chloride, 4.0M in dioxane (7.88 mL, 31.50 mmol) was added to (S)-methyl l-(2- ((tert-butoxycarbonyl)amino)propyl)-4-(2-chloro-5-methylpyri midin-4-yl)-lH-pyrrole-2- carboxylate (0.644 g, 1.58 mmol) in methanol (5 mL) at 22 °C. The resulting mixture was stirred at 22 °C for 2 hours then concentrated in vacuo. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 1M NH3/MeOH to give (S)-methyl l-(2-aminopropyl)-4-(2-chloro-5- methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate as a crude product, m/z: ES+ [M+H]+

309.

(3S)-7-(2-Chloro-5-methylpyrimidin-4-yl)-3-methyl-3^-dihv dropyrrolori,2-a1pyrazin- l(2H -one

Ammonia, 7.0M in methanol (22.49 mL, 157.40 mmol) was added to (S)-methyl l-(2- aminopropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrole- 2-carboxylate (0.486 g, 1.57 mmol) in DCM (4 mL) at 22 °C. The resulting mixture was stirred at 22 °C for 5 hours. The resulting suspension was filtered, and the solid was dried under vacuum to yield (3S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3-methyl-3,4-dihydr opyrrolo[l,2-a]pyrazin- l(2H)-one (342 mg, 1.236 mmol, 78.5 %) as a yellow solid. ^l H NMR (400 MHz, DMSO, 30 °C) 1.20 (3H, d), 2.4 - 2.45 (3H, m), 3.84 - 3.92 (2H, m), 4.25 - 4.34 (1H, m), 7.23 (1H, d), 7.81 (1H, d), 7.92 (1H, s), 8.49 (1H, d). m/z: ES+ [M+H]+ 277. (3 S)-7-(2-Chloro-5-methyl yrimidin-4-yl)-3 -methyl -2-((6-methylpyridin-2-yl)methyl)-3,,4- dihydropyrrolor 1 ,2-alpyrazin- 1 (2H)-one

Sodium hydride (12.56 mg, 0.31 mmol) was added to (S)-7-(2-chloro-5-methylpyrimidin- 4-yl)-3-methyl-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (79 mg, 0.29 mmol) in DMF (3 mL) at 22 °C under nitrogen. The resulting suspension was stirred at RT for 30 minutes, then 2-(chloromethyl)-6-methylpyridine (0.038 mL, 0.31 mmol) was added. The resulting solution was stirred at 22 °C for 3 hours. The reaction mixture was quenched with saturated NH ₄ C1 (20 mL) and then the mixture extracted with DCM (2 x 20 mL) and evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0.5 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford (3S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3-methyl-2-((6- methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin- l(2H)-one (91 mg, 83 %) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 1.15 (3H, d), 2.43 (3H, s), 2.46 (3H, s), 3.96 - 4.00 (1H, m), 4.23 (1H, dd), 4.30 (1H, d), 4.38 (1H, dd), 5.13 (1H, d), 7.12 - 7.18 (2H, m), 7.28 (1H, d), 7.65 (1H, t), 7.86 (1H, d), 8.50 (1H, s). m/z: ES+ [M+H]+ 382.

Example 3a (1 ^st eluted isomer)

(3S)-3-(methox ethyl)-7-r5-methyl-2-r(2-methylpyrazol-3-yl)aminolpyrimidin- 4-yll-2- r(6-methyl-2- yridyl)methyll-3,4-dihvdropyrrolon,2-alpyrazin-l-one (1 ^st eluted isomer)

and Example 3b (2 ^nd eluted isomer)

(3R)-3-(methox ethyl)-7-r5-methyl-2 (2-m

[(6-meth l-2-pyridyl)methyll-3^-dihydropyrrolo[l,2-alpyrazin-l-one (2 ^nd eluted isomer)

7-(2-Chloro-5-methylpyrimidin-4-yl)-3-(methoxymethyl)-2-((6- methylpyridin-2- yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (620 mg, 1.51 mmol), 1-methyl- lH-pyrazol-5 -amine (307 mg, 3.16 mmol) and cesium carbonate (1569 mg, 4.82 mmol) were suspended in anhydrous, deoxygenated tert-butanol (10 mL), then BrettPhos 3rd generation pre-catalyst (68.2 mg, 0.08 mmol) was added. The reaction was heated to 83 °C for 4 hours. The reaction mixture was evaporated to dryness, dissolved in dichloromethane and methanol and loaded onto an SCX-2 column, washed with methanol. Then product was eluted with 7N ammonia in methanol and evaporation gave a brown oil which was dissolved in dichloromethane and suction columned eluting with 0-2-5-10%

methanol/dichloromethane. Evaporation gave 3-(methoxymethyl)-7-(5-methyl-2-((l- methyl-lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6-methylpyr idin-2-yl)methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (467 mg, 66 %) as a yellow foam. The racemic product was separated by preparative HPLC (Chiral Technologies IA column, 20 μιη silica, 50 mm diameter, 250 mm length), EtOH 100%. 1 ^st eluted peak fractions were evaporated to give (3S)-3-(methoxymethyl)-7-[5-methyl-2-[(2-methylpyrazol-3- yl)amino]pyrimidin-4-yl] -2-[(6-methyl-2-pyridyl)methyl] -3 ,4-dihydropyrrolo [ 1 ,2- a]pyrazin-l-one (214 mg) as a white solid. ^l H NMR (400 MHz, DMSO, 30 °C) 2.32 (3H, s), 2.46 (3H, s), 3.22 (3H, s), 3.30 (1H, s), 3.38 - 3.49 (1H, m), 3.69 (3H, s), 4.00 (1H, d), 4.21 - 4.52 (3H, m), 5.17 (1H, d), 6.26 (1H, d), 7.16 (2H, dd), 7.24 (1H, d), 7.33 (1H, d), 7.57 - 7.74 (2H, m), 8.16 - 8.32 (1H, m), 9.07 (1H, s). m/z: ES+ [M+H]+ 473.

2 ^nd eluted peak fractions were evaporated to give (3R)-3-(methoxymethyl)-7-[5-methyl-2- [(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-2-[(6-methyl-2- pyridyl)methyl]-3,4- dihydropyrrolo[l,2-a]pyrazin-l-one (213 mg) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 2.32 (3H, s), 2.46 (3H, s), 3.22 (3H, s), 3.30 (1H, s), 3.38 - 3.49 (1H, m), 3.69 (3H, s), 4.00 (1H, d), 4.21 - 4.52 (3H, m), 5.17 (1H, d), 6.26 (1H, d), 7.16 (2H, dd), 7.24 (1H, d), 7.33 (1H, d), 7.57 - 7.74 (2H, m), 8.16 - 8.32 (1H, m), 9.07 (1H, s). m/z: ES+ [M+H]+ 473. tert-Butyl ( 1 -hydroxy- 3 -methoxypropan-2-yl)carbamate

To a solution of 2-((tert-butoxycarbonyl)amino)-3-methoxypropanoic acid (9.99 g, 45.57 mmol) and 4-methylmorpholine (5.51 mL, 50.12 mmol) in THF (50 mL) at -5 °C under nitrogen was added dropwise isobutyl carbonochloridate (6.50 mL, 50.12 mmol) and the RM stirred at this temp for 30 mins. Then solid sodium tetrahydroborate (5.34 g, 141.26 mmol) was added portionwise, water (20 mL) was then added dropwise and the RM stirred at -5 °C for 30 mins. The reaction was then extracted with ethyl acetate (200 mL), the organic layer washed with sat brine (200 mL), dried over anhydrous sodium sulphate and evaporated to give a yellow oil. The product was purified by a suction column eluting with 0-10% diethylether/dichloromethane then 50-100% diethylether/dichloromethane. Pure fractions were combined and evaporated to give tert-butyl (l-hydroxy-3-methoxypropan-2- yl)carbamate (7.50 g, 80 %) as an oil. ^! H NMR (400 MHz, CDCb, 30 °C) 1.45 (9H, s), 2.64 (1H, s), 3.36 (3H, s), 3.55 (2H, td), 3.65 - 3.72 (1H, m), 3.79 (2H, dd), 5.15 (1H, s). tert-Butyl 4-(methoxymethvD- 1 ,2,3-oxathiazolidine-3-carboxylate 2-oxide

O To a solution of sulfurous dichloride (1.166 mL, 16.08 mmol) in dichloromethane (75 mL) at -78 °C under nitrogen was added triethylamine (4.48 mL, 32.16 mmol) and 1H- imidazole (3.98 g, 58.46 mmol). The reaction was stired for 20 mins at -78°C. Then tert- butyl (l-hydroxy-3-methoxypropan-2-yl)carbamate (3 g, 14.62 mmol) dissolved in dichloromethane (20 mL) was added dropwise over 10 mins. The resulting mixture was stirred at -78°C for 3 hours. RM was then warmed to room temperature and quenched with water. Extracted with DCM, washed wth sat brine and dried by passing through a phase seperator cartridge. Evaporation at low temperature gave an oil, which was dissolved in dichloromethane and suction columned eluting with 0-10%

diethylether/dichloromethane. Pure fractions were evaporated at low temp to give a clear oil. tert-Butyl 4-(methoxymethyl)-l,2,3-oxathiazolidine-3-carboxylate 2-oxide (3.76 g, 102 %) ¾ NMR (400 MHz, CDCls, 30 °C) 1.53 (9H, s), 3.28 (0.5H, d), 3.38 (3H, d), 3.57 (0.5H, t), 3.86 (1H, dd), 4.18 (1H, s), 4.6 - 4.86 (1H, m), 4.95 (1H, dd). tert-Butyl 4-(methoxymethvD- 1 ,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

To a solution of tert-butyl 4-(methoxymethyl)-l,2,3-oxathiazolidine-3-carboxylate 2-oxide (3.76 g, 14.96 mmol) in acetonitrile (30 mL) at 0 °C under nitrogen was added

sequentially sodium periodate (3.52 g, 16.46 mmol), ruthenium(III) chloride hydrate (0.337 g, 1.50 mmol) and water (30 mL). The reaction was stirred at 0 °C for 2 hours. Reaction was then diluted with water 30ml and extracted with diethylether (100 mL), washed with saturated brine (100 mL) and dried over anhydrous magnessium sulphate. Evaporation gave tert-butyl 4-(methoxymethyl)-l,2,3-oxathiazolidine-3-carboxylate 2,2- dioxide (3.96 g, 99 %) as an oil. ^l H NMR (400 MHz, CDCI3, 30 °C) 1.56 (9H, s), 3.41 (3H, s), 3.59 (1H, t), 3.66 (1H, dd), 4.26 - 4.44 (1H, m), 4.51 - 4.66 (2H, m). Methyl l-(2-((tert-butoxycarbonyl)amino)-3-methoxypropyl)-4-(2-chlo ro-5- methylp yrimidin-4- yl)- 1 H-pyrrole-2-carboxylate

Potassium carbonate (4.94 g, 35.76 mmol) was added to tert-butyl 4-(methoxymethyl)- l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.593 g, 5.96 mmol), methyl 4-(2-chloro- 5-methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate (1.0 g, 3.97 mmol) and 1,4,7,10,13,16- hexaoxacyclooctadecane (0.263 g, 0.99 mmol) in 1,4-dioxane (50 mL) at 22 °C under nitrogen. The resulting mixture was stirred at 50 °C for 18 hours. Water (200 mL) was added and extracted with diethylether (200 mL). Evaporation afforded methyl l-(2-((tert- butoxycarbonyl)amino)-3-methoxypropyl)-4-(2-chloro-5-methylp yrimidin-4-yl)-lH- pyrrole-2-carboxylate (1.74 g, 100 %) as a colourless gum. m/z: ES+ [M-Boc] 339.

7-(2-Chloro-5-methylpyrimidin-4-yl)-3-(methoxymethyl)-3,4 -dihvdropyrrolon,2- alpyrazin- 1 (2H)-one

2,2,2-Trifluoroacetic acid (4.56 mL, 59.60 mmol) was added to methyl l-(2-((tert- butoxycarbonyl)amino)-3-methoxypropyl)-4-(2-chloro-5-methylp yrimidin-4-yl)-lH- pyrrole-2-carboxylate (1.744 g, 3.97 mmol) in DCM (20 mL) at 0 °C. The resulting solution was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness, taken up in methanol and passed through an SCX-2 column eluting with 7N ammonia in methanol. The solution was stirred for 18 hours and then evaporated to dryness to give 7- (2-chloro-5 -methylpyrimidin-4-yl)-3 -(methoxymethyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- l(2H)-one (0.867 g, 71.2 %) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 2.41 (3H, s), 3.27 (3H, s), 3.32 (1H, dd), 3.39 (1H, dd), 3.90 (1H, s), 4.11 - 4.24 (1H, m), 4.31 (1H, dd), 7.23 (1H, d), 7.85 (1H, d), 7.96 (1H, d), 8.49 (1H, d). m/z: ES+ [M+H]+ 307.

7-(2-Chloro-5-methylpyrimidin-4-yl)-3-(methoxymethyl)-2-( (6-methylpyridin-2- yl)methyl)-3 ,4-dihydro yrrolo Γ 1 ,2-alp yrazin- 1 (2H)-one

Sodium hydride (68.4 mg, 1.71 mmol) was added to 7-(2-chloro-5-methylpyrimidin-4-yl)- 3-(methoxymethyl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (477 mg, 1.56 mmol) in DMF (3 mL) at 22 °C under nitrogen. The resulting suspension was stirred at RT for 30 minutes then 2-(bromomethyl)-6-methylpyridine (434 mg, 2.33 mmol) was added. The resulting solution was stirred at 22 °C for 3 hours. The reaction mixture was quenched with saturated NH ₄ C1 (20 mL) and then the mixture extracted with DCM (2 x 20 mL), dried by passing through a phase seperater cartridge and evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0-5%MeOH in DCM. Pure fractions were evaporated to dryness to afford 7-(2-chloro-5- methylpyrimidin-4-yl)-3-(methoxymethyl)-2-((6-methylpyridin- 2-yl)methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (620 mg, 97 %) as a yellow solid. ^l H NMR (400

MHz, DMSO, 30 °C) 2.47 - 2.5 (3H, m), 2.52 (3H, s), 3.28 (3H, s), 3.31 - 3.4 (1H, m), 3.51 (1H, dd), 4.04 - 4.14 (1H, m), 4.36 - 4.59 (3H, m), 5.24 (1H, d), 7.22 (2H, t), 7.33 (1H, d), 7.71 (1H, t), 7.94 (1H, d), 8.56 (1H, d). m/z: ES+ [M+H]+ 412. Example 4

(3S -2-(2-Methoxyethvn-3-methyl-7-r5-methyl-2-r(2-methylpyrazol- 3- yl)aminolpyrimidin-4-yll -3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 -one

(3S)-7-(2-Chloro-5-methylpyrimidin-4-yl)-2-(2-methoxyethyl)- 3-methyl-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (71 mg, 0.21 mmol), 1 -methyl- lH-pyrazol-5- amine (24.71 mg, 0.25 mmol) and cesium carbonate (152 mg, 0.47 mmol) were suspended in tert-butanol (3 mL) and de-gassed for 5 minutes, then BrettPhos 3rd generation pre- catalyst (9.61 mg, 10.60 μιηοΐ) was added. The reaction was sealed in a microwave tube and heated to 100 °C in the microwave for 1 hour. LCMS indicated complete reaction. The reaction mixture was diluted with DCM (30 mL), and washed with brine (30 mL). The aqueous layer was extracted with DCM (2 x 30 mL) then combined organics were evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0.5 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (3S)-2-(2-methoxyethyl)-3-methyl-7-(5-methyl-2-((l- methyl- 1 H-pyrazol-5-yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)- one (56.0 mg, 66.8 %) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 1.13 (3H, d), 2.31 (3H, s), 3.15 - 3.26 (1H, m), 3.28 (3H, s), 3.44 - 3.56 (2H, m), 3.68 (3H, s), 3.92 - 3.98 (2H, m), 4.18 (1H, dd), 4.24 (1H, dd), 6.25 (1H, d), 7.19 (1H, d), 7.32 (1H, d), 7.60 (1H, d), 8.22 (1H, s), 9.05 (1H, s). m/z: ES+ [M+H]+ 396. (3S)-7-(2-chloro-5-methylpyrimidin-4-yl)-2-(2-methoxyethyl)- 3-methyl-3,4- dihydropyrrolor 1 ,2-alpyrazin- 1 (2H)-one

Sodium hydride (12.56 mg, 0.31 mmol) was added to (3S)-7-(2-chloro-5-methylpyrimidin- 4-yl)-3-methyl-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (79 mg, 0.29 mmol) in DMF (3 mL) at 22 °C under nitrogen. The resulting suspension was stirred at RT for 30 minutes then l-bromo-2-methoxyethane (0.030 mL, 0.31 mmol) was added. The resulting solution was stirred at 22 °C for 3 hours. The reaction mixture was quenched with saturated NH ₄ C1 (20 mL) and then the mixture extracted with DCM (2 x 20 mL) and evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0.5 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford (S)-7-(2-chloro-5-methylpyrimidin-4-yl)-2-(2-methoxyethyl)-3 -methyl-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (71.0 mg, 74.3 %) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 1.13 (3H, d), 2.42 (3H, s), 3.17 - 3.25 (1H, m), 3.28 (3H, s), 3.44 - 3.56 (2H, m), 3.92 - 4.04 (2H, m), 4.20 (1H, dd), 4.26 (1H, dd), 7.23 (1H, d), 7.81 (1H, d), 8.49 (1H, d). m/z: ES+ [M+H]+ 335.

Example 5a (1 ^st eluted isomer) and Example 5b (2 ^nd eluted isomer)

4-Methyl-7-(5 -methyl -2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((6- methylp yridin-2- yl)methyl)-3 ,4-dihydrop yrrolo Γ 1 ,2-alpyrazin- 1 (2H)- one

7-(2-Chloro-5-methylpyrimidin-4-yl)-4-methyl-2-((6-methylpyr idin-2-yl)m dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (400 mg, 1.05 mmol), 1 -methyl- lH-pyrazol-5- amine (203 mg, 2.10 mmol), CS2CO3 (1024 mg, 3.14 mmol) and 3rd Generation BrettPhos precatalyst (47.5 mg, 0.05 mmol) were mixture in 1,4-dioxane (3 mL) under N2 and sealed into a microwave tube. The reaction was heated to 120 °C for 1 hour in the microwave reactor and cooled to RT. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing NH4HCO3) and MeCN as eluents.

Fractions containing the desired compound were evaporated to dryness to afford racemic 4-methyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5-yl)amino)pyri midin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin- l(2H)-one (180 mg, 38.8 %) as a white solid. ^! H NMR (DMSO-d6, 300 MHz) δ 1.44 (3H, d), 2.33 (3H, s), 2.44 (3H, s), 3.46-3.58 (1H, m), 3.68 (3H, s), 3.82 (1H, dd), 4.46 - 4.71 (1H, m), 4.72-4.85 (2H, d), 6.26 (1H, d), 7.07 - 7.19 (2H, m), 7.25 (1H, dd),7.32(lH,dd), 7.59 - 7.71 (2H, m), 8.24 (1H, d), 9.12 (1H, s). m/z (ES+), [M+H]+ = 443. Purified by SFC, Chiralpak IB column, 12% MeOH/2M NH4 100/1 in C0 ₂ , 120 bar gave the 1 ^st eluting isomer (41mg). ^l H NMR (400 MHz, DMSO, 30 °C) 1.44 (3H, d), 2.33 (3H, s), 2.44 (3H, s), 3.53 (1H, dd), 3.68 (3H, s), 3.82 (1H, dd), 4.51 - 4.59 (1H, m), 4.65 (1H, d), 4.77 (1H, d), 6.25 (1H, s), 7.13 (2H, dd), 7.25 (1H, s), 7.32 (1H, s), 7.61 - 7.69 (2H, m), 8.23 (1H, s), 9.07 (1H, s). m/z: ES+ [M+H]+ 443 and the 2 ^nd eluting isomer (40mg). ^l H NMR (400 MHz, DMSO, 30 °C) 1.44 (3H, d), 2.33 (3H, s), 2.44 (3H, s), 3.53 (1H, dd), 3.68 (3H, s), 3.82 (1H, dd), 4.51 - 4.59 (1H, m), 4.65 (1H, d), 4.77 (1H, d), 6.25 (1H, s), 7.13 (2H, dd), 7.25 (1H, s), 7.32 (1H, s), 7.61 - 7.69 (2H, m), 8.23 (1H, s), 9.07 (1H, s). m/z: ES+ [M+H]+ 443.

Methyl 1 -( 1 -((tert-butoxycarbonyl)amino)propan-2-yl)-4-(2-chloro-5 -methylp yrimidin-4- - 1 H-p yrrole-2-carboxylate

60% NaH (0.286 g, 11.92 mmol) was added to methyl 4-(2-chloro-5-methylpyrimidin-4- yl)-lH-pyrrole-2-carboxylate (lg, 3.97 mmol) in DMF (20 mL) at 0 °C over a period of 1 minute under nitrogen. The resulting mixture was stirred at 0 °C for 12 minutes, tert-butyl 5-methyl-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.414 g, 5.96 mmol) was added. The mixture was stirrred at RT for 1 hour. The reaction mixture was diluted with EtOAc (200 mL), and washed sequentially with water (100 mL, x2) and saturated brine (100 mL, x2). The organic layer was dried over Na ₂ S04, filtered and evaporated to afford crude product.The crude product was purified by flash silica chromatography, elution gradient 0 to 9% MeOH in DCM. Pure fractions were evaporated to dryness to afford methyl 1-(1- ((tert-butoxycarbonyl)amino)propan-2-yl)-4-(2-chloro-5-methy lpyrimidin-4-yl)-lH- pyrrole-2-carboxylate (1.550 g, 95 %) as a yellow solid. Ή-ΝΜΡν (DMSO-de, 300 MHz) δ 1.22 (9H, s), 1.44 (3H, d), 2.44 (3H, s), 3.78 (3H, s), 3.80 - 4.05 (2H, m), 5.47 (1H, m), 7.46 (1H, d), 7.91 (1H, d), 8.50 (1H, s). m/z (ES+), [M+H]+ = 409.

Methyl 1 -( 1 -aminopropan-2-yl)-4-(2-chloro-5 -methylp yrimidin-4- yl)- 1 H-pyrrole-2- carboxylate

TFA (7 ml, 90.86 mmol) was added to methyl l-(l-((tert-butoxycarbonyl)amino)propan-2- yl)-4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrole-2-carboxy late (1.5g, 3.67 mmol) in DCM (20 mL). The resulting mixture was stirred at RT for 1 hour. The solvent was removed under reduced pressure to afford methyl l-(l-aminopropan-2-yl)-4-(2-chloro-5- methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate (2.300 g, 203 %) as a orange gum. The product was used in the next step directly without further purification. ^-NMR (DMSO- d ₆ , 300 MHz) δ 1.50 (3H, d), 2.46 (3H, s), 3.20 - 3.60 (2H, m), 3.82 (3H, s), 5.51 (IH, m), 7.50 (IH, d), 7.92 (3H, s), 8.09 (IH, d), 8.56 (IH, s). m/z (ES+), [M+H]+ = 309.

7-(2-Chloro-5-methylpyrimidin-4-yl)-4-methyl-2-((6-methyl pyridin-2-yl)methyl)-3,4- dihydropyrrolo[ 1 ,2-a ^" |pyrazin- 1 (2H)-one

Sodium triacetoxyborohydride (2.265 g, 10.69 mmol) was added to methyl 1-(1- aminopropan-2-yl)-4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyr role-2-carboxylate (1. lg, 3.56 mmol), anydrous sodium acetate (0.584 g, 7.13 mmol)and 6-methylpicolinaldehyde (0.432 g, 3.56 mmol) in MeOH (5 mL) at 0 °C over a period of 1 minute under nitrogen. The resulting mixture was stirred at RT for 1 hour. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 7- (2-chloro-5-methylpyrimidin-4-yl)-4-methyl-2-((6-methylpyrid in-2-yl)methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (0.400 g, 29.4 %) as a white solid. ^! H-NMR

(DMSO-de, 300 MHz) δ 1.46 (3H, d), 2.42 (3H, s), 3.30 (3H, s), 3.57 (IH, dd), 3.81 (IH, dd), 4.59 (IH, m), 4.64 - 4.81 (2H, m), 7.10 - 7.17 (2H, m), 7.29 (IH, d), 7.66 (IH, t), 7.85 (IH, d), 8.52 (IH, s). m/z (ES+), [M+H]+ = 382. Example 6

7'-(5-Methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2'-((6-methylpyridin-2 - yl)methyl)-2'^'-dihydro- 1 Ή-spiro [cyclopropane- 1 ,3'-pyrrolo[ 1 ,2-a ^" |pyrazin ^" |- 1 '-one

7'-(2-Chloro-5-methylpyrimidin-4-yl)-2'-((6-methylpyridin-2- yl)methyl)-2',4'-dihydro- H- spiro [cyclopropane- 1, 3 '-pyrrolo[l,2-a]pyrazin]- -one (80 mg, 0.20 mmol), 1-methyl-lH- pyrazol-5 -amine (21.70 mg, 0.22 mmol) and cesium carbonate (132 mg, 0.41 mmol) were suspended in tert-butanol (4 mL) and de-gassed for 10 minutes, then BrettPhos 3rd generation pre-catalyst (9.21 mg, 10.16 μιηοΐ) was added. The reaction was heated to 80 °C for 2 hours under nitrogen. LCMS showed reaction around 75% complete and it was allowed to run overnight. The mixture was cooled to RT, diluted with EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (10 mL) and the layers separated. The aqueous portion was washed with ethyl acetate (50 mL) and the combined organics were dried (sodium sulfate) and concentrated in vacuo to a yellow gum (110 mg). It was taken up in DMSO (5 mL) and filtered. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% N¾) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 7'-(5- methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2'-((6-methylpyridin-2 - yl)methyl)-2',4'-dihydro- 1 Ή-spiro [cyclopropane- 1 ,3'-pyrrolo[ 1 ,2-a]pyrazin]- 1 '-one (49.0 mg, 53.1 %) as a white solid. ^l H NMR (500 MHz, DMSO, 30 °C) 0.8 - 0.9 (2H, m), 1.01 - 1.12 (2H, m), 2.35 (3H, s), 2.46 (3H, s), 3.18 (2H, d), 3.70 (3H, d), 4.61 (2H, s), 6.28 (IH, d), 7.14 (IH, d), 7.17 (IH, d), 7.32 (IH, d), 7.34 (IH, d), 7.61 (IH, d), 7.65 (IH, t), 8.26 (IH, s), 9.09 (IH, s). m/z: ES+ [M+H]+ 455. 7-(2-chloro-5-methyl-pyrimidin-4-yl)-2-r(6-methyl-2-pyridyl) methyl1spiro ρνττοΙοΓ 1 ,2-a1pyrazine-3 , 1 '-cyclopropane! - 1 -one

Sodium hydride (60% dispersion in mineral oil) (11.73 mg, 0.29 mmol) was added to 7'-(2- chloro-5-methylpyrimidin-4-yl)-2',4'-dihydro- H-spiro[cyclopropane-l,3'-pyrrolo[l,2- a]pyrazin]-l'-one (77 mg, 0.27 mmol) in DMF (5 mL) under nitrogen. The resulting solution was stirred at 20 °C for 30 minutes. 2-(Chloromethyl)-6-methylpyridine (41.5 mg, 0.29 mmol) was added and the resulting solution stirred at 20 °C for 18 hours. It was diluted with ethyl acetate (50 mL) and washed with brine (15 mL), dried (sodium sulfate), concentrated in vacuo and adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 7'-(2-chloro-5-methylpyrimidin-4-yl)-2'-((6-methylpyridin- 2-yl)methyl)-2',4'-dihydro- H-spiro[cyclopropane-l,3'-pyrrolo[l,2-a]pyrazin]- -one (83 mg, 79 %) as a white solid. ^l H NMR (400 MHz, DMSO, 30 °C) 0.8 - 0.9 (2H, m), 1.01 - 1.11 (2H, m), 2.44 (6H, s), 4.22 (2H, s), 4.61 (2H, s), 7.14 (2H, dd), 7.34 (IH, d), 7.64 (IH, t), 7.79 (IH, d), 8.49 - 8.53 (IH, m). m/z: ES+ [M+H]+ 394.

Example 7

2'-(2-Methoxyethyl)-7'-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)- 2',4'-dihvdro- 1 'H-spiroTcvclopropane-l 3'-ρνιτοιοΓ 1 ,2-alpyrazinl- 1 '-one

7'-(2-Chloro-5-methylpyrimidin-4-yl)-2'-(2-methoxyethyl)-2', 4'-dihydro-l'H- spiro [cyclopropane- 1, 3 '-pyrrolo[l,2-a]pyrazin]- -one (48 mg, 0.14 mmol), 1-methyl-lH- pyrazol-5 -amine (14.79 mg, 0.15 mmol) and cesium carbonate (90 mg, 0.28 mmol) were suspended in tert-butanol (4 mL) and de-gassed for 10 minutes, then BrettPhos 3rd generation pre-catalyst (6.27 mg, 6.92 μιηοΐ) was added. The reaction was heated to 80 °C for 2 hours under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (10 mL) and the layers separated. The aqueous portion was washed with ethyl acetate (50 mL) and the combined organics were dried (sodium sulfate) and concentrated in vacuo to a yellow gum (64 mg). It was taken up in DMSO (5 mL) and filtered. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH ₃ ) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give impure material. The material was dissolved in methanol, concentrated in vacuo and adsorbed onto silica. The impure product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford 2'-(2-methoxyethyl)-7'-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4- yl)-2',4'-dihydro- H-spiro[cyclopropane-l,3'-pyrrolo[l,2-a]pyrazin]- -one (19.00 mg, 33.7 %) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 0.94 - 1.02 (2H, m), 1.17 (2H, t), 2.37 (3H, d), 3.31 (3H, s), 3.44 (2H, dd), 3.55 (2H, dt), 3.74 (3H, s), 4.15 (2H, s), 6.32 (IH, d), 7.30 (IH, d), 7.39 (IH, d), 7.62 (IH, d), 8.29 (IH, s), 9.13 (IH, s). m/z: ES+ [M+H]+ 408. tert-Butyl ( 1 -(hydroxymethyl)cyclopropyDcarbamate

Di-t-butyldicarbonate (6.23 g, 28.57 mmol) was added to 1 -amino-cyclopropanemethanol hydrochloride (2.943 g, 23.81 mmol), triethylamine (8.31 mL, 59.52 mmol) and 4- dimethylaminopyridine (0.291 g, 2.38 mmol) in DCM (90 mL) under nitrogen. The resulting solution was stirred at 20 °C for 3 hours. It was washed with saturated aqueous sodium bicarbonate (20 mL), dried (sodium sulfate) and concentrated in vacuo to a colourless gum (3.277 g). It was taken up in DCM, concentrated in vacuo and adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl (l-(hydroxymethyl)cyclopropyl)carbamate (2.283 g, 51.2 %) as a white solid. ^l H NMR (400 MHz, DMSO, 30°C) 0.48 - 0.55 (2H, m), 0.58 - 0.64 (2H, m), 1.36 (9H, s), 3.36 (2H, d), 4.51 (lH, t), 6.98 (1H, s). tert-Butyl 6-oxa-5-thia-4-azaspiror2.41heptane-4-carboxylate 5-oxide

Thionyl chloride (0.927 mL, 12.78 mmol) was added to imidazole (3.16 g, 46.49 mmol) and triethylamine (3.57 mL, 25.57 mmol) in DCM (50 mL) at -55 °C over a period of 5 minutes under nitrogen. The resulting suspension was stirred and cooled to -60 °C over 5 minutes, tert-butyl (l-(hydroxymethyl)cyclopropyl)carbamate (2.176 g, 11.62 mmol) in DCM (50 mL) was added over a period of 1.5 hours , then the mixture was stirred and allowed to warm to ambient temperature over 3 days (over weekend). Water (30 mL) was added with vigorous stirring and the layers separated. The aqueous portion was washed with DCM (20 mL) and the combined organics washed with water (30 mL) and brine (30 mL), dried (magnesium sulfate) and concentrated in vacuo to give tert-butyl 6-oxa-5-thia- 4-azaspiro[2.4]heptane-4-carboxylate 5-oxide (2.69 g, 99 %) as a pale yellow oil. ^l H

NMR (400 MHz, CDCb, 30 °C) 0.72 (1H, ddd), 0.82 (1H, ddd), 1.50 (9H, s), 1.57 (1H, dddd), 1.91 - 2.02 (1H, m), 4.21 (1H, d), 5.12 (1H, dd). tert-Butyl 6-oxa-5-thia-4-azaspiror2.4 ^" |heptane-4-carboxylate 5,5-dioxide

Ruthenium(III) chloride hydrate (0.013 g, 0.06 mmol) was added to a stirred mixture of tert-butyl 6-oxa-5-thia-4-azaspiro[2.4]heptane-4-carboxylate 5-oxide (2.65 g, 11.36 mmol) in acetonitrile (22.37 ml) and water (12.05 ml) at -15 °C followed by portionwise addition of sodium periodate (3.04 g, 14.20 mmol), maintaining the temperature in the range -10 to -20 °C then warmed to 20 °C and stirred for 4 hours. A resulting white precipitate was removed by filtration. EtOAc (100 mL) was added to the filtrate and the layers partitioned. The aqueous was extracted with further EtOAc (75 mL), then combined organics were washed with brine (100 mL) then dried (MgS0 ₄ ) and concentrated to yield tert-butyl 6- oxa-5-thia-4-azaspiro[2.4]heptane-4-carboxylate 5,5-dioxide (2.61 g, 92 %) as an off white solid. ¾ NMR (400 MHz, CDCb, 30 °C) 0.74 - 0.8 (2H, m), 1.53 (9H, s), 1.84 (1H, s), 1.87 (lH, d), 4.42 (2H, s).

(tert-Butoxycarbonyl)( 1 -((4-(2-chloro-5 -methylpyrimidin-4-yl)-2-(methoxycarbonyl)- 1 H- pyrrol- 1 - vDmethvDcyclopropyDsulfamic acid

tert-Butyl 6-oxa-5-thia-4-azaspiro[2.4]heptane-4-carboxylate 5,5-dioxide (427 mg, 1.71 mmol) was added to methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrole-2- carboxylate (470 mg, 1.77 mmol), potassium carbonate (2207 mg, 15.97 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (117 mg, 0.44 mmol) in 1,4-dioxane (35 mL) at 22 °C under nitrogen. The resulting suspension was stirred at 50 °C for 18 hours. The mixture was cooled to room temperature and 2M HC1 (9.3 mL) was added dropwise over 5 minutes and the mixture stirred for 3 days (over weekend). LCMS showed no change. The solvents were evaporated to leave product (tert-butoxycarbonyl)(l-((4-(2-chloro-5- methylpyrimidin-4-yl)-2-(methoxycarbonyl)- 1 H-pyrrol- 1 -yl)methyl)cyclopropyl)sulfamic acid as a brown solid (3.32 g). Progressed to the next step with no attempt at purification. m/z: ES- [M-H]- 499.

Methyl l-((l-aminocvclopropyl)methyl)-4-(2-chloro-5-methylpyrimidin -4-yl)-lH-pyrrole-

2-carboxylate

HC1 (4M in dioxane) (26.6 mL, 106.48 mmol) was added to (tert-butoxycarbonyl)(l-((4- (2-chloro-5 -methylpyrimidin-4-yl)-2-(methoxycarbonyl)- 1 H-pyrrol- 1 - yl)methyl)cyclopropyl)sulfamic acid (889 mg, 1.77 mmol) in methanol (50 mL). The resulting solution was stirred at 20 °C for 18 hours. Solid material was removed by filtration and the filtrate concentrated in vacuo. The residue was taken up in methanol. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NEb/MeOH and pure fractions were evaporated to dryness to afford methyl l-((l-aminocyclopropyl)methyl)-4-(2-chloro-5- methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate (292 mg, 51.3 %) as a colourless gum. m/z: ES+ [M+H]+ 321. 7-(2-chloro-5-methyl-pyrimidin-4-yl)s^

cyclopropane! - 1 -one

2M Trimethylaluminum in toluene (1.576 mL, 3.15 mmol) was added over 10 minutes to a solution of methyl l-((l-aminocyclopropyl)methyl)-4-(2-chloro-5-methylpyrimidin -4-yl)- lH-pyrrole-2-carboxylate (337 mg, 1.05 mmol) in 2-methyl tetrahydrofuran (8 mL) in a microwave vial under nitrogen at 20 °C. Gas was evolved during the addition and there was a ~10 °C exotherm. After effervescence had ceased (10 minutes after complete addition), the vial was capped and heated to 80 °C for 30 minutes in microwave reactor. LCMS showed complete reaction. The mixture was added cautiously (care - gas evolved!) to saturated Rochelle's salt (potassium sodium tartrate) (20 mL). Water (10 mL) was added then the mixture was extracted with DCM (2 x 75 mL). The combined organics were dried (sodium sulfate) and concentrated in vacuo and adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 7'-(2-chloro-5-methylpyrimidin- 4-yl)-2',4'-dihydro- H-spiro [cyclopropane- 1 ,3'-pyrrolo[ 1 ,2-a]pyrazin]- 1 '-one (231 mg,

76 %) as a white solid. ^l H NMR (400 MHz, DMSO, 30 °C) 0.86 (4H, s), 2.43 (3H, s), 4.15 (2H, s), 7.27 (1H, d), 7.78 (1H, d), 8.07 (1H, s), 8.47 - 8.53 (1H, m). m/z: ES+

[M+H]+ 289.

7 ^, -(2-Chloro-5-methylpyrimidin-4-vn-2 ^, -(2-methoxyethyl -2 ^, ,4 ^, -dihvdro-l ^, H- spiro [cyclopropane- 1 ,3'-pyrrolor 1 ,2-alpyrazinl- 1 '-one

Sodium hydride (60% dispersion in mineral oil) (11.73 mg, 0.29 mmol) was added to 7'-(2- chloro-5-methylpyrimidin-4-yl)-2',4'-dihydro- H-spiro[cyclopropane-l,3'-pyrrolo[l,2- a]pyrazin]-l'-one (77 mg, 0.27 mmol) in DMF (5 mL) under nitrogen. The resulting solution was stirred at 20 °C for 30 minutes, l-bromo-2-methoxyethane (0.028 mL, 0.29 mmol) was added and the resulting solution stirred at 20 °C for 18 hours. It was diluted with ethyl acetate (50 mL) and washed with brine (15 mL), dried (sodium sulfate), concentrated in vacuo and adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 7'-(2-chloro-5-methylpyrimidin-4-yl)-2'-(2-methoxyethyl)- 2',4'-dihydro- H-spiro[cyclopropane-l,3'-pyrrolo[l,2-a]pyrazin]- -one (50.0 mg, 54.1 %) as a white solid. ¾ NMR (400 MHz, DMSO, 30 °C) 0.88 - 0.96 (2H, m), 1.06 - 1.16 (2H, m), 2.42 (3H, s), 3.24 (3H, s), 3.39 (2H, d), 3.48 (2H, t), 4.10 (2H, s), 7.27 (1H, d), 7.75 (1H, d), 8.50 (1H, s). m/z: ES+ [M+H]+ 347.

Example 8

7-(5-Methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2- yl)methyl)-3 ,4-dihydropyrrolor 1 ,2-alpyrazin- 1 (2H)-one

7-(2-Chloro-5-methylpyrimidin-4-yl)-2-((6-methylpyridin-2-yl )methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (78 mg, 0.21 mmol), 1 -methyl- lH-pyrazol-5- amine (41.2 mg, 0.42 mmol), BrettPhos 3rd generation pre-catalyst (9.61 mg, 10.60 μιηοΐ) and cesium carbonate (173 mg, 0.53 mmol) were suspended in degassed tert-butanol (2 mL) under nitrogen in a microwave vial. The reaction was heated to 100 °C for 1 hour under microwave irradiation. The reaction mixture was diluted with EtOAc (100 mL), and washed with brine (50 mL). The aqueous layer was extracted with DCM (2x) and the combined organics were evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 7-(5-methyl-2-((l-methyl-lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3, 4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one (71.0 mg, 78 %) as a yellow foam. ^l H NMR (400 MHz, DMSO, 30 °C) 2.33 (3H, s), 2.45 (3H, s), 3.68 (3H, s), 3.75 - 3.8 (2H, m), 4.29 - 4.34 (2H, m), 4.72 (2H, s), 6.26 (IH, d), 7.12 (IH, d), 7.14 (IH, d), 7.25 (IH, d), 7.33 (IH, d), 7.6 - 7.68 (2H, m), 8.24 (IH, s), 9.07 (IH, s). m/z: ES+ [M+H]+ 429.

Methyl l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(2-chloro-5-meth ylpyrimidin-4-yl)-lH- pyrrole-2-carboxylate

Sodium hydride (60% dispersion in mineral oil) (0.338 g, 8.44 mmol) was added to methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate (1.7 g, 6.75 mmol) in DMF (30 mL) at 22 °C under nitrogen. The resulting mixture was stirred at 22 °C for 15 minutes then (2-bromoethoxy)(tert-butyl)dimethylsilane (1.594 mL, 7.43 mmol) was added. The resulting mixture was stirred at 60 °C for 2 hours, after which a further portion of (2- bromoethoxy)(tert-butyl)dimethylsilane (0.2 mL, 0.92 mmol) was added and stirred for a further 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water (5x), brine, dried (MgS0 ₄ ) and concentrated. The residue was purified by flash silica chromatography, elution gradient 5 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford methyl l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(2- chloro-5-methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate (1.930 g, 69.7 %) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) -0.12 (6H, s), 0.78 (9H, s), 2.4 - 2.43 (3H, m), 3.79 (3H, s), 3.86 (2H, t), 4.52 (2H, t), 7.48 (1H, d), 7.91 (1H, d), 8.51 (1H, d). m/z: ES+ [M+H]+ 410.

Methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-l-(2-hvdroxyethyl)-lH-py rrole-2-carboxylate

Triethylamine trihydro fluoride (3.89 mL, 23.42 mmol) was added to methyl l-(2-((tert- butyldimethylsilyl)oxy)ethyl)-4-(2-chloro-5-methylpyrimidin- 4-yl)-lH-pyrrole-2- carboxylate (1.92 g, 4.68 mmol) in THF (30 mL) at 22 °C under nitrogen. The resulting solution was stirred at 22 °C for 3.5 hours. The reaction mixture was diluted with NaHC0 ₃ solution (100 mL), and extracted with EtOAc (2 x 200 mL). The organic layer was dried (MgS0 ₄ ) and concentrated to afford crude product. The crude product was triturated with EtOAc, collected by filtration, and dried under vacuum to give methyl 4-(2-chloro-5- methylpyrimidin-4-yl)-l-(2-hydroxyethyl)-lH-pyrrole-2-carbox ylate (1.200 g, 87 %) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 2.41 - 2.44 (3H, m), 3.69 (2H, q), 3.79 (3H, s), 4.46 (2H, t), 4.87 (1H, t), 7.47 (1H, d), 7.91 (1H, d), 8.51 (1H, d). m/z: ES+

[M+H]+ 296. Methyl 4-(2-chloro-5-methyl yrimidin-4-yl)-l-(2-oxoethyl)-lH-pyrrole-2-carboxylate

Dess-Martin Periodinane (1.893 g, 4.46 mmol) was added portionwise to methyl 4-(2- chloro-5-methylpyrimidin-4-yl)-l-(2-hydroxyethyl)-lH-pyrrole -2-carboxylate (1.20 g, 4.06 mmol) in DCM (40 mL) at 20 °C. The resulting solution was stirred at RT for 3 hours. The reaction mixture was poured into saturated NaHC0 ₃ (100 mL) and water (30 mL) containing sodium thiosulfate (4.49 g, 28.41 mmol). The resulting suspension was stirred vigourously for 10 minutes, before separating the layers. The aqueous layer was extracted with further DCM (3 x 200 mL), then organics were dried (MgS0 ₄ ) and evaporated to afford methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-l-(2-oxoethyl)-lH-pyrrol e-2- carboxylate (1.200 g, 101 %) as a white solid. ^l H NMR (400 MHz, DMSO, 30 °C) 2.42 - 2.44 (3H, m), 3.76 (3H, s), 5.34 (2H, s), 7.51 (1H, d), 7.97 (1H, d), 8.54 (1H, d), 9.65 (1H, s). m/z: ES+ [M+H]+ 294.

Methyl 4-(2-chloro-5-methylpyrimidin-4-yl)- 1 -(2-(((6-methylpyridin-2- yl)methyl)amino)ethyl)- 1 H-p yrrole-2-carboxylate

N-Ethyl-N-isopropylpropan-2-amine (0.107 mL, 0.61 mmol) was added to (6- methylpyridin-2-yl)methanamine (68.6 mg, 0.56 mmol), methyl 4-(2-chloro-5- methylpyrimidin-4-yl)-l-(2-oxoethyl)-lH-pyrrole-2-carboxylat e (150 mg, 0.51 mmol) and magnesium sulfate (6.15 mg, 0.05 mmol) in THF (2 mL) and DMA (0.5 mL) at 22 °C. The resulting mixture was stirred at 22 °C for 10 minutes. Sodium triacetoxyborohydride (152 mg, 0.72 mmol) was added, then the mixture was stirred for a further 20 hours. The reaction mixture was diluted with EtOAc (100 mL), and washed with saturated NaHC0 ₃ (50 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organic layers were dried (MgS0 ₄ ) and concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-l-(2-(((6- methylpyridin-2-yl)methyl)amino)ethyl)-lH-pyrrole-2-carboxyl ate (120 mg, 58.8 %) as a colourless gum. ^! H NMR (400 MHz, DMSO, 30 °C) 2.40 (3H, s), 2.41 (3H, s), 2.89 (2H, t), 3.73 (2H, s), 3.77 (3H, s), 4.49 (2H, t), 7.06 (1H, d), 7.09 (1H, d), 7.47 (1H, d), 7.56 (1H, t), 7.98 (1H, d), 8.51 (1H, s). m/z: ES+ [M+H]+ 400.

7-(2-Chloro-5-methylpyrimidin-4-yl)-2-((6-methylpyridin-2 -yl)methyl)-3,4- dihydropyrrolor 1 ,2-alpyrazin- 1 (2H)-one

Trimethylaluminum (2M in toluene) (0.416 mL, 0.83 mmol) was added dropwise to methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-l-(2-(((6-methylpyridin- 2- yl)methyl)amino)ethyl)-lH-pyrrole-2-carboxylate (111 mg, 0.28 mmol) in THF (1.2 mL) and toluene (1.2 mL) at 22 °C in a microwave tube under nitrogen. The resulting solution was stirred at 22 °C, then transferred to a microwave and heated at 150 °C for 30 minutes. Saturated Rochelle's salt (5 mL) was then added cautiously (care - gas evolved !) and water (20 mL) was added then the mixture was extracted with DCM (3 x 50 mL). The organics were concentrated then purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 7-(2-chloro-5- methylpyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2- a]pyrazin-l(2H)-one (88 mg, 86 %) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 2.42 - 2.44 (3H, m), 2.45 (3H, s), 3.76 - 3.81 (2H, m), 4.33 (2H, dd), 4.73 (2H, s), 7.1 - 7.17 (2H, m), 7.29 (1H, d), 7.65 (1H, t), 7.85 (1H, d), 8.51 (1H, d). m/z: ES+ [M+H]+ 368.

Example 9

(3R)-7-(5-Chloro-2-((l-methyl-lH-pyrazol-5-yl)amino)pyrimidi n-4-yl)-3-methyl-2-((6- meth lp yridin-2- yl)methyl)-3 ,4-dihydropyrrolo Γ 1 ,2-alpyrazin- 1 (2H)- one

(3R)-7-(2,5 -Dichloropyrimidin-4-yl)-3 -methyl-2-((6-methylpyridin-2-yl)methyl)-3 ,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (500 mg, 1.24 mmol), 1 -methyl- lH-pyrazol-5- amine (133 mg, 1.37 mmol) and cesium carbonate (1296 mg, 3.98 mmol) were suspended in de-gassed DMA (20 mL), then BrettPhos 3rd generation pre-catalyst (56.3 mg, 0.06 mmol) was added. The reaction was heated to 100 °C for 3.5 hours. The reaction mixture was cooled immediately in iced water and passed through an SCX-2 column washing with methanol then 7N ammonia in methanol. The basic fractions were concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% N¾) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (3R)-7-(5-chloro-2-((l-methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-3 -methyl-2-((6-methylpyridin-2-yl)methyl)-3 ,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (155 mg, 26.9 %) as a white foam. ^! H NMR (400 MHz, DMSO, 30 °C) 1.15 (3H, d), 2.45 (3H, s), 3.68 (3H, s), 3.96 (1H, d), 4.2 - 4.41 (3H, m), 5.12 (1H, d), 6.25 (1H, d), 7.15 (2H, dd), 7.37 (2H, dd), 7.64 (1H, t), 7.95 (1H, d), 8.44 (1H, s), 9.45 (1H, s). m/z: ES+ [M+H]+ 463. Methyl 4-(2,5-dichloropyrimidin-4-yl)-lH-pyrrole-2-carboxylate

Pd(PPh ₃ ) ₄ (1.575 g, 1.36 mmol) was added to a de-gassed solution of 2,4,5- trichloropyrimidine (5 g, 27.26 mmol), 2,4,5 -trichloropyrimidine (5 g, 27.26 mmol) and potassium phosphate (17.36 g, 81.78 mmol) in dioxane (141 ml) and water (47 ml) at 22 °C under nitrogen. The resulting solution was stirred at room temperature for 2 hours then heated at 50 °C for a further 16 hours. The reaction mixture was then cooled to room temperature then extracted with diethylether (2 x 100 mL). The combined organic layers were then dried (MgS0 ₄ ), filtered and evaporated to afford a yellow solid. This was then dissolved in DCM (50 mL) and 2,2,2-trifluoroacetic acid (41.8 mL, 545.40 mmol) was added. The mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated in vacuo. Water was then added and the resulting precipitate was collected by filtration. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in DCM. Pure fractions were evaporated to dryness to afford methyl 4-(2,5-dichloropyrimidin-4-yl)-lH-pyrrole-2-carboxylate (2.297 g, 95%) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 3.82 (3H, s), 7.55 (IH, s), 7.98 (IH, s), 8.77 (IH, s), 12.79 (IH, s). m/z: ES+ [M+H]+ 272.

(R)-Methyl l-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2,5-dichloropyri midin-4-yl)-lH- pyrrole-2-carboxylate

Potassium carbonate (10.50 g, 75.98 mmol) was added to (R)-tert-butyl 4-methyl-l,2,3- oxathiazolidine-3 -carboxylate 2,2-dioxide (2.60 g, 10.97 mmol), methyl 4-(2,5- dichloropyrimidin-4-yl)-lH-pyrrole-2-carboxylate (2.297 g, 8.44 mmol) and

1,4,7,10,13,16-hexaoxacyclooctadecane (0.558 g, 2.11 mmol) in 1,4-dioxane (100 mL) at 22°C under nitrogen. The resulting mixture was stirred at 50 °C for 5 hours.

Water (100 mL) added and extracted with diethylether (2 x 100 mL). The combined organic layers were dried (MgS0 ₄ ), filtered and concentrated in vacuo to give (R)-methyl l-(2-((tert-butoxycarbonyl)amino)propyl)-4-(2,5-dichloropyri midin-4-yl)-lH-pyrrole-2- carboxylate (4.47 g, 123%) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 1.08 (3H, d), 1.17 (9H, s), 3.18 - 3.39 (1H, m), 3.80 (3H, s), 3.95 (1H, d), 4.61 (1H, dd), 6.77 (1H, d), 7.64 (1H, d), 8.05 (1H, d), 8.78 (1H, s). m/z: ES+ [M-Boc] 329. -Methyl l-(2-aminopropyl)-4-(2,5-dichloropyrimidin-4-yl)-lH-pyrrole- 2-carboxylate

NH ₂ 2,2,2-Trifluoroacetic acid (9.69 mL, 126.49 mmol) was added to (R)-methyl l-(2-((tert- butoxycarbonyl)amino)propyl)-4-(2,5-dichloropyrimidin-4-yl)- lH-pyrrole-2-carboxylate (3.62 g, 8.43 mmol) in DCM (50 mL) at 0 °C. The resulting solution was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and then dissolved in

dichloromethane/methanol and water Water layer then neutralized with solid sodium bicarbonate, extracted with dichloromethane/methanol and organic layer dried by passing through a phase separator cartridge. Evaporation afforded (R)-methyl l-(2-aminopropyl)- 4-(2,5-dichloropyrimidin-4-yl)-lH-pyrrole-2-carboxylate as a white solid (2.310 g, 83 %). ¾ NMR (400 MHz, DMSO, 30 °C) 0.80 (3H, d), 1.48 (2H, s), 2.76 - 3.02 (IH, m), 3.63 (3H, s), 3.96 (IH, dd), 4.21 (IH, dd), 7.51 (IH, d), 8.03 (IH, d), 8.62 (IH, s). m/z: ES+ [M+H]+ 329.

(3R)-7-(2,5 -Dichloropyrimidin-4-yl)-3 -methyl-3 ,4-dihydropyrrolor 1 ,2-alpyrazin- 1 (2H)- one

A mixture of (R)-methyl l-(2-aminopropyl)-4-(2,5-dichloropyrimidin-4-yl)-lH-pyrrole- 2- carboxylate (3.7 g, 11.24 mmol) and ammonia 7N in methanol (193 ml, 1348.80 mmol) was stirred at ambient temperature overnight. The resulting precipitate was filtered off and dried to afford (3R)-7-(2,5-dichloropyrimidin-4-yl)-3-methyl-3,4-dihydropyrr olo[l,2- a]pyrazin-l(2H)-one (2.61 g, 78 %) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 1.19 (3H, d), 3.90 (2H, d), 4.33 (IH, d), 7.42 (IH, d), 7.99 (IH, s), 8.08 (IH, d), 8.76 (IH, s). m/z: ES+ [M+H]+ 297. (3R)-7-(2,5 -Dichloropyrimidin-4-yl)-3 -methyl-2-((6-methylpyridin-2-yl)methyl)-3 A- dih dropyrrolor 1 ,2-alpyrazin- 1 (2H)-one

Sodium hydride (111 mg, 2.78 mmol) was added to 2-(bromomethyl)-6-methylpyridine (689 mg, 3.70 mmol) and (3R)-7-(2,5-dichloropyrimidin-4-yl)-3-methyl-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (550 mg, 1.85 mmol) in DMF (5 mL) at RT under nitrogen. The resulting solution was then stirred at RT for 5 mins. The reaction mixture was quenched with ice and extracted with DCM. The organic layer was dried by passing through a phase seperator cartridge. Evaporation afforded a red brown gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM to afford (3R)-7-(2,5-dichloropyrimidin-4-yl)-3-methyl-2-((6-methylpyr idin-2- yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (500 mg, 67.1 %) as a yellow foam. 'H NMR (400 MHz, DMSO, 30 °C) 1.15 (3H, d), 2.45 (3H, s), 3.99 (1H, dt), 4.18 - 4.43 (3H, m), 5.13 (1H, d), 7.15 (2H, t), 7.48 (1H, d), 7.65 (1H, d), 8.14 (1H, d), 8.77 (1H, s). m/z: ES+ [M+H]+ 402.

Example 10

33-Dimethyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5-yl)amino)p yrimidin-4-yl)-2-((6- (trifluoromethvD yridin-2-yl)methyl)-3 ,4-dihydropyrrolo Γ 1 ,2-alpyrazin- 1 (2H)- one

7-(2-Chloro-5 -methylpyrimidin-4-yl)-3 ,3 -dimethyl-2-((6-(trifluoromethyl)pyridin-2- yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (120 mg, 0.27 mmol), 1-methyl- lH-pyrazol-5 -amine (28.5 mg, 0.29 mmol) and cesium carbonate (174 mg, 0.53 mmol) were suspended in tert-butanol (4 mL) and de-gassed for 10 minutes, then BrettPhos 3rd generation pre-catalyst (12.09 mg, 0.01 mmol) was added. The reaction was heated to 80 °C for 2 hours under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (10 mL) and the layers separated. The aqueous portion was washed with ethyl acetate (50 mL) and the combined organics were dried (Na ₂ S04) and concentrated in vacuo to a yellow gum (127 mg). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH ₃ ) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 3,3-dimethyl-7-(5-methyl-2-((l- methyl-lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6-(trifluor omethyl)pyridin-2- yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (80 mg, 58.7 %) as an off white solid. ¾ NMR (500 MHz, DMSO, 30 °C) 1.15 (6H, s), 2.21 (3H, s), 3.56 (3H, s), 4.14 (2H, s), 4.74 (2H, s), 6.13 (IH, d), 7.14 (IH, d), 7.20 (IH, d), 7.53 (IH, d), 7.59 (IH, d), 7.65 (IH, d), 7.92 (IH, t), 8.12 (IH, s), 8.96 (IH, s). m/z: ES+ [M+H]+ 511. tert-Butyl ( 1 -hvdroxy-2-methylpropan-2-yl)carbamate

Di-tert-butyl dicarbonate (21.82 g, 100.00 mmol) was added in portions to a solution of 2- amino-2-methylpropan-l-ol (8.91 g, 100.0 mmol) in DCM (270 ml) at 0 °C. The reaction was stirred at room temperature for 2 hours, then was washed with 2N HC1 (100 mL). The organic phase was dried (MgS0 ₄ ) and concentrated in vacuo to give tert-butyl (1-hydroxy- 2-methylpropan-2-yl)carbamate (18.56 g, 98 %) as a white solid. ^! H NMR (400 MHz,

CDC1 , 27 °C) 1.25 (6H, s), 1.43 (9H, s), 3.58 (2H, d), 4.67 (IH, s). ert-Butyl 4, 4 -dimethyl- 1 ,2,3-oxathiazolidine-3-carboxylate 2-oxide

tert-Butyl (l-hydroxy-2-methylpropan-2-yl)carbamate (9 g, 47.56 mmol) was added in acetontrile (50 mL) to a solution of sulfurous dichloride (8.62 ml, 118.89 mmol) in acetonitrile (168 mL) at -40 °C. After stirring for 5 minutes, pyridine (13.46 ml, 166.44 mmol) was added and the reaction was stirred for 30 min before warming to 0 °C over 30 min. EtOAc (100 mL) was added, and the reaction mixture was washed with IN HC1 (100 mL) and sat. NaHC0 ₃ solution (100 mL), then dried (MgS0 ₄ ), filtered and concentrated to give tert-butyl 4,4-dimethyl-l,2,3-oxathiazolidine-3-carboxylate 2-oxide (10.51 g, 94 %) as a brown oil. ^! H NMR (400 MHz, CDC1 ₃ , 27 °C) 1.42 (3H, s), 1.53 (9H, s), 1.61 (3H, s), 4.34 (1H, d), 4.83 (1H, d). tert-Butyl 4,4-dimethyl- 1 ,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

Sodium periodate (11.25 g, 52.59 mmol) and ruthenium (II) chloride hydrate (0.044 g, 0.21 mmol) were added to a cooled solution of tert-butyl 4,4-dimethyl-l,2,3- oxathiazolidine-3-carboxylate 2-oxide (9.9 g, 42.07 mmol) in acetonitrile (105 mL) / water (105 mL). The reaction was stirred vigourously for 30 min, then allowed to warm to room temperature for a further 30 min. Diethyl ether (100 mL) was added and the layers separated. The organic was extracted with diethyl ether (100 mL), then the combined organics were washed with water, brine, then dried (MgS0 ₄ ), filtered and concentrated to give tert-butyl 4,4-dimethyl-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (9.55 g, 90 %) as a cream coloured solid. ^l H NMR (400 MHz, CDC1 , 27 °C) 1.56 (9H, s), 1.59 (6H, s), 4.23 (2H, s). Methyl l-(2-amino-2-methylpropyl)-4-(2-chloro-5-methylpyrimidin-4-y l)-lH-pytTole-2- carboxylate

tert-Butyl 4,4-dimethyl-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.807 g,

7.19 mmol) was added to methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrole-2- carboxylate (1.465 g, 5.53 mmol), potassium carbonate (6.88 g, 49.77 mmol) and

1,4,7,10,13,16-hexaoxacyclooctadecane (0.365 g, 1.38 mmol) in 1,4-dioxane (100 mL) at 22 °C under nitrogen. The resulting suspension was stirred at 100 °C stirred under reflux for 24 hours. The reaction mixture was cooled to room temperature and the solid inorganic residue removed by filtration. The filtrate was concentrated in vacuo to give a brown gum. This was then dissolved in MeOH (125 mL) and HC1 (4M in dioxane) (83 mL, 331.63 mmol) was added. The resulting solution was stirred at 20 °C for 3 days. It was then concentrated in vacuo and azetroped once with toluene to leave a dark gum. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 1M NEb/MeOH and pure fractions were evaporated to dryness to afford methyl l-(2-amino-2-methylpropyl)-4-(2-chloro-5- methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate (0.954 g, 53.5 %) as a brown gum.

¾ NMR (400 MHz, DMSO, 30 °C) 0.96 (6H, s), 2.42 (3H, s), 3.16 (3H, s), 4.35 (2H, d), 7.46 (1H, d), 7.94 (1H, d), 8.49 (1H, d). m/z: ES+ [M+H]+ 323. 7-(2-Chloro-5-methylpyrim

l(2H -one

2M Trimethylaluminum in toluene (4.41 mL, 8.83 mmol) was added over 10 minutes to a solution of methyl l-(2-amino-2-methylpropyl)-4-(2-chloro-5-methylpyrimidin-4-y l)-lH- pyrrole-2-carboxylate (950 mg, 2.94 mmol) in 2-methyl tetrahydrofuran (10 mL) in a microwave vial under nitrogen at 20 °C. Gas was evolved during the addition and there was a ~10 °C exotherm. After effervescence had ceased, the vial was capped and heated to 80 °C for 30 minutes in microwave reactor. The mixture was added cautiously to saturated Rochelle's salt (potassium sodium tartrate) (20 mL). Water (10 mL) was added then the mixture was extracted with DCM (2 x 100 mL). The combined organics were dried (Na ₂ S04), concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 7-(2-chloro-5-methylpyrimidin-4-yl)-3,3-dimethyl-3,4- dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one (400 mg, 46.7 %) as a grey solid. ^! H NMR (400 MHz, DMSO, 30 °C) 1.23 (6H, s), 2.42 (3H, s), 4.07 (2H, s), 7.24 (IH, d), 7.81 (IH, d), 7.94 (IH, s), 8.49 (IH, s). m/z: ES+ [M+H]+ 291.

7-(2-Chloro-5-methylpyrimidin-4-yl)-33-dimethyl-2-((6-(tr ifluoromethyl)pyridin-2- yl)methyl)-3 ,4-dihydro yrrolor 1 ,2-alpyrazin- 1 (2H)-one

Sodium hydride (60% dispersion in mineral oil) (12.11 mg, 0.30 mmol) was added to 7-(2- chloro-5 -methylpyrimidin-4-yl)-3 ,3 -dimethyl-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one (80 mg, 0.28 mmol) in DMF (5 mL) under nitrogen. The resulting solution was stirred at 20 °C for 30 minutes. 2-(Bromomethyl)-6-(trifluoromethyl)pyridine (72.6 mg, 0.30 mmol) was added and the resulting solution stirred at 20 °C for 18 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with brine (15 mL), dried (Na ₂ S04) and

concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 7-(2-chloro-5-methylpyrimidin-4-yl)-3,3-dimethyl-2-((6-(trif luoromethyl)pyridin-2- yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (124 mg, 100 %) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 1.27 (6H, s), 2.44 (3H, s), 4.28 (2H, s), 4.87 (2H, s), 7.30 (1H, d), 7.72 (1H, d), 7.77 (1H, d), 7.85 (1H, d), 8.04 (1H, t), 8.49 - 8.53 (1H, m). m/z: ES+ [M+H]+ 450.

Example 11

2-(2-Methoxyethyl)-3,3-dimethyl-7-(5-methyl-2-((l-methyl-lH- pyrazol-5- yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo[ 1 ,2-a ^" |pyrazin- 1 (2H)-one

7-(2-Chloro-5-methylpyrimidin-4-yl)-2-(2-methoxyethyl)-3,3-d imethyl-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (48 mg, 0.14 mmol), 1 -methyl- lH-pyrazol-5- amine (14.70 mg, 0.15 mmol) and cesium carbonate (90 mg, 0.28 mmol) were suspended in tert-butanol (4 mL) and de-gassed for 10 minutes, then BrettPhos 3rd generation pre- catalyst (6.24 mg, 6.88 μιηοΐ) was added. The reaction was heated to 80 °C for 2 hours under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (10 mL) and the layers separated. The aqueous portion was washed with ethyl acetate (50 mL) and the combined organics were dried (Na ₂ S0 ₄ ) and concentrated in vacuo to a yellow gum. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% N¾) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(2-methoxyethyl)-3 ,3 -dimethyl-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l( 2H)-one (44.0 mg, 78 %) as an off white solid. ^! H NMR (500 MHz, DMSO, 30 °C) 1.11 (6H, s), 2.11 - 2.14 (3H, m), 3.08 (3H, s), 3.25 (2H, t), 3.38 (2H, t), 3.49 (3H, s), 3.93 (2H, s), 6.06 (IH, d), 7.01 (IH, d), 7.13 (IH, d), 7.38 (IH, d), 8.04 (IH, d), 8.87 (IH, s). m/z: ES+ [M+H]+ 410.

7-(2-Chloro-5-methylpyrimidin-4-yl)-2-(2-methoxyethyl)-3, 3-dimethyl-3,4- dihydro yrrolor 1 ,2-alpyrazin- 1 (2H)-one

Sodium hydride (60% dispersion in mineral oil) (12.11 mg, 0.30 mmol) was added to 7-(2- chloro-5 -methylpyrimidin-4-yl)-3 ,3 -dimethyl-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one (80 mg, 0.28 mmol) in DMF (5 mL) under nitrogen. The resulting solution was stirred at 20 °C for 30 minutes. l-Bromo-2-methoxyethane (0.029 mL, 0.30 mmol) was added and the resulting solution stirred at 20 °C for 18 hours. It was diluted with ethyl acetate (50 mL) and washed with brine (15 mL), dried (Na ₂ S04), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 7-(2- chloro-5 -methylpyrimidin-4-yl)-2-(2-methoxyethyl)-3 ,3 -dimethyl-3 ,4-dihydropyrrolo [ 1 ,2- a]pyrazin-l(2H)-one (50.0 mg, 52.1 %) as a white solid. ^l H NMR (400 MHz, DMSO, 30 °C) 1.30 (6H, s), 2.42 (3H, s), 3.27 (3H, s), 3.44 (2H, t), 3.58 (2H, t), 4.14 (2H, s), 7.24 (IH, d), 7.78 (IH, d), 8.49 (IH, s). m/z: ES+ [M+H]+ 349. Example 12

33-Dimethyl-7-(5-methyl-2-((l^

meth lpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)- one

7-(2-Chloro-5-methylpyrimidin-4-yl)-3,3-dimethyl-2-((6-methy lpyridin-2-yl)m

dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (105 mg, 0.27 mmol), 1 -methyl- lH-pyrazol-5- amine (28.3 mg, 0.29 mmol) and cesium carbonate (173 mg, 0.53 mmol) were suspended in tert-butanol (4 mL) and de-gassed for 10 minutes, then BrettPhos 3rd generation pre- catalyst (12.02 mg, 0.01 mmol) was added. The reaction was heated to 80 °C for 18 hours under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (10 mL) and the layers separated. The aqueous portion was washed with ethyl acetate (50 mL) and the combined organics were dried (Na ₂ S04), filtered and concentrated in vacuo to a yellow gum. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH ₃ ) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 3,3-dimethyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3, 4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one (67.0 mg, 55.3 %) as an off white solid. ^! H NMR (500 MHz, DMSO, 30 °C) 1.26 (6H, s), 2.35 (3H, s), 2.47 (3H, s), 3.70 (3H, s), 4.25 (2H, s), 4.75 (2H, s), 6.27 (1H, d), 7.11 (1H, d), 7.16 (1H, d), 7.27 (1H, d), 7.34 (1H, d), 7.6 - 7.66 (2H, m), 8.26 (1H, s), 9.09 (1H, s). m/z: ES+ [M+H]+ 457. 7-(2-Chloro-5-methylpyrimidin-4-v0^

dihydropyrrolor 1 ,2-alpyrazin- 1 (2H)-one

Sodium hydride (60% dispersion in mineral oil) (12.11 mg, 0.30 mmol) was added to 7-(2- chloro-5 -methylpyrimidin-4-yl)-3 ,3 -dimethyl-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one (80 mg, 0.28 mmol) in DMF (5 mL) under nitrogen. The resulting solution was stirred at 20 °C for 30 minutes. 2-(chloromethyl)-6-methylpyridine (42.9 mg, 0.30 mmol) was added and the resulting solution stirred at 20 °C for 18 hours. It was diluted with ethyl acetate (50 mL) and washed with brine (15 mL), dried (Na ₂ S04), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 7-(2-chloro-5- methylpyrimidin-4-yl)-3,3-dimethyl-2-((6-methylpyridin-2-yl) methyl)-3,4- dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one (109 mg, 100 %) as a white solid. ^! H NMR

(400 MHz, DMSO, 30 °C) 1.25 (6H, s), 2.45 (6H, d), 4.25 (2H, s), 4.74 (2H, s), 7.10 (1H, d), 7.15 (1H, d), 7.29 (1H, d), 7.61 (1H, t), 7.84 (1H, d), 8.51 (1H, s). m/z: ES+ [M+H]+

396.

Example 13

3.3 -Dimetfayl-2-( ( 1 -methyl- 1 H-p yrazol-5 -vOmethylV 7-( 5 -methyl-2-( ( 1 -methyl- 1 H- pyrazol-5-yl)amino)pyrimidin-4-yl)-3^-dihvdropyrrolori,2-a1p yrazin-l(2H)-one

7-(2-Chloro-5-methylpyrimidin-4-yl)-3, 3 -dimethyl-2-((l -methyl- 1 H-pyrazol-5 -yl)methyl)- 3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (92 mg, 0.24 mmol), 1 -methyl- 1 H-pyrazol-5 - amine (25.5 mg, 0.26 mmol) and cesium carbonate (156 mg, 0.48 mmol) were suspended in tert-butanol (4 mL) and de-gassed for 10 minutes, then BrettPhos 3rd generation pre- catalyst (10.83 mg, 0.01 mmol) was added. The reaction was heated to 80 °C for 2 hours under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (10 mL) and the layers separated. The aqueous portion was washed with ethyl acetate (50 mL) and the combined organics were dried (Na ₂ S04), filtered and concentrated in vacuo to a yellow gum. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 3,3-dimethyl-2-((l-methyl-lH-pyrazol-5-yl)methyl)-7-(5-methy l-2- (( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- l(2H)-one (58.0 mg, 54.5 %) as a white solid. ^! H NMR (500 MHz, DMSO, 30 °C) 1.29 (6H, s), 2.34 (3H, s), 3.70 (3H, s), 3.83 (3H, s), 4.23 (2H, s), 4.76 (2H, s), 6.16 (IH, d), 6.27 (IH, d), 7.27 (IH, d), 7.29 (IH, d), 7.34 (IH, d), 7.64 (IH, d), 8.25 (IH, s), 9.09 (IH, s). m/z: ES+ [M+H]+ 446.

7-(2-Chloro-5-methylpyrimidin-4-yl)-3 ,3 -dimethyl-2-((l -methyl- 1 H-pyrazol-5 -yDmethyl)-

3 ,4-dihydropyrrolo [1 ,2-a ^" |pyrazin- 1 (2H)-one

Sodium hydride (12.11 mg) was added to 7-(2-chloro-5-methylpyrimidin-4-yl)-3,3- dimethyl-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (80 mg, 0.28 mmol) in DMF (2.5 mL) at 20 °C under nitrogen. The resulting suspension was stirred at RT for 30 minutes. Sodium hydride (12.11 mg) was added to 5 -(chloromethyl)-l -methyl- lH-pyrazole hydrochloride (50.6 mg, 0.30 mmol) in DMF (2.5 mL), and the mixture was stirred at 20 °C for 10 minutes then added to the main reaction mixture. The resulting mixture was stirred for 18 hours. The mixture was quenched with brine (20 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layers were dried (Na ₂ S04), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 7-(2-chloro-5-methylpyrimidin-4-yl)-3,3-dimethyl-2-((l -methyl- lH-pyrazol-5- yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one (95 mg, 90 %) as a white solid. ^! H NMR (400 MHz, DMSO, 30 °C) 1.28 (6H, s), 2.44 (3H, s), 3.81 (3H, s), 4.24 (2H, s), 4.75 (2H, s), 6.15 (1H, d), 7.29 (2H, dd), 7.83 (1H, d), 8.51 (1H, s). m/z: ES+ [M+H]+ 385.

Example 14

7-(5-Methyl-2-((2-methylpyridin-3-yl)amino)pyrimidin-4-yl)-2 -((6-methylpyridin yl)methyl)-3 ,4-dihydropyrrolor 1 ,2-alpyrazin- 1 (2H)-one

7-(2-Chloro-5-methylpyrimidin-4-yl)-2-((6-methylpyridin-2-yl )methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (309 mg, 0.84 mmol), 2-methylpyridin-3 -amine (100 mg, 0.92 mmol) and cesium carbonate (602 mg, 1.85 mmol) were suspended in ^l BuOH (15 mL) and de-gassed for 5 minutes. BrettPhos 3rd generation pre-catalyst (38.1 mg, 0.04 mmol) was added and the reaction was heated to 100 °C for 1 hour. The reaction mixture was filtered through a layer of celite, and washed through with MeOH and DCM. The organic solution was evaporated to dryness and the crude product purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH ₃ ) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 7-(5-methyl-2-((2-methylpyridin-3-yl)amino)pyrimidin-4-yl)-2 -((6- methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin- l(2H)-one (73 mg, 20 %) as a solid. ^! H NMR (400 MHz, DMSO, 30 °C) 2.33 (3H, s), 2.46 (3H, s), 2.47 (3H, s), 3.61 - 3.91 (3H, m), 4.27 - 4.35 (2H, m), 4.72 (2H, s), 7.13 (2H, dd), 7.17 - 7.26 (2H, m), 7.62 - 7.68 (2H, m), 8.03 (1H, dd), 8.17 (1H, dd), 8.22 (1H, s), 8.52 (1H, s). m/z: ES+ [M+H]+ 440.

Example 15a (1 ^st eluting isomer) and Example 15b (2nd eluting isomer)

4-(Methox ethyl)-7-(5-methyl-2^

((6-methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a ^" |pyrazin- 1 (2H)-one

Sodium acetate (323 mg, 3.94 mmol) was added to methyl l-(l-amino-3-methoxypropan- 2-yl)-4-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)- 1 H-pyrrole-2- carboxylate dihydrochloride (620 mg, 1.31 mmol) and 6-methylpicolinaldehyde (159 mg, 1.31 mmol) in MeOH (18 mL) at 20 °C under nitrogen. The resulting solution was stirred at 20 °C for 1 hour. Sodium triacetoxyborohydride (835 mg, 3.94 mmol) was added to the reaction mixture at 0 °C and stirred at 20 °C for 1 hour and then at 60 °C for 2 hours. The reaction mixture was quenched with water (10 mL), extracted with DCM (3 x 50 mL), the organic layer was dried over Na ₂ S04, filtered and evaporated to afford a crude yellow oil. The crude product was purified by preparative HPLC (XSelect CSH Prep C18 OBD column, 5μ silica, 19 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.01% NH4HCO3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford racemic 4-(methoxymethyl)-7-(5- methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2- yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (270 mg, 43.5 %>) as a colourless oil.

Purification by preparative chiral-HPLC on a Chiralpak IA column, eluting isocratically with 50% heptane in IPA (modified with 0.2% DEA) as eluent. The fractions containing the desired compound were evaporated to dryness to afford (1 ^st eluted enantiomer) 4- (methoxymethyl)-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin- l(2H)-one (174 mg, 64.3 %) as a white solid, ^! H NMR (400 MHz, CDCb, 24.4°C) δ 2.42 (3H, s), 2.62 (3H, s), 3.29 (3H, s), 3.59-3.61 (2H, d), 3.79-3.86 (4H, m), 3.93-3.98 (1H, m), 4.39-4.44 (1H, m), 4.78- 4.81 (1H, d), 4.98-5.02 (1H, d), 6.35-6.36 (1H, d), 7.02-7.03 (1H, m), 7.13-7.15 (1H, d), 7.28-7.31 (1H, m), 7.48 (2H, s), 7.63-7.67 (2H, m), 8.20 (1H, s), m/z: ES+ [M+H]+ 473 and (2 ^nd eluted enantiomer) 4-(methoxymethyl)-7-(5-methyl-2-((l -methyl- lH-pyrazol-5 - yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3, 4-dihydropyrrolo[l,2- a]pyrazin-l(2H)-one (89.1 mg,33.0%) as a white solid. ^l H NMR (400 MHz, CDCb, 24.5 °C) δ 2.42 (3H, s), 2.60 (3H, s), 3.29 (3H, s), 3.58-3.60 (2H, d), 3.79-3.86 (4H, m), 3.93-3.98 (1H, m), 4.38-4.43 (1H, m), 4.75-4.79 (1H, d), 4.96-5.00 (1H, d), 6.34-6.35 (1H, d), 7.02-7.03 (1H, m), 7.11-7.14 (1H, d), 7.27-7.28 (1H, m), 7.48 (2H, s), 7.59-7.64 (2H, m), 8.20 (1H, s) m/z: ES+ [M+H]+ 473. tert-Butyl 5-(methoxymethy0- 1 ,2,3-oxathiazolidine-3-carboxylate 2-oxide

A solution of tert-butyl (2-hydroxy-3-methoxypropyl)carbamate (3.9 g, 19.00 mmol) in DCM (40 mL) was added dropwise to a stirred mixture of sulfurous dichloride (2.60 g, 21.85 mmol), lH-imidazole (5.17 g, 76.00 mmol) and TEA (6.09 mL, 43.70 mmol) in DCM (50 mL) at -60 °C, over a period of 20 minutes under nitrogen. The resulting mixture was stirred at -60 °C to room temperature for 16 hours. The reaction mixture was quenched with water (100 mL), extracted with DCM (2 x 200 mL), the organic layer was dried over Na ₂ S04, filtered and evaporated to afford colourless residue. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl 5-(methoxymethyl)- l,2,3-oxathiazolidine-3-carboxylate 2-oxide (3.14 g, 65.8 %) as a colourless oil. tert-Butyl 5-(methoxymethyl)-2,2-dioxo-oxathiazolidine-3-carboxylate

Ruthenium (III) chloride (0.141 g, 0.62 mmol) was added to tert-butyl 5-(methoxymethyl)- l,2,3-oxathiazolidine-3-carboxylate 2-oxide (3.14 g, 12.50 mmol) in acetonitrile (50 mL) and water (25 mL) cooled to 0 °C under nitrogen. A solution of sodium metaperiodate (3.34 g, 15.62 mmol) in water (25 mL) was added dropwise, maintaining the temperature below 10 °C. The resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with water (100 mL), saturated brine (2 xlOO mL). The organic layer was dried over Na ₂ S04, filtered and evaporated to afford desired product tert-butyl 5-(methoxymethyl)-l,2,3-oxathiazolidine-3- carboxylate 2,2-dioxide (2.86 g, 86 %) as a white solid. ^! H NMR (400 MHz, CDCb, 21.4 °C) δ 1.54(9H, s), 3.45(3H, s), 3.72-3.74(2H, m), 3.88-3.93(lH, m), 4.02-4.06(lH, m), 4.91-4.95(lH, m).

Methyl l-(l-((tert-butoxycarbonyl)amino)-3-methoxypropan-2-yl)-4-(2 -chloro-5- methyl yrimidin-4- yl)- 1 H-p yrrole-2-carboxylate

Tert-butyl 5-(methoxymethyl)-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.593 g, 5.96 mmol) was added to methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrole-2- carboxylate (lg, 3.97 mmol) and K2CO3 (1.647 g, 11.92 mmol) in acetonitrile (50 mL) at 25 °C under nitrogen. The resulting mixture was stirred at 85 °C for 16 hours. The reaction mixture was poured into water (50 mL), extracted with EtOAc (3 x 75 mL), the organic layer was dried over Na ₂ S04, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 1-(1- ((tert-butoxycarbonyl)amino)-3-methoxypropan-2-yl)-4-(2-chlo ro-5-methylpyrimidin-4- yl)-lH-pyrrole-2-carboxylate (1.100 g, 63.1 %) as a white solid, m/z: ES+ [M+H]+ 439.

Methyl 1 -( 1 -((tert-butoxycarbonyl)amino)-3 -methoxypropan-2-yl)-4-(5 -methyl-2-(( 1 - methyl- 1 H- yrazol-5 - yl)amino)pyrimidin-4-yl)- 1 H-p yrrole-2-carboxylate

3rd generation BrettPhos pre-catalyst (0.227 g, 0.25 mmol) was added to methyl 1-(1- ((tert-butoxycarbonyl)amino)-3-methoxypropan-2-yl)-4-(2-chlo ro-5-methylpyrimidin-4- yl)-lH-pyrrole-2-carboxylate (1.1 g, 2.51 mmol), 1 -methyl- lH-pyrazol-5 -amine (0.487 g, 5.01 mmol) and cesium carbonate (2.041 g, 6.27 mmol) in 1,4-dioxane (30 mL) at 25 °C under nitrogen. The resulting solution was stirred at 85 °C for 3 hours. The reaction mixture was poured into water (25 mL), extracted with EtOAc (3 x 50 mL), the organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated to afford crude yellow solid. The crude product was purified by flash silica chromatography, elution gradient 80 to 90% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 1-(1- ((tert-butoxycarbonyl)amino)-3 -methoxypropan-2-yl)-4-(5 -methyl-2-(( 1 -methyl- 1 H- pyrazol-5-yl)amino)pyrimidin-4-yl)-lH-pyrrole-2-carboxylate (0.700 g, 55.9 %) as a white foam, m/z: ES+ [M+H]+ 500. Methyl 1 -(1 -amino-3 -methoxypropan-2-yl)-4-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 - yl)amino) yrimidin-4-yl)- 1 H-pyrrole-2-carboxylate.

HC1 gas in MeOH (20 mL) was added to methyl l-(l-((tert-butoxycarbonyl)amino)-3- methoxypropan-2-yl)-4-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)- lH-pyrrole-2-carboxylate (700 mg, 1.40 mmol) under nitrogen. The resulting solution was stirred at 20 °C for 12 hours. The reaction mixture was evaporated to afford methyl 1-(1- amino-3-methoxypropan-2-yl)-4-(5-methyl-2-((l -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-lH-pyrrole-2-carboxylate.HCl (671 mg, 101 %) as a white solid, m/z: ES+ [M+H]+ 400.

Example 16

(3R)-3-(Methoxymethyl)-7-(5-methyl-2-(pyrimidin-4-ylamino)py rimidin-4-yl)-2-((6- meth lpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-a ^" |pyrazin- 1 (2H)- one

BrettPhos 3rd generation pre-catalyst (23.11 mg, 0.03 mmol) was added to a degassed solution of pyrimidin-4-amine (48.5 mg, 0.51 mmol), (3R)-7-(2-chloro-5- methylpyrimidin-4-yl)-3-(methoxymethyl)-2-((6-methylpyridin- 2-yl)methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (210 mg, 0.51 mmol) and cesium carbonate (332 mg, 1.02 mmol) in ^l BuOH (8 mL) under nitrogen. The resulting suspension was stirred at 100 °C for 4 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was dried over MgS0 ₄ , filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% N¾) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (3R)-3-(methoxymethyl)-7-(5-methyl-2-(pyrimidin-4-ylamino)py rimidin- 4-yl)-2-((6-methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[l, 2-a]pyrazin-l(2H)-one (157 mg, 65.4 %) as a yellow solid. ^! H NMR (500 MHz, DMSO, 27 °C) 2.41 (3H, s), 2.48 (3H, s), 3.24 (3H, s), 3.33 (1H, s), 3.48 (1H, dd), 4.04 (1H, d), 4.33 - 4.55 (3H, m), 5.20 (1H, d), 7.18 (2H, dd), 7.36 (1H, d), 7.67 (1H, t), 7.83 (1H, d), 8.25 - 8.38 (1H, m), 8.43 (1H, s), 8.57 (1H, d), 8.76 (1H, s), 10.18 (1H, s). m/z: ES+ [M+H]+ 471.

(R)- tert-Butyl ( 1 -hydroxy- 3 -methoxypropan-2- vDcarbamate

isoButyl chloroformate (0.599 mL, 4.56 mmol) was added dropwise to (S)-2-((tert- butoxycarbonyl)amino)-3-methoxypropanoic acid (1 g, 4.56 mmol) and N- methylmorpholine (0.501 mL, 4.56 mmol) in THF (6 mL) and cooled to 0 °C over a period of 15 minutes under nitrogen. The resulting suspension was stirred at 0 °C for a further 15 minutes. Sodium borohydride (0.500 g, 13.23 mmol) dissolved in water (1.200 mL) was added slowly to the reaction at 0 °C. The reaction was stirred for 30 minutes before being diluted with EtOAc (50 mL) and neutralised with aqueous HC1 (2M). Water was added (50 mL) and the organic layer was separated, washed with brine (50mL) and dried over MgS0 ₄ . The evaporation of the solvent gave a crude product which was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl (l-hydroxy-3-methoxypropan-2- yl)carbamate (0.510 g, 54.5 %) as a colourless oil. ¾ NMR (500 MHz, CDCb, 27 °C) 1.45 (9H, s), 3.36 (3H, s), 3.5 - 3.62 (2H, m), 3.64 - 3.73 (1H, m), 3.74 - 3.84 (2H, m), 5.16 (1H, s). m/z: ES+ [M+Na]+ 228.

(4S)-tert-Butyl 4-(methoxymethyl)-l ,2,3-oxathiazolidine-3-carboxylate 2-oxide

Imidazole (1.629 g, 23.92 mmol) was added in one portion to thionyl chloride (1.746 mL, 23.92 mmol) and triethylamine (3.33 mL, 23.92 mmol) in DCM (100 mL) and cooled to -78 °C under nitrogen. The resulting solution was stirred for 20 minutes. A solution of (R)- tert-butyl (l-hydroxy-3-methoxypropan-2-yl)carbamate (4.91 g, 23.92 mmol) in DCM (26.7 mL) was added dropwise over 10 minutes. The resulting solution was stirred at - 78 °C for 3 hours and then allowed to warm to room temperature. To the reaction mixture was added water (100 mL), and then extracted with DCM (2 x 100 mL). The organics were combined and washed with brine (100 mL), dried over MgS0 ₄ and evaporated to afford a crude product. The crude product was purified by flash silica chromatography, eluting with 10% Et ₂ 0 in DCM. Pure fractions were evaporated to dryness to afford (4S)-tert-butyl 4-(methoxymethyl)-l,2,3-oxathiazolidine-3-carboxylate 2-oxide (3.34 g, 55.6 %) as a colourless oil. ¾ NMR (500 MHz, CDCb, 27 °C) 1.55 - 1.58 (9H, m), 3.31 (0.5 H, t), 3.41 (3H, s), 3.52 - 3.63 (1H, m), 3.90 (0.5 H, dd), 4.17 - 4.4 (1H, m), 4.64 - 4.92 (1H, m), 4.94 - 5.07 (1H, m). m/z: ES+ [M+H]+ 252.

(4S)-tert-Butyl 4-(methoxymethyl)-l ,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide To a solution of (4S)-tert-butyl 4-(methoxymethyl)-l,2,3-oxathiazolidine-3-carboxylate 2- oxide (3.34 g, 13.29 mmol) in acetonitrile (30 mL) at 0 °C under nitrogen was added sequentially sodium metaperiodate (3.13 g, 14.62 mmol), ruthenium(III) chloride (0.276 g, 1.33 mmol) and water (30.0 mL) and then stirred at 0 °C for 3 hours. The reaction mixture was diluted with water (100 mL) and filtered to remove insoluble inorganic salts. The resulting solution was extracted with ether (2 x lOOmL), washed with brine (2 xlOO mL) and dried over MgS0 ₄ to give (S)-tert-butyl 4-(methoxymethyl)-l,2,3-oxathiazolidine-3- carboxylate 2,2-dioxide (2.86 g, 80 %) as an oil. ^! H NMR (500 MHz, CDCb, 27 °C) 1.56 (9H, s), 3.41 (3H, s), 3.59 (1H, t), 3.66 (1H, ddd), 4.38 (1H, dddd), 4.52 - 4.67 (2H, m). m/z: ES+ [M+H]+ 268.

(R)-Methyl l-(2-((tert-butoxycarbonyl)amino)-3-methoxypropyl)-4-(2-chlo ro-5- methylp yrimidin-4- yl)- 1 H-p yrrole-2-carboxylate

Potassium carbonate (3089 mg, 22.35 mmol) was added to (S)-tert-butyl 4- (methoxymethyl)-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (996 mg, 3.73 mmol), methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate (625 mg, 2.48 mmol) and 1,4,7, 10,13, 16-hexaoxacyclooctadecane (164 mg, 0.62 mmol) in 1,4-dioxane (30 mL) under nitrogen. The resulting solution was then stirred at 50 °C for 18 hours. The reaction mixture was concentrated and diluted with EtOAc (100 mL), washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried over MgS0 ₄ , filtered and evaporated to afford (R)-methyl l-(2-((tert-butoxycarbonyl)amino)-3- methoxypropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrol e-2-carboxylate (1250 mg, 115 %) as a white solid. ¾ NMR (500 MHz, CDCb, 27 °C) 1.30 (9H, s), 2.44 (3H, s), 3.37 (3H, s), 3.70 (1H, s), 3.86 (3H, s), 4.17 (1H, dd), 4.39 (1H, d), 4.64 (1H, dd), 5.07 (1H, d), 7.52 (1H, s), 7.66 (1H, s), 8.30 (1H, s). m/z: ES+ [M+H]+ 439.

(3R)-7-(2-Chloro-5-methylpyrm

al yrazin- 1 (2H)-one

Trifluoroacetic acid (2.87 mL, 37.25 mmol) was added to methyl l-(2-((tert- butoxycarbonyl)amino)-3-methoxypropyl)-4-(2-chloro-5-methylp yrimidin-4-yl)-lH- pyrrole-2-carboxylate (1.090 g, 2.48 mmol) in DCM (12 mL) cooled to 0 °C under nitrogen. The resulting solution was stirred at 20 °C for 18 hours. The reaction mixture was evaporated to dryness, re-dissolved in 7N ammonia in MeOH and stirred at room temperature for 5 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (100 mL) and washed sequentially with water (100 mL) and brine (10 mL). The organic layer was dried over MgS0 ₄ , filtered and evaporated to afford (3R)-7-(2-chloro-5- methylpyrimidin-4-yl)-3 -(methoxymethyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one (0.670 g, 88 %) as a white solid. ^! H NMR (500 MHz, DMSO, 27 °C) 2.37 - 2.46 (3H, m), 3.32 (3H, s), 3.33 - 3.36 (1H, m), 3.41 (1H, dd), 3.91 (1H, dt), 4.19 (1H, dd), 4.32 (1H, dd), 7.88 (1H, d), 8.00 (1H, d), 8.51 (1H, d). m/z: ES+ [M+H]+ 307.

(3R)-7-(2-Chloro-5-methylpyrimidin-4-yl)-3-(methoxymethyl )-2-((6-methylpyridin-2- yl)methyl)-3 ,4-dihydro yrrolor 1 ,2-alpyrazin- 1 (2H)-one

Sodium hydride (28.7 mg, 0.72 mmol) was added in one portion to (3R)-7-(2-chloro-5- methylpyrimidin-4-yl)-3 -(methoxymethyl)-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one (200 mg, 0.65 mmol) in DMF (8 mL). The resulting solution was stirred at 20 °C for 30 minutes. 2-(bromomethyl)-6-methylpyridine (121 mg, 0.65 mmol) was added to the reaction and stirring was continued for 4 hours. The reaction mixture was quenched with the addition of saturated aqueous NH ₄ C1 (25 mL) solution and extracted with DCM (2 x 25 mL). Evaporated to dryness to afford a crude material which was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NEb/MeOH and pure fractions were evaporated to dryness to afford (3R)-7-(2-chloro-5-methylpyrimidin-4-yl)-3-(methoxymethyl)-2 -((6-methylpyridin-2- yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (210 mg, 78 %) as a cream solid. ¾ NMR (500 MHz, DMSO, 27 °C) 2.44 (3H, s), 2.47 (3H, s), 3.23 (3H, s), 3.26 - 3.31 (IH, m), 3.46 (IH, dd), 3.96 - 4.08 (IH, m), 4.35 - 4.41 (2H, m), 4.46 (IH, dd), 5.19 (IH, d), 7.17 (2H, t), 7.28 (IH, d), 7.66 (IH, t), 7.90 (IH, d), 8.52 (IH, d). m/z: ES+ [M+H]+ 412.

Example 17a (1 ^st eluting isomer) and Example 17b (2 ^nd eluting isomer)

2-((5-Fluoro-6-methylpyridin-2-yl)methyl)-3-(methoxymethyl)- 7-(5-methyl-2-((l-methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-3^-dihvdropyrrolori,2- a1pyrazin-l(2H)-one

BrettPhos 3rd generation pre-catalyst (25.09 mg, 0.03 mmol) was added to a de-gassed solution of 7-(2-chloro-5-methylpyrimidin-4-yl)-2-((5-fluoro-6-methylpyr idin-2- yl)methyl)-3-(methoxymethyl)-3,4-dihydropyrrolo[l,2-a]pyrazi n-l(2H)-one (238 mg, 0.55 mmol), l-methyl-5-aminopyrazole (59.1 mg, 0.61 mmol) and cesium carbonate (361 mg, 1.11 mmol) in ^l BuOH (5 mL). The resulting solution was stirred at 100 °C for 4 hours. The reaction was evaporated to dryness and diluted with DCM (50 mL), washed with water (50 mL) then saturated brine (50 mL). The organic layer was dried over MgS0 ₄ , filtered and evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH ₃ ) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (±)- 2-((5-fluoro-6-methylpyridin-2-yl)methyl)-3-(methoxymethyl)- 7-(5-methyl- 2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a]pyrazin- l(2H)-one as a white solid. The racemic product was purified by preparative HPLC (Chiral Technologies IA column, 20 μιη silica, 50 mm diameter, 250 mm length), using a 50/50 mixture of Heptane/IP A as eluents 100 ml / min. Fractions containing the desired enantiomer compounds were evaporated to dryness to afford chirally pure sample of first eluted enantiomer. ^! H NMR (500 MHz, DMSO, 30 °C) 2.33 (3H, s), 2.45 (3H, d), 3.23 (3H, s), 3.30 (1H, m), 3.45 (1H, dd), 3.69 (3H, s), 3.98 - 4.07 (1H, m), 4.28 - 4.47 (3H, m), 5.17 (1H, d), 6.27 (1H, d), 7.25 (1H, d), 7.28 (1H, dd), 7.34 (1H, d), 7.54 - 7.65 (1H, m), 7.68 (1H, d), 8.25 (1H, s), 9.08 (1H, s).m/z: ES+ [M+H]+ 491 and second eluted enantiomer ^! H NMR (500 MHz, DMSO, 30 °C) 2.20 (3H, s), 2.32 (3H, d), 3.10 (3H, s), 3.17 (1H, m), 3.32 (1H, dd), 3.56 (3H, s), 3.83 - 3.92 (1H, m), 4.18 - 4.36 (3H, m), 5.03 (1H, d), 6.14 (1H, d), 7.11 (1H, d), 7.15 (1H, dd), 7.21 (1H, d), 7.42 - 7.5 (1H, m), 7.55 (1H, d), 8.12 (1H, s), 8.95 (1H, s). m/z: ES+ [M+H]+ 491.

7-(2-Chloro-5-methylpyrimidin-4-yl)-2-((5-fluoro-6-methyl pyridin-2-yl)methyl)-3- (methoxymethyl)-3 ,4-dihydropyrrolor 1 ,2-alpyrazin- 1 (2H)-one

Sodium hydride (61.7 mg, 1.54 mmol) was added to 7-(2-chloro-5-methylpyrimidin-4-yl)- 3-(methoxymethyl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (430 mg, 1.40 mmol) and 6-(chloromethyl)-3-fluoro-2-methylpyridine (224 mg, 1.40 mmol) in DMF (8 mL) under nitrogen. The resulting solution was stirred at 20 °C for 30 minutes. 6-(chloromethyl)-3- fluoro-2-methylpyridine (224 mg, 1.40 mmol) dissolved in DMF (1.00 mL) and added to the reaction and stirred for 18 hours. An additional portion of 6-(chloromethyl)-3-fluoro-2- methylpyridine (224 mg, 1.40 mmol) was added to the reaction. The reaction mixture was quenched with saturated NH ₄ C1 (20 mL) and the precipitate was collected by filtration. The solid was dissolved in DCM and passed through a phase separator cartridge. The solvent was removed by evaporation to give 7-(2-chloro-5-methylpyrimidin-4-yl)-2-((5- fluoro-6-methylpyridin-2-yl)methyl)-3 -(methoxymethyl)-3 ,4-dihydropyrrolo [ 1 ,2- a]pyrazin-l(2H)-one (238 mg, 39.5 %) as a yellow solid. ^! H NMR (500 MHz, DMSO, 27 °C) 2.39 - 2.46 (6H, m), 3.22 (3H, s), 3.25 - 3.3 (1H, m), 3.44 (1H, dd), 3.96 - 4.12 (1H, m), 4.29 - 4.52 (3H, m), 5.16 (1H, d), 7.28 (2H, dd), 7.5 - 7.7 (1H, m), 7.88 (1H, d), 8.51 (1H, d). m/z: ES+ [M+H]+ 430.

Example 18

(3 S)-3-Methyl-7-(5 -methyl -2-((3-methylpyridazin-4-yl)amino)pyrimidin-4-yl)-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one

3-Methylpyridazin-4-amine, HC1 (196 mg, 1.34 mmol), (3S)-7-(2-chloro-5- methylpyrimidin-4-yl)-3-methyl-2-((3-methylpyrazin-2-yl)meth yl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (468 mg, 1.22 mmol) and cesium carbonate (1275 mg, 3.91 mmol) were suspended in ^l BuOH (15 mL) and de-gassed for 5 minutes, then BrettPhos 3rd generation pre-catalyst (55.4 mg, 0.06 mmol) was added. The reaction was heated to 100 °C for 1 hr. The reaction mixture was passed through a layer of celite, washed through with MeOH and DCM. Evaporation afforded crude product which was chromato graphed on silica eluting with 0-30% MeOH in DCM and fractions containing desired product were evaporated to dryness. The solid was dissolved in MeOH and passed through an SCX-2 column, washed through with MeOH, and the product eluted from the column with IN ammonia in MeOH and evaporated to dryness to give crude product. The crude product was then purified by preparative HPLC (Waters XBridge Prep C 18 OBD column, 5μ silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% N¾) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (3S)-3-methyl-7-(5-methyl-2-((3- methylpyridazin-4-yl)amino)pyrimidin-4-yl)-2-((3-methylpyraz in-2-yl)methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (115 mg, 20.71 %) as a solid. ^l H NMR

(400 MHz, DMSO, 30 °C) 1.19 (3H, d), 2.39 (3H, s), 2.57 (3H, s), 2.69 (3H, s), 3.89 - 3.98 (IH, m), 4.20 (IH, dd), 4.32 - 4.44 (2H, m), 5.35 (IH, d), 7.31 - 7.35 (IH, m), 7.76 (IH, s), 8.37 (IH, d), 8.41 (3H, d), 8.75 (IH, s), 8.85 (IH, d). m/z: ES+ [M+H]+ 456.

(3 S)-7-(2-Chloro-5-methylpyrimidin-4-yl)-3 -methyl -2-((3-methylpyrazin-2-yl)methyl)-

3 ,4-dihydro yrrolor 1 ,2-alpyrazin- 1 (2H)-one

Sodium hydride (159 mg, 3.98 mmol) was added to (3S)-7-(2-chloro-5-methylpyrimidin-4- yl)-3-methyl-3,4-dihydropyrrolo[l ,2-a]pyrazin-l(2H)-one (500 mg, 1.81 mmol) in DMF (2 mL) at RT under nitrogen. The resulting suspension was stirred at RT for 30 minutes, then 2-(chloromethyl)-3-methylpyrazine.HCl (340 mg, 1.90 mmol) was added and stirred for 2 hours. The reaction was quenched with the addition of saturated aqueous NH ₄ C1 (20 mL) solution and the resulting precipitation was collected by filtration and washed with water. The residue solid was dissolved in a mixture DCM and MeOH and passed through an SCX-2 column. Washed through with MeOH and the product was eluted from the column with 7N ammonia in MeOH. Evaporation to dryness afforded (S)-7-(2-chloro- 5 -methylpyrimidin-4-yl)-3 -methyl-2-((3 -methylpyrazin-2-yl)methyl)-3 ,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (383 mg, 40.9 %) as a brown solid. ^! H NMR

(400 MHz, DMSO, 30 °C) 1.18 (3H, d), 2.44 (3H, s), 2.58 (3H, s), 3.96 (IH, dt), 4.22 (IH, dd), 4.32 - 4.44 (2H, m), 5.35 (1H, d), 7.23 - 7.31 (1H, m), 7.85 (1H, s), 8.38 - 8.46 (2H, m), 8.51 (1H, s). m/z: ES+ [M+H]+ 383.

Example 19

(3 S)-3-Methyl-7-(5 -methyl -2-(( 1 -methyl- lH-pyrazol-5 -yl)amino)p yrimidin-4-yl)-2-((2- methylpyridin-3-yl)methyl)-3,4-dihvdropyrrolori,2-a1pyrazin- l(2H)-one

(3S)-7-(2-Chloro-5-methylpyrimidin-4-yl)-3-methyl-2-((2-meth ylpyridin-3-yl)methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (118 mg, 0.31 mmol), 1 -methyl- lH-pyrazol-5- amine (33.0 mg, 0.34 mmol), cesium carbonate (201 mg, 0.62 mmol) and BrettPhos 3rd generation pre-catalyst (14.01 mg, 0.02 mmol) were suspended in tert-butanol (5 mL) and de-gassed for 10 minutes. The reaction was heated to 80 °C for 18 hours under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (10 mL) and the layers separated. The aqueous portion was washed with ethyl acetate (50 mL) and the combined organics were dried (sodium sulfate) and concentrated in vacuo to a brown gum (198 mg). The solid was taken up in DMSO (5 mL) and filtered. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH ₃ ) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (3S)-3- methyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5-yl)amino)pyrimi din-4-yl)-2-((2- methylpyridin-3-yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin- l(2H)-one (74.0 mg,

54.1 %) as a white solid. ^l H NMR (400 MHz, DMSO, 30 °C) 1.14 (3H, d), 2.32 (3H, s), 3.68 (3H, s), 3.81 (1H, d), 4.16 - 4.27 (2H, m), 4.34 (1H, dd), 5.12 (1H, d), 6.26 (1H, d), 7.20 (1H, dd), 7.27 (1H, d), 7.33 (1H, d), 7.58 - 7.7 (2H, m), 8.23 (1H, s), 8.35 (1H, d), 9.06 (1H, s). m/z: ES+ [M+H]+ 442. (3 S)-7-(2-Chloro-5-methyl yrimidin-4-yl)-3 -methyl -2-((2-methyl yridin-3-yl)methyl)-3,4- dihydropyrrolor 1 ,2-alpyrazin- 1 (2H)-one

Sodium hydride (17 mg) was added to (3S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3- methyl-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (100 mg, 0.36 mmol) in DMF (3 mL) under nitrogen. The resulting suspension was stirred at 20 °C for 30 minutes. A solution of 3-(chloromethyl)-2-methylpyridine hydrochloride (77 mg, 0.43 mmol) and sodium hydride (17 mg) in DMF (2 mL) was added followed by tetrabutylammonium iodide (26.7 mg, 0.07 mmol) and the resulting solution stirred at 20 °C for 18 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride (25 mL) and the resulting precipitate collected by filtration, washed with water, azeotroped once with toluene and dried under vacuum to give (3S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3-methyl-2-((2- methylpyridin-3-yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin- l(2H)-one (120 mg, 87 %) as a mustard coloured solid. ^! H NMR (400 MHz, DMSO, 30 °C) 1.14 (3H, d), 2.43 (3H, s), 3.82 (1H, dd), 4.19 - 4.29 (2H, m), 4.36 (1H, dd), 5.12 (1H, d), 7.20 (1H, dd), 7.30 (1H, d), 7.62 (1H, d), 7.86 (1H, d), 8.35 (1H, dd), 8.50 (1H, s). m/z: ES+ [M+H]+ 382.

Example 20

(3 S)-3-Methyl-7-(5 -methyl -2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((3- methylpyrazin-2-yl)methyl)-3 ,4-dihvdropyrrolor 1 ,2-alpyrazin- 1 (2H)-one

(3 S)-7-(2-Chloro-5-methylpyrimidin-4-yl)-3 -methyl -2-((3-methylpyrazin-2-yl)methyl)- 3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (125 mg, 0.33 mmol), 1 -methyl- lH-pyrazol- 5-amine (34.9 mg, 0.36 mmol), cesium carbonate (213 mg, 0.65 mmol) and BrettPhos 3rd generation pre-catalyst (14.80 mg, 0.02 mmol) were suspended in tert-butanol (5 mL) and de-gassed for 10 minutes. The reaction was heated to 80 °C for 18 hours under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (10 mL) and the layers separated. The aqueous portion was washed with ethyl acetate (50 mL) and the combined organics were dried (sodium sulfate) and concentrated in vacuo to a brown gum which was taken up in DMSO (5 mL) and filtered. The crude product was purified by preparative HPLC (Waters XBridge Prep CI 8 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH ₃ ) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (3S)-3-methyl-7-(5-methyl-2- (( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((3 -methylpyrazin-2-yl)methyl)-3 ,4- dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one (97 mg, 67.0 %) as a white solid. ^! H NMR (500 MHz, DMSO, 30 °C) 1.43 (3H, d), 2.58 - 2.6 (3H, m), 2.83 (3H, s), 3.94 (3H, s), 4.15 - 4.25 (1H, m), 4.44 (1H, dd), 4.55 - 4.67 (2H, m), 5.60 (1H, d), 6.52 (1H, d), 7.50 (1H, d), 7.59 (1H, d), 7.90 (1H, d), 8.49 (1H, d), 8.64 - 8.71 (2H, m), 9.33 (1H, s). m/z: ES+

[M+H]+ 443.

Example 21

(3 S)-3-Methyl-7-(5 -methyl -2-((l -methyl- lH-pyrazol-5 -yl)amino)p yrimidin-4-yl)-2-((6- methylp yrimidin-4- yl)methyl)-3 ,4-dihydrop yrrolo Γ 1 ,2-alp yrazin- 1 (2H)-one

(3 S)-7-(2-Chloro-5-methylpyrimidin-4-yl)-3 -methyl -2-((6-methylpyrimidin-4-yl)methyl)- 3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (135 mg, 0.35 mmol), 1 -methyl- lH-pyrazol- 5-amine (37.7 mg, 0.39 mmol), cesium carbonate (230 mg, 0.71 mmol) and BrettPhos 3rd generation pre-catalyst (15.98 mg, 0.02 mmol) were suspended in tert-butanol (4 mL) and de-gassed for 10 minutes. The reaction was heated to 80 °C for 18 hours under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (10 mL) and the layers separated. The aqueous portion was washed with ethyl acetate (50 mL) and the combined organics were dried (sodium sulfate) and concentrated in vacuo to a brown gum (198 mg) which was taken up in DMSO (5 mL) and filtered. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH ₃ ) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (3S)-3- methyl-7-(5-methyl-2-((l-methyl-lH-pyrazol-5-yl)amino)pyrimi din-4-yl)-2-((6- methylpyrimidin-4-yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazi n-l(2H)-one (56.0 mg, 35.8 %) as a white solid. ^! H NMR (500 MHz, DMSO, 30 °C) 1.20 (3H, d), 2.34 (3H, s), 2.47 (3H, s), 3.18 (2H, d), 3.70 (3H, s), 4.33 (IH, d), 4.50 (IH, dd), 5.11 (IH, d), 6.27 (IH, d), 7.27 (IH, d), 7.34 (IH, d), 7.39 (IH, s), 7.69 (IH, d), 8.25 (IH, s), 8.97 (IH, d), 9.09 (IH, s). m/z: ES+ [M+H]+ 444.

(3 S)-7-(2-Chloro-5-methylpyrimidin-4-yl)-3 -methyl -2-((6-methylp yrimidin-4-yl)methyl)-

3 ,4-dih dropyrrolo[ 1 ,2-a ^" |pyrazin- 1 (2H)-one

Sodium hydride (16 mg) was added to (3S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3- methyl-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (100 mg, 0.36 mmol) in DMF (5 mL) under nitrogen. The resulting suspension was stirred at 20 °C for 30 minutes. A solution of 4-(chloromethyl)-6-methylpyrimidine hydrochloride (64.7 mg, 0.36 mmol) and sodium hydride (16 mg) in DMF (2 mL) was added and the resulting solution stirred at 20 °C for 3 days. The temperature was raised to 70 °C and stirring for a further 2 hours. A solution of 4-(chloromethyl)-6-methylpyrimidine hydrochloride (64.7 mg, 0.36 mmol) and sodium hydride (16 mg) in DMF (2 mL) was added and stirring at 70 °C was continued for 18 hours. The reaction was cooled to room temperature and diluted with saturated aqueous ammonium chloride (30 mL). The resulting solution was concentrated in vacuo to a dark brown solid and the product extracted from this by trituration with ethyl acetate (2 x 100 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo to give (3 S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3 -methyl -2-((6-methylpyrimidin-4-yl)methyl)- 3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (137 mg, 99 %) as a brown solid, m/z: ES+ [M+H]+ 383.

Example 22

(3 S V2-(Y 6-(Fluoromethvnpyridin-2-vnmethvn-3 -methyl-7-( 5 -methyl-2-( ( 1 -methyl- 1 H- pyrazol-5-yl)amino)pyrimidin-4-yl)-3^-dihvdropyrrolori,2-a1p yrazin-l(2H)-one

(3S)-7-(2-Chloro-5-methylpyrimidin-4-yl)-2-((6-(fluoromethyl )pyridin-2-yl)methyl)-3- methyl-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (215 mg, 0.54 mmol), 1-methyl-lH- pyrazol-5 -amine (62.7 mg, 0.65 mmol) and cesium carbonate (385 mg, 1.18 mmol) were suspended in tert-butanol (3 mL) and de-gassed for 5 minutes, then BrettPhos 3rd generation pre-catalyst (24.37 mg, 0.03 mmol) was added. The reaction was heated at 100 °C. Further cesium carbonate (385 mg, 1.18 mmol), 1 -methyl- lH-pyrazol-5 -amine (62.7 mg, 0.65 mmol) and BrettPhos 3rd generation pre-catalyst (24.37 mg, 0.03 mmol) were added and RM heated overnight. The reaction mixture was filtered through a layer of celite, washed with DCM and MeOH and evaporated to dryness. The residue was dissolved in DCM and extracted with water remove. Dried by passing through a phase separator cartridge and chromatographed on silica eluting with 0-2-5-% MeOH/DCM. Evaporated to dryness to afford crude product which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% N¾) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (3S)-2- ((6-(fluoromethyl)pyridin-2-yl)methyl)-3 -methyl-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l( 2H)-one (25.3 mg, 10.2 %).

^ NMR ^OO MHz, DMSO, 30 °C) 1.17 (3H, s), 2.34 (3H, s), 3.69 (3H, s), 3.99 (IH, s), 4.21 (IH, d), 4.39 (2H, s), 5.18 (IH, d), 5.41 (IH, s), 5.53 (IH, s), 6.27 (IH, s), 7.26 (IH, s), 7.37 (3H, d), 7.66 (IH, s), 7.87 (IH, s), 8.24 (IH, s), 9.06 (IH, s). m/z: ES+ [M+H]+

461.

(3S)-7-(2-Chloro-5-methylpyrimidin-4-yl)-2-((6-(fluoromet hyl)pyridin-2-yl)methyl)-3- meth l-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)- one

Sodium hydride (27.0 mg, 0.68 mmol) was added to (3S)-7-(2-chloro-5-methylpyrimidin- 4-yl)-3-methyl-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (170 mg, 0.61 mmol) in DMF (2 mL) at 22 °C under nitrogen. The resulting suspension was stirred at RT for 30 minutes, then 2-(bromomethyl)-6-(fluoromethyl)pyridine (144 mg, 0.71 mmol) was added and stirred at RT for a further 30 mins. The reaction mixture was quenched with saturated aqueous NH ₄ C1 (20 mL). The resulting white solid precipitation was collected by filtration and washed with water. The solid was dissolved in DCM and dried by passing through a phase seperator cartridge. Evaporation afforded (3S)-7-(2-chloro-5-methylpyrimidin-4-yl)- 2-((6-(fluoromethyl)pyridin-2-yl)methyl)-3 -methyl-3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazin- l(2H)-one (222 mg, 90 %) as a white solid. ^l H NMR (400 MHz, DMSO, 30 °C) 1.17 (3H, d), 2.44 - 2.45 (3H, m), 4.01 (IH, ddd), 4.25 (IH, dd), 4.3 - 4.48 (2H, m), 5.19 (IH, d), 5.42 (IH, s), 5.53 (IH, s), 7.30 (IH, d), 7.40 (2H, t), 7.8 - 7.93 (2H, m), 8.51 (IH, d). m/z: ES+ [M+H]+ 400. m/z: ES+ [M+H]+ 400. Example 23

(3 S)-3-Methyl-7-(5 -methyl -2-((l -methyl- lH-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2- meth lpyrimidin-4-yl)methyl)-3 ,4-dihydropyrrolo [ 1 ,2-alpyrazin- 1 (2H)-one

(3 S)-7-(2-Chloro-5-methylpyrimidin-4-yl)-3 -methyl -2-((2-methylpyrimidin-4-yl)methyl)- 3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (122 mg, 0.32 mmol), 1 -methyl- lH-pyrazol- 5-amine (37.1 mg, 0.38 mmol) and cesium carbonate (228 mg, 0.70 mmol) were suspended in tert-butanol (2 mL) and de-gassed with nitrogen for 5 minutes, then BrettPhos 3rd generation pre-catalyst (14.44 mg, 0.02 mmol) was added. The reaction was heated to 100 °C in the microwave for 1 hour, then allowed to cool to ambient temperature, diluted with DCM (30ml), washed with brine (30ml), separated, dried (MgS0 ₄ ) and evaporated to afford crude product, which was purified by preparative HPLC (Waters XBridge Prep C 18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% N¾) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (3S)-3-methyl-7-(5-methyl-2-((l- methyl-lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((2-methylpyr imidin-4-yl)methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (67.2 mg, 47.5 %) as a pale yellow gum. ^! H NMR

(500 MHz, DMSO, 30 °C) 1.20 (3H, d), 2.34 (3H, s), 2.62 (3H, s), 3.70 (3H, s), 3.97 - 4.05 (1H, m), 4.24 (1H, dd), 4.34 (1H, d), 4.47 (1H, dd), 5.10 (1H, d), 6.27 (1H, d), 7.27 (1H, d), 7.29 (1H, d), 7.34 (1H, d), 7.69 (1H, d), 8.25 (1H, s), 8.63 (1H, d), 9.09 (1H, s). m/z: ES+ [M+H]+ 444. (3 S)-7-(2-Chloro-5-methyl yrimidin-4-yl)-3 -methyl -2-((2-methylpyrimidin-4-yl)methyl)- 3 ,4-dihydropyrrolor 1 ,2-alpyrazin- 1 (2H)-one

Sodium hydride (60% in mineral oil) (22.55 mg, 0.56 mmol) was added to a stirred solution of (3S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3-methyl-3,4-dihydr opyrrolo[l,2- a]pyrazin-l(2H)-one (130 mg, 0.47 mmol) in DMF (3 mL) at ambient temperature under nitrogen and the resulting suspension was stirred for 30 minutes. Tetrabutylammonium iodide (17.35 mg, 0.05 mmol) was then added, followed by a solution of 4-(chloromethyl)- 2-methylpyrimidine (80 mg, 0.56 mmol) in DMF (1 mL) and the reaction mixture was stirred at ambient temperature for 20 hours. The reaction was quenched with saturated aqueous NH ₄ C1 solution (30ml) and the precipitate formed was collected by filtration, washed with water (10ml), azeotroped with MeOH (30ml) and toluene (2 x 30ml) and dried under vacuum to give (3S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3-methyl-2-((2- methylpyrimidin-4-yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazi n-l(2H)-one (129 mg, 71.7

%) as a cream solid. ^l H NMR (400 MHz, DMSO, 30 °C) 1.18 (3H, d), 2.43 (3H, s), 2.60 (3H, s), 3.95 - 4.06 (1H, m), 4.26 (1H, dd), 4.34 (1H, d), 4.47 (1H, dd), 5.09 (1H, d), 7.26 - 7.31 (2H, m), 7.88 (1H, d), 8.51 (1H, s), 8.61 (1H, d). m/z: ES+ [M+H]+ 383.

Example 25 Exemplifying General Method A

(i?)-3-(Methoxymethyl)-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)- 2-((2-methylpyrimidin-4-yl)^

(i?)-7-(2-Chloro-5-methylpyrimidin-4-yl)-3-(methoxymethyl)-2 -((2-methylpyrimidin-4- yl)methyl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (150 mg, 0.36 mmol), 1-methyl- lH-pyrazol-5-amine (70.6 mg, 0.73 mmol), CS2CO3 (355 mg, 1.09 mmol) and 3rd

Generation BrettPhos precatalyst (16.47 mg, 0.02 mmol) in 1,4-dioxane (5 mL) was stirred under an atmosphere of nitrogen at 100 °C for 12 hours. The solvent was removed by distillation under vacuum. The crude product was purified by flash silica chromatography, elution gradient 4 to 6% MeOH in DCM. Pure fractions were evaporated to dryness to afford a yellow solid. This product was then further purified by preparative HPLC

(XSelect CSH Prep C18 OBD column, 5μ silica, 19 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.01% NH4HCO3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (i?)-3- (methoxymethyl)-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((2- methylpyrimidin-4-yl)methyl)-3,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one (46.3 mg, 26.9%) as a white solid. ¾ NMR (400 MHz, CDCI3, 23.8 °C) 2.43 (3H, s), 2.74 (3H, s), 3.34 (3H, s), 3.37 - 3.41 (IH, t), 3.49 - 3.53 (IH, dd), 3.83 (3H, s), 3.98 - 4.04 (IH, tt), 4.27 - 4.31 (IH, d), 4.37 - 4.41 (2H, d), 5.41 - 4.45 (IH, d), 6.34 - 6.35 (IH, d), 6.94 - 7.02 (IH, d), 7.18 - 7.20 (IH, d), 7.47 - 7.54 (3H, m), 8.21 (IH, s), 8.61-8.62 (IH, d). m/z (ES+), [M+H]+ = 474. (R)-7-(2-Chloro-5-methylpyrim

yl)methyl)-3 ,4-dihydropyrrolor 1 ,2-alpyrazin- 1 (2H)-one

Trimethylaluminum (0.583 g, 8.09 mmol) in hexane (2.5 mL) solution was added to (R)- methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-l-(3-methoxy-2-(((2-meth ylpyrimidin-4- yl)methyl)amino)propyl)-lH-pyrrole-2-carboxylate (0.9 g, 2.02 mmol) in toluene (20 mL) The resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was poured into 2M NaOH (50 mL) and extracted with DCM (150 mL). The organic layer was dried over Na ₂ S04, filtered and evaporated to afford a pale yellow oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% DCM in MeOH. Pure fractions were evaporated to dryness to afford (i?)-7-(2-chloro-5-methylpyrimidin-4-yl)-3- (methoxymethyl)-2-((2-methylpyrimidin-4-yl)methyl)-3,4-dihyd ropyrrolo[l,2-a]pyrazin- l(2H)-one (0.700 g, 84 %) as a pale yellow solid. ^l H NMR (300 MHz, CDCb, 23.8 °C) 2.52 (3H, s), 2.79 (3H, s), 3.35-3.45 (4H, m), 3.5-3.56 (1H, m), 4.01-4.08 (1H, m), 4.31 - 4.40 (3H, m), 5.38- 5.45 (1H, d), 7.25 (1H, dd), 7.45 (1H, d), 7.70 (1H, s), 8.37 (1H, s), 8.63 (1H, dd). m/z (ES+), [M+H]+ = 413.

(7?)-Methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-l-(3-methoxy-2-(((2-meth ylpyrim yl)methyl)amino)propyl)-lH-pyrrole-2-carboxylate

2-Methylpyrimidine-4-carbaldehyde (0.45 g, 3.68 mmol) was added to (i?)-methyl l-(2- amino-3-methoxypropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-l H-pyrrole-2-carboxyl^ hydrochloride (lg, 2.66 mmol) in DCM (30 mL) and stirred at 40 °C for 10 hours. The reaction was cooled to room temperature and sodium triacetoxyborohydride (1.694 g, 7.99 mmol) was added and the reaction mixture stirred at 20 °C for 2 hours. The reaction mixture was poured into saturated NaHC0 ₃ (250 mL), extracted with DCM (3 x 100 mL) and the organic layers were dried over Na ₂ S04, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (i?)-methyl 4- (2-chloro-5-methylpyrimidin-4-yl)-l-(3-methoxy-2-(((2-methyl pyrimidin-4- yl)methyl)amino)propyl)-lH-pyrrole-2-carboxylate (0.90 g, 76%) as a pale yellow solid. ^l H NMR (300 MHz, CDC1 , 23.8 °C) 2.46 (3H, s), 2.67 (3H, s), 3.18 - 3.22 (1H, m), 3.33 - 3.43 (4H, m), 3.50 - 3.56 (2H, m), 3.83 (3H, s), 3.87 - 3.96 (2H, m), 4.51 - 4.56 (2H, dd), 7.05 (1H, dd), 7.58 (1H, d), 7.78 (1H, d), 8.34 (1H, s), 8.51 (1H, dd). m/z (ES+), M+ =

445. (7?)-methyl 1 -(2-amino-3-methoxypropyl)-4-(2-chloro-5-methylpyrimidin-4-y l)- 1H- pyrrole-2-carboxylate hydrochloride

(R)-methyl l-(2-((tert-butoxycarbonyl)amino)-3-methoxypropyl)-4-(2-chlo ro-5- methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate (3 g, 6.84 mmol) was added to HC1 (0.208 mL, 6.84 mmol) in MeOH (20 mL) at 25 °C. The resulting solution was stirred at 25°C for 12 hours. The solvent was removed under reduced pressure.The dried solid was titurated with EtOAc (5 x 50 mL) and filtered to get afford (i?)-methyl l-(2-amino-3- methoxypropyl)-4-(2-chloro-5-methylpyrimidin-4-yl)-lH-pyrrol e-2-carboxylate hydrochloride (3.07 g) as a light yellow solid, which was used in the next step without further purification, m/z (ES+), [M+H]+ = 339. -Methylpyrimidine-4-carbaldehyde

3N HClaq (30 mL, 90.00 mmol) was added to 4-(dimethoxymethyl)-2-methylpyrimidine (3 g, 17.84 mmol) at room teperature. The resulting solution was stirred at 50 °C for 4 hours. The solvent was removed under reduced pressure to afford 2-methylpyrimidine-4- carbaldehyde (2.50 g, 88 %) as a red oil. ^! H NMR (DMSO, 24 °C, 400Hz) 2.81 (3H, s), 7.71(1H, d), 9.02 (1H, d), 9.93 (1H, s). m/z (ES+), [M+H]+ = 123.

The following examples were made in an analogous manner to Example 25 which exemplifies General Method A. In this method the appropriate pyrrole 2-carboxylate is reacted with the appropriate sulfamidate or mesylate and the Boc protecting group is removed before reductive amination with the appropriate aldehyde. The resulting secondary amine is then lactamised, followed by a palladium catalysed incorporation of the appropriate amino heterocycle on the C2 position of the pyrimidine. Where the required sulfamidate, mesylate, aldehyde or amino-heterocycle are not commercially, they are well known in the art or their preparation immediately follows the table below. Where chiral separation has been performed to isolate pure disateromers or enantiomers, of undefined absolute stereochemistry, the chiral purification method, elution order and retention time is recorded under the chemical name in the table.

Example Example Chemical Name ^-NMR Mass Number (chiral purification Spectru information if performed) m m/z

26 7'-(5-methyl-2-((l-methyl- (300 MHz, DMSO, 30 °C) 1.35 - 1.42 ES+ lH-pyrazol-5- (2H, m), 1.89 - 2.03 (2H, m), 2.34 [M+H]+ yl)amino)pyrimidin-4-yl)- (3H, s), 2.43 (3H, s), 3.51 - 3.59 (2H, = 499

2'-((6-methylpyridin-2- m), 3.69 (3H, s), 3.70 - 3.75 (2H, m), 4.66 (2H, s), 4.82 (2H, s), 6.27 (1H, s), hexahydro-ΓΗ- 7.10 - 7.17 (2H, m), 7.28 (1H, s), 7.33 spiro[pyran-4,3'- (1H, s), 7.59 - 7.64 (1H, m), 7.74 (1H, pyrrolo[l ,2-a]pyrazin]-l'- s), 9.12 (1H, s).

one

27 2'-(cyclopropylmethyl)-7'- (400 MHz, DMSO, 22.5 °C) 0.38 - ES+

(5-methyl-2-(pyrimidin-4- 0.39 (2H, d), 0.47 - 0.49 (2H, d), 1.02 [M+H]+ ylamino)pyrimidin-4-yl)- (1H, m), 1.56 - 1.59 (2H, d), 2.08 - = 446

2,2',3,4',5,6-hexahydro- 2.15 (2H, m), 2.33 (3H, s), 3.45 - 3.47 H-spiro[pyran-4,3'- (2H, d), 3.60 - 3.66 (2H, t), 3.81 - 3.85 pyrrolo[l ,2-a]pyrazin]-l'- (2H, dd), 4.60 (2H, s), 7.32 - 7.33 (1H, one d), 7.81 - 7.82 (1H, d), 8.31 - 8.33

(1H, dd), 8.43 (1H, s), 8.56 - 8.58 (1H, d), 8.76 (1H, s), 10.20 (1H, s). 7'-(5 -methyl-2-(( 1 -methyl- (400 MHz, DMSO, 25. FC) 1.76 - ES+ lH-pyrazol-5- 1.83 (4H, m), 2.35 - 2.39 (5H, m), [M+H]+ yl)amino)pyrimidin-4-yl)- 2.48 (3H, s), 3.69 (3H, s), 4.51 (2H, s), = 469 2'-((6-methylpyridin-2- 4.94 (2H, s), 6.27 - 6.28 (IH, d), 7.10 - yl)methyl)-2',4'-dihydro- 7.13 (2H, t), 7.24 - 7.25 (IH, d), 7.34

1 Ή-spiro [cyclobutane- - 7.36 (IH, d), 7.60 - 7.64 (IH, t), 7.72 l,3'-pyrrolo[l,2- (IH, s), 8.25 (IH, s), 9.1 1 (1H, s) .

ajpyrazin] - l'-one

2'-(2-methoxyethyl)-7'-(5- (400 MHz, DMSO, 25°C) 1.85 (2H, ES+ methyl-2-(( 1 -methyl- 1 H- d), 1.92 (2H, d), 2.33 (3H, s), 2.45 [M+H]+ pyrazol-5- (2H, d), 3.29 (3H, s), 3.42 (2H, t), 3.69 = 422 yl)amino)pyrimidin-4-yl)- (3H, s), 3.77 (2H, t), 4.37 (2H, s), 6.27

2',4'-dihydro-rH- (IH, s), 7.19 (IH, s), 7.34 (IH, s), 7.68 spiro[cyclobutane-l ,3'- (IH, s), 8.24 (IH, s), 9.10 (IH, s).

pyrrolo[l,2-a]pyrazin]- l'- one

(R)-7-(2-((l,3-dimethyl- (300 MHz, CDC13, 23°C) 2.31 (3H, ES+ lH-pyrazol-5-yl)amino)-5- s), 2.43 (3H, s), 2.71 (3H, s), 3.37 (3H, [M+H]+ methylpyrimidin-4-yl)-3 - s), 3.35 - 3.45 (IH, m), 3.50 - 3.60 = 488 (methoxymethyl)-2-((2- (IH, m), 3.96 - 4.10 (IH, ms), 4.30

methylpyrimidin-4- (IH, d), 4.40 (2H, s), 5.55 (IH, d),

yl)methyl)-3,4- 6.13 (IH, s), 6.85 (IH, bs), 7.20 (IH, dihydropyrrolo[ 1 ,2- d), 7.45 - 7.55 (2H, m), 8.22 (IH, s), ajpyrazin- 1 (2H)-one 8.62 (IH, d).

2-((l -methyl- 1 H-pyrazol- (400 MHz, DMSO, 30°C) 2.32 (3H, ES+ 5 -yl)methyl)-7-(5 -methyl - s), 3.65 (2H, dd), 3.68 (3H, s), 3.81 [M+H]+ 2-((l -methyl- 1 H-pyrazol- (3H, s), 4.23 - 4.29 (2H, m), 4.74 (2H, = 418 5-yl)amino)pyrimidin-4- s), 6.26 (2H, t), 7.26 (IH, d), 7.33 (IH, yi)-3,4- d), 7.35 (IH, d), 7.63 (IH, d), 8.22 - dihydropyrrolo[ 1 ,2- 8.24 (IH, m), 9.07 (IH, s).

ajpyrazin- 1 (2H)-one (R)-2-((6- (400 MHz,CDC13, 23.0°C) 2.43 (3H, ES+

(fluoromethyl)pyridin-2- s), 3.33 - 3.37 (4H, m), 3.46 - 3.50 [M+H]+ yl)methyl)-3- (IH, dt), 3.83 (3H, s), 4.00 - 4.07 (IH, = 491

(methoxymethyl)-7-(5 - dq), 4.24 - 4.38 (3H, m), 5.42 (IH, s), methyl-2-(( 1 -methyl- 1 H- 5.48 - 5.51 (IH, d), 5.54 (IH, s), 6.34 - pyrazol-5- 6.36 (IH, d), 6.98 (IH, s), 7.36 - 7.41

yl)amino)pyrimidin-4-yl)- (2H, t), 7.46 - 7.48 (IH, d), 7.49 - 7.51

3,4-dihydropyrrolo[l,2- (2H, d), 7.74 - 7.78 (IH, t), 8.20 (IH, ajpyrazin- 1 (2H)-one s).

a 3 ,4-dimethyl-7-(5 -methyl- (400 MHz, DMSO, 23°C) 1.22 (6H, ES+

2-((3 -methylpyridazin-4- dd), 2.40 (3H, s), 2.60 (3H, s), 2.70 [M+H]+ yl)amino)pyrimidin-4-yl)- (3H, s), 3.71 (IH, q), 4.28 (IH, d), = 470

2-((3 -methylpyrazin-2- 4.43 (IH, q), 5.40 (IH, d), 7.34 (IH,

yl)methyl)-3,4- d), 7.83 (IH, d), 8.36 - 8.50 (4H, m),

dihydropyrrolo[ 1 ,2- 8.79 (IH, s), 8.87 (IH, d).

ajpyrazin- 1 (2H)-one.

(ChiralCel IC column,

eluting isocratically with

50% MeOH in DCM

(modified with 0.1%DEA)

as eluent. 1st eluting,

retention time 3.29 mins)

b 3,4-dimethyl-7-(5-methyl- (400 MHz, DMSO, 23°C) 1.22 (6H, ES+

2-((3 -methylpyridazin-4- dd), 2.40 (3H, s), 2.60 (3H, s), 2.70 [M+H]+ yl)amino)pyrimidin-4-yl)- (3H, s), 3.71 (IH, q), 4.28 (IH, d), = 470

2-((3 -methylpyrazin-2- 4.43 (IH, q), 5.40 (IH, d), 7.34 (IH,

yl)methyl)-3,4- d), 7.83 (IH, d), 8.36 - 8.50 (4H, m),

dihydropyrrolo[ 1 ,2- 8.79 (IH, s), 8.87 (IH, d).

ajpyrazin- 1 (2H)-one.

(ChiralCel IC column,

eluting isocratically with 50% MeOH in DCM

(modified with 0.1%DEA)

as eluent. 2nd eluting,

retention time 3.66 mins)

c 3,4-dimethyl-7-(5-methyl- (400 MHz, DMSO, 22°C) 1.06 (3H, ES+

2-((3 -methylpyridazin-4- d), 1.54 (3H, d), 2.42 (3H, s), 2.59 [M+H]+ yl)amino)pyrimidin-4-yl)- (3H, s), 2.70 (3H, s), 3.81 (IH, dt), = 470

2-((3 -methylpyrazin-2- 4.38 (IH, d), 4.59 - 4.68 (IH, m), 5.38 yl)methyl)-3,4- (IH, d), 7.34 (IH, d), 7.70 (IH, d),

dihydropyrrolo[ 1 ,2- 8.35 - 8.47 (4H, m), 8.79 - 8.89 (2H,

ajpyrazin- 1 (2H)-one. m).

(ChiralCel IC column,

eluting isocratically with

50% MeOH in DCM

(modified with 0.1%DEA)

as eluent. 3rd eluting,

retention time 4.05 mins)

d 3,4-dimethyl-7-(5-methyl- (400 MHz, DMSO, 22°C) 1.06 (3H, ES+

2-((3 -methylpyridazin-4- d), 1.54 (3H, d), 2.42 (3H, s), 2.59 [M+H]+ yl)amino)pyrimidin-4-yl)- (3H, s), 2.70 (3H, s), 3.81 (IH, dt), = 470

2-((3 -methylpyrazin-2- 4.38 (IH, d), 4.59 - 4.68 (IH, m), 5.38 yl)methyl)-3,4- (IH, d), 7.34 (IH, d), 7.70 (IH, d),

dihydropyrrolo[ 1 ,2- 8.35 - 8.47 (4H, m), 8.79 - 8.89 (2H,

ajpyrazin- 1 (2H)-one. m).

(ChiralCel IC column,

eluting isocratically with

50% MeOH in DCM

(modified with 0.1%DEA)

as eluent. 4th eluting,

retention time 6.16 mins) a 3 ,4-dimethyl-7-(5 -methyl- (300 MHz, DMSO, 24.2°C) 1.12 (3H, ES+

2-((l -methyl- 1 H-pyrazol- d), 1.21 (3H, d), 2.31 (3H, s), 2.45 [M+H]+

5-yl)amino)pyrimidin-4- (3H, s), 3.68 (3H, s), 3.70 (IH, t), 4.17 = 457 yl)-2-((6-methylpyridin-2- (IH, d), 4.39 (IH, q), 5.18 (IH, d),

yl)methyl)-3,4- 6.27 (IH, s), 7.16 (2H, t), 7.21 (IH, s), dihydropyrrolo[ 1 ,2- 7.32 (IH, d), 7.68 (2H, t), 8.22 (IH, s), ajpyrazin- 1 (2H)-one 9.10 (IH, s).

(Chiralpak IA 2*25cm,

5um Chiral-

P(IA)008S90IA0SCJ-

QE001 column, eluting

isocratically with 50%

EtOH in heptane

(modified with DEA) as

eluent; 1st eluting,

retention time 2.00 mins)

b 3,4-dimethyl-7-(5-methyl- (300 MHz, DMSO, 21.6°C) 1.00 (3H, ES+

2-((l -methyl- 1 H-pyrazol- d), 1.51 (3H, d), 2.32 (3H, s), 2.47 [M+H]+

5-yl)amino)pyrimidin-4- (3H, s), 3.68 (3H, s), 3.82 (IH, t), 4.28 = 457 yl)-2-((6-methylpyridin-2- (IH, d), 4.63 (IH, q), 5.16 (IH, d),

yl)methyl)-3,4- 6.24 (IH, s), 7.15 (2H, t), 7.26 (IH, s), dihydropyrrolo[ 1 ,2- 7.32 (IH, s), 7.59 (IH, s), 7.63 (2H, t), ajpyrazin- 1 (2H)-one. 8.23 (IH, s), 9.11 (IH, s).

(Chiralpak IA 2*25cm,

5um Chiral-

P(IA)008S90IA0SCJ-

QE001 column, eluting

isocratically with 50%

EtOH in heptane

(modified with DEA) as

eluent; 2nd eluting,

retention time 2.85 mins) c 3 ,4-dimethyl-7-(5 -methyl- (300 MHz, DMSO, 24.0°C) 1.12 (3H, ES+

2-((l -methyl- 1 H-pyrazol- d), 1.21 (3H, d), 2.31 (3H, s), 2.45 [M+H]+

5-yl)amino)pyrimidin-4- (3H, s), 3.68 (3H, s), 3.70 (IH, t), 4.17 = 457 yl)-2-((6-methylpyridin-2- (IH, d), 4.39 (IH, q), 5.18 (IH, d),

yl)methyl)-3,4- 6.27 (IH, s), 7.16 (2H, t), 7.25 (IH, s), dihydropyrrolo[ 1 ,2- 7.32 (IH, d), 7.68 (2H, t), 8.22 (IH, s), ajpyrazin- 1 (2H)-one. 9.10 (IH, s).

(Chiralpak IA 2*25cm,

5um Chiral-

P(IA)008S90IA0SCJ-

QE001 column, eluting

isocratically with 50%

EtOH in heptane

(modified with DEA) as

eluent; 3rd eluting,

retention time 3.67 mins)

d 3,4-dimethyl-7-(5-methyl- (300 MHz, DMSO, 21.6°C) 1.00 (3H, ES+

2-((l -methyl- 1 H-pyrazol- d), 1.51 (3H, d), 2.32 (3H, s), 2.47 [M+H]+

5-yl)amino)pyrimidin-4- (3H, s), 3.68 (3H, s), 3.82 (IH, t), 4.28 = 457 yl)-2-((6-methylpyridin-2- (IH, d), 4.63 (IH, q), 5.16 (IH, d),

yl)methyl)-3,4- 6.24 (IH, s), 7.15 (2H, t), 7.26 (IH, s), dihydropyrrolo[ 1 ,2- 7.32 (IH, s), 7.59 (IH, s), 7.63 (IH, t), ajpyrazin- 1 (2H)-one. 8.23 (IH, s), 9.11 (IH, s).

(Chiralpak IA 2*25cm,

5um Chiral-

P(IA)008S90IA0SCJ-

QE001 column, eluting

isocratically with 50%

EtOH in heptane

(modified with DEA) as

eluent; 4 ^th eluting,

retention time 5.28 mins) (R)-3-(methoxymethyl)-7- (400MHz, DMSO, 23°C) 2.40 (3H, s), ES+ (5-methyl-2-((3- 2.47 (3H, s), 2.70 (3H, s), 3.24 (3H, s), [M+H]+ methylpyridazin-4- 3.30 (1H, s), 3.45 - 3.49 (1H, s), 4.04 = 485 yl)amino)pyrimidin-4-yl)- (1H, s), 4.37 - 4.48 (3H, m), 5.19 (1H,

2-((6-methylpyridin-2- s), 7.15-7.19 (2H, m), 7.34 (1H, s),

yl)methyl)-3,4- 7.64-7.68 (1H, m), 7.82 (1H, s), 8.38 - dihydropyrrolo[ 1 ,2- 8.41 (2H, m), 8.79 (1H, s), 8.86 (1H,

ajpyrazin- 1 (2H)-one d).

3 ,3 -dimethyl-7-(5 -methyl- (400 MHz, DMSO, 23°C) 1.28 (6H, ES+ 2-((l -methyl- 1 H-pyrazol- s), 2.34 (3H, s), 2.61 (3H, s), 3.69 (3H, [M+H]+ 5-yl)amino)pyrimidin-4- s), 4.30 (2H, s), 4.72 (2H, s), 6.27 (1H, = 458 yl)-2 -((2 -methylpyrimidin- d), 7.25 - 7.37 (3H, m), 7.67 (1H, d),

4-yl)methyl)-3,4- 8.26 (1H, s), 8.60 (1H, d), 9.13 (1H,

dihydropyrrolo[ 1 ,2- s).

ajpyrazin- 1 (2H)-one

(R)-2-((6- (400 MHz, DMSO, 23.3°C) 2.33 (3H, ES+

(difluoromethyl)pyridin-2- s), 3.23 (3H, s), 3.30 - 3.34 (1H, m), [M+H]+ yl)methyl)-3- 3.46 - 3.50 (1H, dd), 3.69 (3H, s), 4.05 = 509 (methoxymethyl)-7-(5 - - 4.08 (1H, m), 4.42 - 4.44 (2H, d),

methyl-2-(( 1 -methyl- 1 H- 4.50 - 4.54 (1H, d), 5.23 - 5.27 (1H,

pyrazol-5- d), 6.26 - 6.28 (1H, d), 6.83 - 7.11

yl)amino)pyrimidin-4-yl)- (1H, t), 7.24 - 7.26 (1H, d), 7.33 - 7.35

3,4-dihydropyrrolo[l,2- (1H, d), 7.57 - 7.62 (2H, dd), 7.70 - ajpyrazin- 1 (2H)-one 7.71 (1H, d), 7.97 - 8.01 (1H, t), 8.25

(1H, s), 9.12 (1H, s).

2-(2-methoxyethyl)-3 ,4- (300 MHz, MeOD, 26°C) 1.25 (3H, ES+ dimethyl-7-(5 -methyl-2- d), 1.50 (3H, d), 2.42 (3H, s), 3.18 - [M+H]+ (( 1 -methyl- 1 H-pyrazol-5 - 3.26 (1H, m), 3.30 (3H, s), 3.59 - 3.70 = 410 yl)amino)pyrimidin-4-yl)- (2H, m), 3.78 (3H, s), 3.87 - 3.93 (1H,

3,4-dihydropyrrolo[l,2- m), 4.21 - 4.29 (1H, m), 4.36 - 4.42

ajpyrazin- 1 (2H)-one. (Chiralpak IB column, (IH, m), 6.35 (IH, s), 7.45 (2H, s),

eluting isocratically with 7.66 (IH, s), 8.19 (IH, s).

50% EtOH in heptane

(modified with IP A) as

eluent. 1st eluting,

retention time 2.32 mins)

b 2-(2-methoxyethyl)-3 ,4- (300 MHz, MeOD, 26°C) 1.25 (3H, ES+ dimethyl-7-(5 -methyl-2- d), 1.50 (3H, d), 2.42 (3H, s), 3.18 - [M+H]+

(( 1 -methyl- 1 H-pyrazol-5 - 3.26 (IH, m), 3.30 (3H, s), 3.59 - 3.70 = 410 yl)amino)pyrimidin-4-yl)- (2H, m), 3.78 (3H, s), 3.87 - 3.93 (IH,

3,4-dihydropyrrolo[l,2- m), 4.21 - 4.29 (IH, m), 4.36 - 4.42

ajpyrazin- 1 (2H)-one. (IH, m), 6.35 (IH, s), 7.45 (2H, s),

(Chiralpak IB column, 7.66 (lH ,s) , 8.19 (IH, s).

eluting isocratically with

50% EtOH in heptane

(modified with IP A) as

eluent. 2nd eluting,

retention time 3.43 mins)

a 3,4-dimethyl-7-(5-methyl- (300 MHz, DMSO, 24°C) 1.19 (6H, ES+

2-(pyrimidin-4- td), 2.39 (3H, s), 2.59 (3H, s), 3.66 - [M+H]+ ylamino)pyrimidin-4-yl)- 3.77 (IH, m), 4.27 (IH, d), 4.36 - 4.47 = 456

2-((3 -methylpyrazin-2- (IH, m), 5.39 (IH, d), 7.34 (IH, d),

yl)methyl)-3,4- 7.83 (IH, d), 8.32 (IH, dd), 8.44 (3H, dihydropyrrolo[ 1 ,2- dd), 8.56 (IH, d), 8.75 (IH, s), 10.18

ajpyrazin- 1 (2H)-one. (IH, s).

(ChiralCel IC column,

eluting isocratically with

30% DCM in MeOH

(modified with 0.1%IPA)

as eluent. 1st eluting,

retention time 2.12 mins) b 3 ,4-dimethyl-7-(5 -methyl- (300 MHz, DMSO, 24°C) 1.19 (6H, ES+

2-(pyrimidin-4- td), 2.39 (3H, s), 2.59 (3H, s), 3.66 - [M+H]+ ylamino)pyrimidin-4-yl)- 3.77 (IH, m), 4.27 (IH, d), 4.36 - 4.47 = 456

2-((3 -methylpyrazin-2- (IH, m), 5.39 (IH, d), 7.34 (IH, d),

yl)methyl)-3,4- 7.83 (IH, d), 8.32 (IH, dd), 8.44 (3H, dihydropyrrolo[ 1 ,2- dd), 8.56 (IH, d), 8.75 (IH, s), 10.18

ajpyrazin- 1 (2H)-one. (IH, s).

(ChiralCel IC column,

eluting isocratically with

30% DCM in MeOH

(modified with 0.1%IPA)

as eluent. 2nd eluting,

retention time 3.21 mins)

c 3,4-dimethyl-7-(5-methyl- 400 MHz, DMSO, 22°C) 1.07 (3H, d), ES+

2-(pyrimidin-4- 1.54 (3H, d), 2.43 (3H, s), 2.59 (3H, [M+H]+ ylamino)pyrimidin-4-yl)- s), 3.82 (IH, dd), 4.38 (IH, d), 4.65 = 456

2-((3 -methylpyrazin-2- (IH, dd), 5.38 (IH, d), 7.35 (IH, d),

yl)methyl)-3,4- 7.72 (IH, d), 8.33 (IH, dd), 8.39 - 8.47 dihydropyrrolo[ 1 ,2- (3H, m), 8.56 (IH, d), 8.76 (IH, s),

ajpyrazin- 1 (2H)-one. 10.24 (IH, s).

(ChiralCel IC column,

eluting isocratically with

30% DCM in MeOH

(modified with 0.1%IPA)

as eluent. 3rd eluting,

retention time 4.39 mins)

d 3,4-dimethyl-7-(5-methyl- (400 MHz, DMSO, 22°C) 1.07 (3H, ES+

2-(pyrimidin-4- d), 1.54 (3H, d), 2.43 (3H, s), 2.59 [M+H]+ ylamino)pyrimidin-4-yl)- (3H, s), 3.82 (IH, dd), 4.38 (IH, d), = 456

2-((3 -methylpyrazin-2- 4.65 (IH, dd), 5.38 (IH, d), 7.35 (IH, yl)methyl)-3,4- d), 7.72 (IH, d), 8.33 (IH, dd), 8.39 - dihydropyrrolo[ 1 ,2- 8.47 (3H, m), 8.56 (IH, d), 8.76 (IH, ajpyrazin- 1 (2H)-one. s), 10.24 (IH, s). m/z (ES+), [M+H]+

(ChiralCel IC column, = 456

eluting isocratically with

30% DCM in MeOH

(modified with 0.1%IPA)

as eluent. 4th eluting,

retention time 9.37 mins)

7'-(5-methyl-2-((l-methyl- (400 MHz, DMSO, 20°C,) 1.75 - 1.84 ES+ lH-pyrazol-5- (4H, m), 2.35 (3H, s), 2.39 - 2.43 (2H, [M+H]+ yl)amino)pyrimidin-4-yl)- m), 2.62 (3H, s), 3.69 (3H, s), 4.50 = 470 2'-((3-methylpyrazin-2- (2H, s), 5.10 (2H, s), 6.27 (IH, s), 7.21 yl)methyl)-2',4'-dihydro- (IH, s), 7.34 (IH, s), 7.73 (IH, s), 8.26

1 Ή-spiro [cyclobutane- (IH, s), 8.37 (2H, d), 9.12 (IH, s).

l,3'-pyrrolo[l,2- ajpyrazin] - l'-one

(R)-3-(methoxymethyl)-7- (300 MHz, CDC13, 26.2°C) 2.46 (3H, ES+ (5-methyl-2-((3- s), 2.68 (3H, s), 2.76 (3H, s), 3.34 - [M+H]+ methylpyridazin-4- 3.44 (4H, m), 3.50 - 3.55 (IH, m), = 486 yl)amino)pyrimidin-4-yl)- 4.05 (IH, s), 4.25 - 4.47 (3H, m), 5.65

2-((3 -methylpyrazin-2- - 5.70 (IH, d), 7.10 (IH, s), 7.50 (2H, yl)methyl)-3,4- s), 8.31 - 8.34 (2H, m), 8.39 - 8.40

dihydropyrrolo[ 1 ,2- (IH, d), 8.68 - 8.70 (lH, d), 8.91 - ajpyrazin- 1 (2H)-one 8.93 (IH, d)).

(R)-3-(methoxymethyl)-7- (400 MHz, CDC13, 23.8°C) 2.50 (3H, ES+

(5-methyl-2-((3- s), 2.75 (3H, s), 2.81 (3H, s), 3.36 (3H, [M+H]+ methylpyridazin-4- s), 3.38 - 3.46 (IH, m), 3.53 - 3.57 = 486 yl)amino)pyrimidin-4-yl)- (IH, dd), 4.07 (IH, s), 4.29 - 4.33 (IH,

2-((2-methylpyrimidin-4- d), 4.45 (2H, s), 5.43 - 5.47 (IH, d),

yl)methyl)-3,4- 7.20 - 7.23 (2H, m), 7.55 - 7.56 (2H, dihydropyrrolo[ 1 ,2- d), 8.36 (IH, s), 8.62 - 8.63 (IH, d),

ajpyrazin- 1 (2H)-one 8.82 (IH, s), 8.98 (IH, s).

(R)-3-(methoxymethyl)-7- (400 MHz, DMSO, 21.2°C) 2.30 (3H, ES+ (5 -methyl -2-(( 1 -methyl- s), 2.57 (3H, s), 3.24 (3H, s), 3.29 - [M+H]+ lH-pyrazol-5- 3.32 (IH, d), 3.46 - 3.50 (IH, dd), 3.69 = 474 yl)amino)pyrimidin-4-yl)- (3H, s), 3.97 (IH, s), 4.31 - 4.47 (3H,

2-((3 -methylpyrazin-2- m), 5.35 - 5.39 (IH, d), 6.26 - 6.28

yl)methyl)-3,4- (IH, d), 7.22 - 7.24 (IH, d), 7.33 - dihydropyrrolo[ 1 ,2- 7.34 (IH, d), 7.68 - 7.69 (IH, d), 8.25 ajpyrazin- 1 (2H)-one (IH, s), 8.41 - 8.43 (2H, m), 9.12 (IH,

s).

a 7-(2-((l,3-dimethyl-lH- (400 MHz, DMSO, 2FC) 1.20 (6H, ES+ pyrazol-5 -yl)amino)-5 - dd), 2.12 (3H, s), 2.32 (3H, s), 2.59 [M+H]+ methylpyrimidin-4-yl)- (3H, s), 3.59 (3H, s), 3.68 (IH, q), = 472 3,4-dimethyl-2-((3- 4.26 (IH, d), 4.40 (IH, q), 5.39 (IH,

methylpyrazin-2- d), 6.03 (IH, s), 7.25 (IH, d), 7.69

yl)methyl)-3,4- (IH, d), 8.22 (IH, s), 8.45 (2H, dd),

dihydropyrrolo[ 1 ,2- 9.02 (IH, s).

ajpyrazin- 1 (2H)-one.

(Chiralpak IA column,

eluting isocratically with

30% EtOH in Hex

(modified with 0.2%DEA)

as eluent. 1st eluting,

retention time 3.55 mins)

b 7-(2-((l,3-dimethyl-lH- (400 MHz, DMSO, 2FC) 1.20 (6H, ES+ pyrazol-5-yl)amino)-5- dd), 2.12 (3H, s), 2.32 (3H, s), 2.59 [M+H]+ methylpyrimidin-4-yl)- (3H, s), 3.59 (3H, s), 3.68 (IH, q), = 472

3,4-dimethyl-2-((3- 4.26 (IH, d), 4.40 (IH, q), 5.39 (IH,

methylpyrazin-2- d), 6.03 (IH, s), 7.25 (IH, d), 7.69

yl)methyl)-3,4- dihydropyrrolo[ 1 ,2- (IH, d), 8.22 (IH, s), 8.45 (2H, dd),

ajpyrazin- 1 (2H)-one. 9.02 (IH, s).

(Chiralpak IA column,

eluting isocratically with

30% EtOH in Hex

(modified with 0.2%DEA)

as eluent. 2nd eluting,

retention time 4.24 mins)

c 7-(2-((l,3-dimethyl-lH- (400 MHz, DMSO, 2FC) 1.05 (3H, ES+ pyrazol-5-yl)amino)-5- d), 1.51 (3H, d), 2.11 (3H, s), 2.34 [M+H]+ methylpyrimidin-4-yl)- (3H, s), 2.58 (3H, s), 3.60 (3H, s), 3.79 = 472

3,4-dimethyl-2-((3- (IH, dd), 4.36 (IH, d), 4.62 (IH, dd), methylpyrazin-2- 5.38 (IH, d), 6.05 (IH, s), 7.25 (IH,

yl)methyl)-3,4- d), 7.61 (IH, d), 8.23 (IH, s), 8.39 - dihydropyrrolo[ 1 ,2- 8.46 (2H, m), 9.06 (IH, s).

ajpyrazin- 1 (2H)-one.

(Chiralpak IA column,

eluting isocratically with

30% EtOH in Hex

(modified with 0.2%DEA)

as eluent. 3rd eluting,

retention time 5.09 mins)

d 7-(2-((l,3-dimethyl-lH- (400 MHz, DMSO, 2FC) 1.05 (3H, ES+ pyrazol-5-yl)amino)-5- d), 1.51 (3H, d), 2.11 (3H, s), 2.34 [M+H]+ methylpyrimidin-4-yl)- (3H, s), 2.58 (3H, s), 3.60 (3H, s), 3.79 = 472

3,4-dimethyl-2-((3- (IH, dd), 4.36 (IH, d), 4.62 (IH, dd), methylpyrazin-2- 5.38 (IH, d), 6.05 (IH, s), 7.25 (IH,

yl)methyl)-3,4- d), 7.61 (IH, d), 8.23 (IH, s), 8.39 - dihydropyrrolo[ 1 ,2- 8.46 (2H, m), 9.06 (IH, s).

ajpyrazin- 1 (2H)-one. (Chiralpak IA column,

eluting isocratically with

30% EtOH in Hex

(modified with 0.2%DEA)

as eluent. 4th eluting,

retention time 6.45 mins)

a 3,4-dimethyl-7-(5-methyl- (400 MHz, DMSO, 22°C) 1.19 (6H, ES+ 2-((l -methyl- 1 H-pyrazol- dd), 2.33 (3H, s), 2.59 (3H, s), 3.69 [M+H]+ 5-yl)amino)pyrimidin-4- (4H, s), 4.26 (IH, d), 4.40 (IH, q), = 458 yl)-2-((3 -methylpyrazin-2- 5.39 (IH, d), 6.28 (IH, d), 7.25 (IH,

yl)methyl)-3,4- d), 7.34 (IH, d), 7.70 (IH, d), 8.24

dihydropyrrolo[ 1 ,2- (IH, s), 8.45 (2H, dd), 9.10 (IH, s).

ajpyrazin- 1 (2H)-one

(Chiralpak IA column,

eluting isocratically with

50% IPA in Hex (modified

with 0.1%DEA) as eluent;

1st eluting compound,

retention time 2.4 mins)

b 3,4-dimethyl-7-(5-methyl- (400 MHz, DMSO, 23°C) 1.02 - 1.08 ES+

2-((l -methyl- 1 H-pyrazol- (3H, m), 1.51 (3H, d), 2.35 (3H, s), [M+H]+ 5-yl)amino)pyrimidin-4- 2.58 (3H,s), 3.69 (3H, s), 3.79 (IH, = 458 yl)-2-((3 -methylpyrazin-2- dt), 4.36 (IH, d), 4.62 (IH, dd), 5.37

yl)methyl)-3,4- (IH, d), 6.26 (IH, d), 7.25 (IH, d),

dihydropyrrolo[ 1 ,2- 7.33 (IH, d), 7.59 (IH, d), 8.25 (IH,

ajpyrazin- 1 (2H)-one s), 8.38 - 8.46 (2H, m), 9.12 (IH, s).

(Chiralpak IA column,

eluting isocratically with

50% IPA in Hex (modified

with 0.1%DEA) as eluent; 2nd eluting, retention time

3.31 mins)

c 3,4-dimethyl-7-(5-methyl- (400 MHz, DMSO, 22°C) 1.19 (6H, ES+

2-((l -methyl- 1 H-pyrazol- dd), 2.33 (3H, s), 2.59 (3H, s), 3.69 [M+H]+

5-yl)amino)pyrimidin-4- (4H, s), 4.26 (IH, d), 4.40 (IH, q), = 458 yl)-2-((3 -methylpyrazin-2- 5.39 (IH, d), 6.28 (IH, d), 7.25 (IH,

yl)methyl)-3,4- d), 7.34 (IH, d), 7.70 (IH, d), 8.24

dihydropyrrolo[ 1 ,2- (IH, s), 8.45 (2H, dd), 9.10 (IH, s).

ajpyrazin- 1 (2H)-one

(Chiralpak IA column,

eluting isocratically with

50% IPA in Hex (modified

with 0.1%DEA) as eluent;

2nd eluting, retention time

3.31 mins, 3rd eluting,

retention time 5.5 mins)

d 3,4-dimethyl-7-(5-methyl- (400 MHz, DMSO, 23°C) 1.02 - 1.08 ES+

2-((l -methyl- 1 H-pyrazol- (3H, m), 1.51 (3H, d), 2.35 (3H, s), [M+H]+

5-yl)amino)pyrimidin-4- 2.58 (3H, s), 3.69 (3H, s), 3.79 (IH, = 458 yl)-2-((3 -methylpyrazin-2- dt), 4.36 (IH, d), 4.62 (IH, dd), 5.37

yl)methyl)-3,4- (IH, d), 6.26 (IH, d), 7.25 (IH, d),

dihydropyrrolo[ 1 ,2- 7.33 (IH, d), 7.59 (IH, d), 8.25 (IH,

ajpyrazin- 1 (2H)-one. s), 8.38 - 8.46 (2H, m), 9.12 (IH, s).

(Chiralpak IA column,

eluting isocratically with

50% IPA in Hex (modified

with 0.1%DEA) as eluent;

4th eluting, retention time

7.28 mins) a 7-(2-((l,3-dimethyl-lH- 1H NMR (400 MHz, DMSO, 23°C) ES+ pyrazol-4-yl)amino)-5- 1.20 (6H, dd), 2.11 (3H, s), 2.30 (3H, [M+H]+ methylpyrimidin-4-yl)- s), 2.59 (3H, s), 3.74 (4H, s), 4.26 (1H, = 472

3,4-dimethyl-2-((3- d), 4.40 (1H, q), 5.40 (1H, d), 7.26

methylpyrazin-2- (1H, s), 7.70 (1H, d), 7.81 (1H, s),

yl)methyl)-3,4- 8.16 (1H, s), 8.36 (1H, s), 8.41 - 8.49

dihydropyrrolo[ 1 ,2- (2H, m).

ajpyrazin- 1 (2H)-one.

(Chiralpak IA column,

eluting isocratically with

50% IPA in Hex (modified

with 0.2%DEA) as eluent.

1st eluting, retention time

3.12 mins)

b 7-(2-((l,3-dimethyl-lH- (400 MHz, DMSO, 23°C) 1.06 (3H, ES+ pyrazol-4-yl)amino)-5- d), 1.52 (3H, d), 2.12 (3H, s), 2.32 [M+H]+ methylpyrimidin-4-yl)- (3H, s), 2.58 (3H, s), 3.71 - 3.84 (4H, = 472

3,4-dimethyl-2-((3- m), 4.36 (1H, d), 4.56 - 4.67 (1H, m), methylpyrazin-2- 5.38 (1H, d), 7.23 - 7.28 (1H, m), 7.62 yl)methyl)-3,4- (1H, d), 7.84 (1H, s), 8.17 (1H, s),

dihydropyrrolo[ 1 ,2- 8.36 - 8.47 (3H, m).

ajpyrazin- 1 (2H)-one.

(Chiralpak IA column,

eluting isocratically with

50% IPA in Hex (modified

with 0.2%DEA) as eluent.

2nd eluting, retention time

4.55 mins)

c 7-(2-((l,3-dimethyl-lH- (400 MHz, DMSO, 23°C) 1.20 (6H, ES+ pyrazol-4-yl)amino)-5- dd), 2.11 (3H, s), 2.30 (3H, s), 2.59 [M+H]+ methylpyrimidin-4-yl)- (3H, s), 3.74 (4H, s), 4.26 (1H, d), = 472 3,4-dimethyl-2-((3- 4.40 (IH, q), 5.40 (IH, d), 7.26 (IH,

methylpyrazin-2- s), 7.70 (IH, d), 7.81 (IH, s), 8.16

yl)methyl)-3,4- (IH, s), 8.36 (IH, s), 8.41 - 8.49 (2H, dihydropyrrolo[ 1 ,2- m).

ajpyrazin- 1 (2H)-one.

(Chiralpak IA column,

eluting isocratically with

50% IPA in Hex (modified

with 0.2%DEA) as eluent.

3rd eluting, retention time

8.69 mins)

7-(2-((l,3-dimethyl-lH- (400 MHz, DMSO, 23°C) 1.06 (3H, ES+ pyrazol-4-yl)amino)-5- d), 1.52 (3H, d), 2.12 (3H, s), 2.32 [M+H]+ methylpyrimidin-4-yl)- (3H, s), 2.58 (3H, s), 3.71 - 3.84 (4H, = 472

3,4-dimethyl-2-((3- m), 4.36 (IH, d), 4.56 - 4.67 (IH, m), methylpyrazin-2- 5.38 (IH, d), 7.23 - 7.28 (IH, m), 7.62 yl)methyl)-3,4- (IH, d), 7.84 (IH, s), 8.17 (IH, s),

dihydropyrrolo[ 1 ,2- 8.36 - 8.47 (3 H, m).

ajpyrazin- 1 (2H)-one.

(Chiralpak IA column,

eluting isocratically with

50% IPA in Hex (modified

with 0.2%DEA) as eluent.

4th eluting, retention time

11.97 mins)

(S)-3-methyl-7-(5-methyl- (300 MHz, CD30D, 23°C) 1.37 (3H, ES+

2-((l -methyl- 1 H-pyrazol- d), 2.43 (3H, s), 3.78 (3H, s), 4.10 - [M+H]+

5-yl)amino)pyrimidin-4- 4.20 (IH, m), 4.21 - 4.28 (IH, d), 4.55 = 498 yl)-2-((3- - 4.63 (IH, m), 4.68 (IH, d), 5.65 (IH,

(trifluoromethyl)pyrazin- d), 6.35 (IH, s), 7.45 - 7.48 (2H, m),

2-yl)methyl)-3,4- 7.75 (IH, s), 8.20 (IH, s), 8.87 (IH, dihydropyrrolo[ 1 ,2- d), 8.95 (1H, d) exchangeable proton ajpyrazin- 1 (2H)-one not seen

7-(2-((l,3-dimethyl-lH- (400 MHz, DMSO, 23°C) 1.28 (6H, ES+ pyrazol-5-yl)amino)-5- s), 2.12 (3H, s), 2.34 (3H, s), 2.61 (3H, [M+H]+ methylpyrimidin-4-yl)- s), 3.60 (3H, s), 4.30 (2H, s), 4.73 (2H, = 472 3,3-dimethyl-2-((2- s), 6.04 (1H, s), 7.25 - 7.34 (2H, m),

methylpyrimidin-4- 7.67 (1H, d), 8.24 (1H, s), 8.60 (1H,

yl)methyl)-3,4- d), 9.04 (1H, s).

dihydropyrrolo[ 1 ,2- ajpyrazin- 1 (2H)-one

(R)-3-(methoxymethyl)-7- (400 MHz, CDC13, 23.2°C) 2.48 (3H, ES+

(5-methyl-2-(pyrimidin-4- s), 2.75 (3H, s), 3.36 (3H, s), 3.38 - [M+H]+ ylamino)pyrimidin-4-yl)- 3.46 (1H, t), 3.53 - 3.56 (1H, dd), 4.03 = 472

2-((2-methylpyrimidin-4- -4.07 (1H, td), 4.28 - 4.32 (1H, d),

yl)methyl)-3,4- 4.43 - 4.46 (2H, d), 5.43 - 5.47 (1H,

dihydropyrrolo[ 1 ,2- d), 7.20 - 7.23 (1H, d), 7.54 (2H, s),

ajpyrazin- 1 (2H)-one 8.38 (1H, s), 8.42 (1H, s), 8.48 - 8.49

(1H, d), 8.62 - 8.63 (2H, d), 8.90 (1H, s).

(R)-7-(2-((l,3-dimethyl- (400 MHz, CDC13, 23°C) 2.25 (3H, ES+ lH-pyrazol-5-yl)amino)-5- s), 2.40 (3H, s), 3.30 (3H, s), 3.35 - [M+H]+ methylpyrimidin-4-yl)-2- 3.50 (2H, m), 3.73 (3H, s), 3.95 - 4.10 = 505 ((6-(fluoromethyl)pyridin- (1H, m), 3.28 - 3.42 (3H, m), 5.35 - 2-yl)methyl)-3- 5.55 (3H, m), 6.10 (1H, s), 6.73 (1H,

(methoxymethyl)-3 ,4- s), 7.25 - 7.45 (3H, m), 7.75 (1H, m), dihydropyrrolo[ 1 ,2- 8.18 (1H, s).

ajpyrazin- 1 (2H)-one

(R)-3-(methoxymethyl)-7- (300 MHz, CD30D, 23°C) 2.42 (3H, ES+ (5 -methyl -2-(( 1 -methyl- s), 3.45 - 3.55 (1H, m), 3.60 - 3.65 [M+H]+ lH-pyrazol-5- (1H, m) 3.78 (3H, s), 4.10 - 4.20 (1H, = 528 yl)amino)pyrimidin-4-yl)- m), 4.50 - 4.55 (2H, m), 4.75 (1H, d), 2-((2- 4.95 (4H, m), 5.38 (IH, d), 6.35 (IH,

(trifluoromethyl)pyrimidin d), 7.45-7.50 (2H, dd), 7.67 (IH, d),

-4-yl)methyl)-3,4- 7.74 (IH, d), 8.21 (IH, s), 8.93 (IH,

dihydropyrrolo[ 1 ,2- d).

ajpyrazin- 1 (2H)-one

3 ,3 -dimethyl-7-(5 -methyl- (400 MHz, DMSO, 23°C) 1.31 (6H, ES+ 2-((l -methyl- 1 H-pyrazol- s), 2.34 (3H, s), 2.61 (3H, s), 3.69 (3H, [M+H]+ 5-yl)amino)pyrimidin-4- s), 4.22 (2H, s), 4.86 (2H, s), 6.27 (IH, = 458 yl)-2-((3 -methylpyrazin-2- d), 7.22 (IH, d), 7.34 (IH, d), 7.64

yl)methyl)-3,4- (IH, d), 8.25 (IH, s), 8.37 (2H, s),

dihydropyrrolo[ 1 ,2- 9.12 (IH, s).

ajpyrazin- 1 (2H)-one

(R)-3-(methoxymethyl)-7- (300 MHz, CDC13, 26.2°C) 2.46 (3H, ES+ (5-methyl-2-(pyrimidin-4- s), 2.68 (3H, s), 2.68 - 3.44 (4H, m), [M+H]+ ylamino)pyrimidin-4-yl)- 3.50 - 3.55 (IH, m), 4.04 (IH, s), 4.30 = 472 2-((3 -methylpyrazin-2- - 4.47 (3H, m), 5.64 - 5.70 (IH, d),

yl)methyl)-3,4- 7.50 (2H, s), 8.34 - 8.40 (4H, m), 8.46 dihydropyrrolo[ 1 ,2- - 8.48 (IH, d), 8.55 - 8.57 (IH, d),

ajpyrazin- 1 (2H)-one 8.85 (IH, s).

3.3 - dimethyl-7-(5 -methyl- (400 MHz, DMSO, 22°C) 1.29 (6H, ES+ 2-((l -methyl- 1 H-pyrazol- s), 2.34 (3H, s), 3.70 (3H, s), 4.23 (2H, [M+H]+ 5-yl)amino)pyrimidin-4- s), 4.84 (2H, s), 6.28 (IH, d), 7.26 = 449 yl)-2-(thiazol-4-ylmethyl)- (IH, d), 7.35 (IH, d), 7.55 (IH, d),

3.4- dihydropyrrolo[l,2- 7.64 (IH, d), 8.25 (IH, s), 9.06 (IH,

ajpyrazin- 1 (2H)-one d), 9.13 (IH, s).

4-methyl-2-((l -methyl- (400 MHz, CDC13, 20.8°C 1.48 - 1.51 ES+ 1 H-pyrazol-5 -yl)methyl)- (3H, d), 2.43 (3H, s), 3.35 - 3.40 (IH, [M+H]+ 7-(5-methyl-2-((l-methyl- dd), 3.60 - 3.64 (IH, dd), 3.82 (3H, s), = 432 1 H-pyrazol-5 - 3.92 (3H, s), 4.31 - 4.38 (IH, m), 4.84 yl)amino)pyrimidin-4-yl)- (2H, s), 6.27 - 6.28 (IH, d), 6.33 - 6.34 3,4-dihydropyrrolo[l,2- (1H, d), 6.94 (IH, s), 7.47 - 7.4 9(3H, ajpyrazin- 1 (2H)-one dd), 7.57 (IH, s), 8.21 (IH, s).

(S)-3-methyl-7-(5-methyl- 400 MHz, MeOD, 22.2°C) 1.35 - 1.37 ES+ 2-((l -methyl- 1 H-pyrazol- (3H, d), 2.42 (3H, s), 3.77 (3H, s), [M+H]+ 5-yl)amino)pyrimidin-4- 4.17 - 4.26 (2H, m), 4.46-4.64 (IH, = 498 yl)-2-((6- dd), 4.68 - 4.89 (IH, d), 5.37 - 5.40

(trifluoromethyl)pyrazin- (IH, d), 5.90 (IH, s), 6.34 - 6.35 (IH,

2-yl)methyl)-3,4- d), 7.44 - 7.45 (IH, d), 7.49 - 7.50

dihydropyrrolo[ 1 ,2- (IH, d), 7.65 - 7.66 (IH, d), 8.19 (IH, ajpyrazin- 1 (2H)-one d), 8.98 - 9.00 (2H, d).

(S)-3-methyl-7-(5-methyl- (400 MHz, CDC13, 23.4°C) 1.33 - ES+ 2-((l -methyl- 1 H-pyrazol- 1.35 (3H, d), 2.45 (3H, s), 2.58 (3H, [M+H]+ 5-yl)amino)pyrimidin-4- s), 3.84 (3H, s), 3.97 - 4.09 (2H, m), = 444 yl)-2-((6-methylpyrazin-2- 4.25 - 4.29 (IH, d), 4.36 - 4.40 (IH,

yl)methyl)-3,4- dd), 5.47 - 5.51 (IH, d), 6.35 - 6.36

dihydropyrrolo[ 1 ,2- (IH, d), 7.49 - 7.50 (2H, dd), 7.58

ajpyrazin- 1 (2H)-one (IH, s), 8.21 (IH, s), 8.41 (IH, s), 8.54

(IH, s).

7'-(5-methyl-2-((l-methyl- (400 MHz, DMSO, 20°C) 1.81 - 1.89 ES+ lH-pyrazol-5- (4H, m), 2.31 - 2.35 (5H, m), 2.57 [M+H]+ yl)amino)pyrimidin-4-yl)- (3H, s), 3.70 (3H, s), 4.61 (2H, s), 4.88 = 469 2'-((2-methylpyridin-3 - (2H, s), 6.27 (IH, s), 7.14 - 7.17 (IH, yl)methyl)-2',4'-dihydro- m), 7.25 (IH, s),7.34 (IH, s), 7.46

1 Ή-spiro [cyclobutane- (IH, d), 7.76 (IH, s), 8.26 (IH, s),

l,3'-pyrrolo[l,2- 8.31 (IH, s), 9.14 (IH, s).

ajpyrazin] - l'-one

(R)-2-((6- (400 MHz, DMSO, 22°C) 2.41 (3H, ES+

(fluoromethyl)pyridin-2- s), 2.51 (3H, s), 3.24 (3H, s), 3.31 - [M+H]+ yl)methyl)-3- 3.34 (IH, m), 3.50 - 3.56 (IH, m), = 503 (methoxymethyl)-7-(5 - 4.06 (IH, s), 4.45 - 4.49 (3H, m), 5.24 methyl-2-((2- (IH, d), 5.43 (IH, s), 5.55 (IH, s), methylpyrimidin-4- 7.36 (1H, s), 7.39 - 7.43 (2H, m), 7.85 yl)amino)pyrimidin-4-yl)- (1H, s), 7.87 (1H, d), 8.23 (1H, d),

3,4-dihydropyrrolo[l,2- 8.45 (1H, s), 8.53 (1H, s), 10.51 (1H, ajpyrazin- 1 (2H)-one s).

7-(2-((l,3-dimethyl-lH- (400 MHz, DMSO, 23°C) 1.28 (6H, ES+ pyrazol-5 -yl)amino)-5 - s), 2.12 (3H, s), 2.34 (3H, s), 2.45 (3H, [M+H]+ methylpyrimidin-4-yl)- s), 3.60 (3H, s), 4.31 (2H, s), 4.73 (2H, = 472 3,3-dimethyl-2-((6- s), 6.04 (1H, s), 7.27 (1H, d), 7.39

methylpyrimidin-4- (1H, s), 7.67 (1H, d), 8.24 (1H, s),

yl)methyl)-3,4- 8.95 (1H, d), 9.04 (1H, s).

dihydropyrrolo[ 1 ,2- ajpyrazin- 1 (2H)-one

(R)-2-((6- (400 MHz, DMSO, 20°C) 2.40 (3H, ES+

(fluoromethyl)pyridin-2- s), 2.51 (3H, s), 3.24 (3H, s), 3.30 - [M+H]+ yl)methyl)-3- 3.34 (1H, m), 3.50 - 3.56 (1H, m), = 503 (methoxymethyl)-7-(5 - 4.05 (1H, s), 4.39 - 4.48 (3H, m), 5.24 methyl-2-((3- (1H, d), 5.43 (1H, s), 5.55 (1H, s),

methylpyridazin-4- 7.34 (1H, s), 7.35 - 7.43 (2H, m), 7.83 yl)amino)pyrimidin-4-yl)- (1H, s), 7.83 - 7.90 (1H, s), 8.38 (1H,

3,4-dihydropyrrolo[l,2- d), 8.42 (1H, s), 8.81 (1H, s), 8.87

ajpyrazin- 1 (2H)-one (IH, d).

2-(2-methoxyethyl)-7-(5- (400 MHz, CDC13, 30°C) 2.39 (3H, ES+ methyl-2-(( 1 -methyl- 1 H- s), 3.36 (3H, s), 3.62 (2H, t), 3.73 (2H, [M+H]+ pyrazol-5- t), 3.78 (3H, s), 3.83 (2H, dd), 4.15 - = 382 yl)amino)pyrimidin-4-yl)- 4.2 (2H, m), 6.30 (IH, d), 6.74 (IH, s),

3,4-dihydropyrrolo[l,2- 7.37 - 7.42 (2H, m), 7.46 (IH, d), 8.16 ajpyrazin- 1 (2H)-one (IH, s).

7-(2-((l,3-dimethyl-lH- (400 MHz, DMSO, 22°C) 1.29 (6H, ES+ pyrazol-5 -yl)amino)-5 - s), 2.12 (3H, s), 2.33 (3H, s), 3.60 (3H, [M+H]+ methylpyrimidin-4-yl)- s), 4.23 (2H, s), 4.84 (2H, s), 6.04 (IH, = 463 3,3-dimethyl-2-(thiazol-4- s), 7.27 (IH, d), 7.56 (IH, d), 7.63 ylmethyl)-3,4- (1H, d), 8.24 (IH, s), 9.01 - 9.09 (2H, dihydropyrrolo[ 1 ,2- m).

ajpyrazin- 1 (2H)-one

(R)-2-((l,3-dimethyl-lH- (500 MHz, DMSO, 30°C) 1.16 (3H, ES+ 1 ,2,4-triazol-5-yl)methyl)- d), 2.19 (3H, s), 2.32 (3H, s), 3.68 [M+H]+ 3 -methyl-7 -(5 -methyl-2- (3H, s), 3.79 (3H, s), 3.96 - 4.03 (IH, = 447 (( 1 -methyl- 1 H-pyrazol-5 - m), 4.18 (IH, dd), 4.27 (IH, dd), 4.40 yl)amino)pyrimidin-4-yl)- (IH, d), 5.13 (IH, d), 6.26 (IH, d),

3,4-dihydropyrrolo[l,2- 7.25 (IH, d), 7.33 (IH, d), 7.64 (IH,

ajpyrazin- 1 (2H)-one d), 8.24 (IH, s), 9.07 (IH, s).

2'-(cyclopropylmethyl)-7'- (400 MHz, DMSO, 20°C) 0.37 (2H, t), ES+ (5 -methyl -2-(( 1 -methyl- 0.43 - 0.52 (2H, m), 1.01 (IH, s), 1.55 [M+H]+ 1 H-pyrazol-5 - (2H, d), 2.11 (2H, td), 2.33 (3H, s), = 448 yl)amino)pyrimidin-4-yl)- 3.44 (2H, d), 3.57 - 3.72 (5H, m), 3.81

2,2',3,4',5,6-hexahydro- (2H, dd), 4.57 (2H, s), 6.28 (IH, d),

H-spiro[pyran-4,3'- 7.21 (IH, d), 7.35 (IH, d), 7.69 (IH,

pyrrolo[l,2-a]pyrazin]- - d), 8.25 (IH, s), 9.12 (IH, s).

one

(R)-3-(methoxymethyl)-7- (400 MHz, DMSO, 2FC) 2.33 (3H, ES+ (5 -methyl -2-(( 1 -methyl- s), 2.51 (3H, s), 3.22 (3H, s), 3.27 - [M+H]+ 1 H-pyrazol-5 - 3.30 (IH, m), 3.42 - 3.46 (IH, m), = 473 yl)amino)pyrimidin-4-yl)- 3.69 (3H, s), 3.87 (IH, s), 4.30 - 4.42

2-((2-methylpyridin-3 - (3H, m), 5.16 (IH, d), 6.27 (IH, s),

yl)methyl)-3,4- 7.20 (IH, s), 7.21 (IH, s), 7.34 (IH, s), dihydropyrrolo[ 1 ,2- 7.63 (IH, s), 7.70 (IH, s), 8.25 (IH, s), ajpyrazin- 1 (2H)-one 8.36 (IH, s), 9.12 (IH, s).

(R)-3-(methoxymethyl)-7- (400 MHz, DMSO, 22.FC) 2.33 (3H, ES+ (5 -methyl -2-(( 1 -methyl- s), 2.46 (3H, s), 3.23 (3H, s), 3.36 (IH, [M+H]+ 1 H-pyrazol-5 - s), 3.47 - 3.51 (IH, m), 3.69 (3H, s), = 474 yl)amino)pyrimidin-4-yl)- 4.04 (IH, s), 4.37 - 4.52 (3H, m), 5.11

2-((6-methylpyrimidin-4- - 5.16 (lH, d), 6.26 - 6.27 (lH, d), yl)methyl)-3,4- 7.24 - 7.25 (IH, d), 7.33 - 7.34 (IH,

dihydropyrrolo[ 1 ,2- d), 7.38 (IH, s), 7.71 - 7.72 (IH, d), ajpyrazin- 1 (2H)-one 8.25 (IH, s), 8.96 - 8.97 (IH, d), 9.12

(IH, s).

71 2'-(cyclopropylmethyl)-7'- (400 MHz, DMSO, 24°C) 0.33 - 0.42 ES+

(5-methyl-2-((3- (2H, m), 0.44 - 0.53 (2H, m), 1.01 [M+H]+ methylpyridazin-4- (IH, d), 1.57 (2H, d), 2.12 (2H, td), = 460 yl)amino)pyrimidin-4-yl)- 2.40 (3H, s), 2.70 (3H, s), 3.45 (2H,

2,2',3,4',5,6-hexahydro- d), 3.63 (2H, t), 3.83 (2H, dd), 4.59

H-spiro[pyran-4,3'- (2H, s), 7.30 (IH, d), 7.80 (IH, d), pyrrolo[l,2-a]pyrazin]- - 8.34 - 8.44 (2H, m), 8.80 (IH, s), 8.88 one (IH, d).

75 7-(5-chloro-2-((l-methyl- (400 MHz, DMSO, 24.0°C) 2.50 (3H, ES+ lH-pyrazol-5- s), 3.69 (3H, s), 3.77-3.80 (2H, t), [M+H]+ yl)amino)pyrimidin-4-yl)- 4.32-4.35 (2H, t), 4.72 (2H, s), 6.26 = 449

2-((6-methylpyridin-2- (IH, s), 7.11-7.16 (2H, m), 7.37-7.39 yl)methyl)-3,4- (2H, d), 7.63-7.69 (IH, t), 7.96 (IH, dihydropyrrolo[ 1 ,2- s), 8.46 (IH, s), 9.49 (IH, s).

ajpyrazin- 1 (2H)-one

137 (R)-2-((6- (400Hz, DMSO, 22°C) 2.33 (3H, s), ES+

(fluoromethyl)pyridin-2- 2.51 (3H, s), 3.24 (3H, s), 3.42 (IH, s), [M+H]+ yl)methyl)-3- 3.47 - 3.51 (IH, m), 4.06 (IH, s), 4.40 = 489

(methoxymethyl)-7-(5 - - 4.48 (3H, m), 5.23 (IH, d), 5.43

methyl-2-(pyrimidin-4- (IH, s), 5.54 (IH, s), 7.36 (IH ,s), 7.39 ylamino)pyrimidin-4-yl)- - 7.43 (2H, m), 7.84 - 7.90 (2H, m),

3,4-dihydropyrrolo[l,2- 8.33 (IH, d), 8.44 (IH, d), 8.56 (IH, ajpyrazin- 1 (2H)-one d), 8.7 6 (IH, s), 10.13 (IH, s). Example 26 sulfamidate intermediate

rt-Butyl 3,8-dioxa-2-thia-l-azaspiror4.51decane-l-carboxylate 2,2-dioxide

Sodium periodate (154 mg, 0.72 mmol) was added to ruthenium(III) chloride (14.96 mg, 0.07 mmol) and tert-butyl 3,8-dioxa-2-thia-l-azaspiro[4.5]decane-l-carboxylate 2-oxide (200mg, 0.72 mmol) in MeCN (10 mL) water (4.00 mL) under nitrogen at -25 °C. The resulting mixture was stirred at -25 °C for 20 hours. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (3 x 25 mL), the organic layer was dried over Na ₂ S04, filtered and evaporated to afford yellow oil. The crude product was purified by flash silica chromatography, elution gradient 1 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl 3,8-dioxa-2-thia-l- azaspiro[4.5]decane-l-carboxylate 2,2-dioxide (150 mg, 70.9 %) as a white solid. ^! H NMR (300 MHz, DMSO, 30 °C) 1.48 (9H, s), 1.70 (2H, d), 2.56 (2H, t), 3.39 (2H, t), 3.79-3.86 (2H, m), 4.84 (2H, s). fert-Butyl 3,8-dioxa-2-thia-l-azaspiror4.51decane-l-carboxylate 2-oxide

Sulfurous dichloride (103 mg, 0.86 mmol) was added to lH-imidazole (177 mg, 2.59 mmol) and triethylamine (175 mg, 1.73 mmol) in DCM (10 mL) under nitrogen. The resulting mixture was stirred at -50 °C for 30 minutes. tert-Butyl (4- (hydroxymethyl)tetrahydro-2H-pyran-4-yl)carbamate (200mg, 0.86 mmol) was then added and the resulting mixture stirred at -50 °C for 30 minutes then slowly warmed to room temperature and stirred at 25 °C for 4 hours. The reaction mixture was quenched with water (15 mL), extracted with DCM (3 x 20 mL), the organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated to afford a yellow oil. The crude product was purified by flash silica chromatography, elution gradient 1 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl 3,8-dioxa-2-thia-l-azaspiro[4.5]decane-l- carboxylate 2-oxide (0.20 g, 83 %) as a colourless oil. ^l H NMR (300 MHz, DMSO, 30°C) 1.45 (10H, m), 1 1.56 (1H, d), 2.24 (1H, t), 2.75 (1H, t), 3.25 (1H, t), 3.54 (1H, t), 3.80-3.89 (2H, m), 4.73 (1H, d), 5.23 (1H, m). fert-Butyl (4-(hvdroxymethyl)tetrahvdro-2H-pyran-4-yl)carbamate

Di-tert-butyl dicarbonate (6.39 g, 29.27 mmol) was added to triethylamine (3.70 g, 36.59 mmol), (4-aminotetrahydro-2H-pyran-4-yl)methanol (3.2 g, 24.40 mmol) in THF (40 mL) under nitrogen. The resulting mixture was stirred at 70 °C for 5 hours. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (3 x 50 mL), the organic layer was then dried over Na ₂ S04, filtered and evaporated to afford yellow oil. The crude product was purified by flash silica chromatography, elution gradient 10 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl (4- (hydroxymethyl)tetrahydro-2H-pyran-4-yl)carbamate (4.20 g, 74%) as a white solid. ^! H NMR (300 MHz, DMSO, 30°C) 1.45 (9H, s), 1.50-1.84 (2H, m), 3.31-3.61 (6H ,m), 4.61- 4.66 (1H, m), 6.36 (1H, s). m/z (ES+), [M+H]+ = 232.

Example 28 Mesylate intermediate

( 1 -((tert-Butoxycarbonyl)amino)cyclobutyl)methyl methanesulfonate

Methanesulfonyl chloride (2.32 mL, 29.81 mmol) was added to tert-butyl (1- (hydroxymethyl)cyclobutyl)carbamate (3 g, 14.91 mmol) and triethylamine (5.19 mL, 37.26 mmol) in DCM (50 mL) cooled to 0 °C under nitrogen. The resulting mixture was stirred at 25 °C for 12 hours then quenched with water (150 mL), extracted with DCM (2 x 150 mL), the organic layer was dried over Na2S04, filtered and evaporated to afford the desired product (l-((tert-butoxycarbonyl)amino)cyclobutyl)methyl methanesulfonate (4.10 g, 98 %) as a white solid. ^! H NMR (400 MHz, CDCb, 24 °C) 1.46 (9H, s), 1.81 - 1.94 (1H, m), 2.01 (1H, dp), 2.20 (4H, t), 3.04 (3H, s), 4.45 (2H, s), 4.83 (1H, s).

Example 33a-d, 35a-d, 40a-d, 41a-d, 46a-d, 47a-d, 48a-d Sulfamidate Intermediate (+/-)-fert-Butyl 4,5-dimethyl-l ,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

Ruthenium (III) chloride (1.006 g, 4.46 mmol) was added to (+/-)-tert-butyl 4,5-dimethyl- l ,2,3-oxathiazolidine-3-carboxylate 2-oxide (21 g, 89.25 mmol) in acetonitrile (300 mL) and water (150 mL) cooled to 0 °C under nitrogen. A solution of sodium metaperiodate (23.86 g, 1 1 1.56 mmol) in water (lOOmL) was then added dropwise at a rate to maintain the temperature below 10 °C. The resulting mixture was stirred at 25 °C for 12 hours then diluted with EtOAc (400 mL), washed sequentially with water (200 mL) and saturated brine (400 mL). The organic layer was dried over Na ₂ S04, filtered and evaporated to afford desired product {+l-)-tert-bvXy\ 4,5-dimethyl-l , 2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (20 g, 89%) as a white solid. ^! H NMR (400 MHz, CDCb, 23 °C) 1.39 (3H, d), 1.43 - 1.55 (3H, m), 1.57 (9H, s), 4.32 (1H, p), 4.99 - 5.10 (1H, m).

(+/-)-tert-Butyl 4,5-dimethyl-l ,2,3-oxathiazolidine-3-carboxylate 2-oxide

A solution of (+/-)-tert-butyl (3-hydroxybutan-2-yl)carbamate (24 g, 126.82 mmol) in DCM (200 mL) was added dropwise to a stirred mixture of sulfurous dichloride (17.35 g, 145.84 mmol), lH-imidazole (34.5 g, 507.26 mmol) and triethylamine (40.7 mL, 291.67 mmol) in DCM (300 mL) at -60 °C, over a period of 30 minutes under nitrogen. The resulting mixture was stirred at -60 °C to room temperature for 16 hours. The reaction mixture was quenched with water (200 mL), extracted with DCM (2 x 500 mL), the organic layer was dried over Na ₂ S04, filtered and evaporated to afford a colourless residue. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford (+/-)-tert- butyl 4,5-dimethyl-l,2,3-oxathiazolidine-3-carboxylate 2-oxide (21 g, 70.4%) as a colourless oil. ¾ NMR (300 MHz, CDC13, 24°C) 1.15 (1H, d), 1.21 - 1.38 (1H, m), 1.40 - 1.58 (14H, m), 4.06 - 4.20 (1H, m).

(+/ -)- fert-Butyl (3 -hvdroxybutan-2-yl)carbamate

Sodium borohydride (10.10 g, 267.04 mmol) was added portionwise to {+l-)-tert-bvXy\ (3- oxobutan-2-yl)carbamate (25 g, 133.52 mmol) in MeOH (100 mL) at 20°C . The resulting mixture was stirred at 25 °C for 30 minutes. The reaction mixture was quenched with water (100 mL), extracted with EtOAc (2 x 200 mL), the organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated to afford the desired product {+l-)-tert-bvXy\ (3-hydroxybutan-2- yl)carbamate (25 g, 99 %) as a colourless oil. m/z (ES+), [M-tBu]+ = 134.

(+/ -)- fert-Butyl (3 -oxobutan-2-yl)carbamate

-(methoxy(methyl)amino)-l-oxopropan-2-yl)carbamate (55 g, 236.79 mmol) in THF(100 mL) was added dropwise to CH3L1 (444 mL, 1.6M in ether, 710.36 mmol) in THF (200 mL) cooled to -78 °C over a period of 30 minutes under nitrogen. The resulting mixture was allowed to warm to room temperature and stirred at 25 °C for 12 hours. The reaction mixture was quenched with saturated NH ₄ C1 (200 mL), extracted with EtOAc (2 x 300 mL), the organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated to afford the desired product {+l-)-tert- vXy\ (3-oxobutan-2-yl)carbamate (25 g, 56.4%>) as a colourless oil. m/z (ES+), [M-tBu]+ = 132. (+/ -)- fert-Butyl ( 1 -(methoxy(methyl)amino)- 1 -oxopropan-2- vDcarbamate

—

N, O-dimethylhydroxylamine hydrochloride (38.7 g, 396.39 mmol) was added to (+/-)-2- ((tert-butoxycarbonyl)amino)propanoic acid (50 g, 264.26 mmol), HATU (111 g, 290.68 mmol) and DIEA (138 mL, 792.77 mmol) in DMF (150 mL) at 25 °C under air. The resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated and diluted with EtOAc (1 L), and washed sequentially with water (200 mL) and saturated brine (600 mL). The organic layer was dried over Na ₂ S04, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% THF in petroleum ether. Pure fractions were evaporated to dryness to afford (+/-)-tert-butyl (l-(methoxy(methyl)amino)-l-oxopropan-2-yl)carbamate (58 g, 94 %) as a white solid, m/z (ES+), [M+H]+ = 233.

Example 71a (1 ^st eluting isomer) and 71b (2 ^nd eluting isomer)

(R and SD-3 -( ethoxymethylV3-methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5 - yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3, 4- dihydropyrrolo[ 1 ,2-a ^" |pyrazin- 1 (2H)-one

Trimethylaluminium (1.793 mL, 2M in toluene, 3.59 mmol) was added in one portion to methyl (+/-)-l-(3-methoxy-2-methyl-2-(((6-methylpyridin-2-yl)methyl )amino)propyl)-4- (5 -methyl -2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)- lH-pyrrole-2-carboxylate (930 mg, 1.79 mmol) in toluene (15 mL) at 25 °C under nitrogen. The resulting solution was stirred at 80 °C for 1 hour then quenched with 2N NaOH (100 mL), diluted with EtOAc (100 mL) and washed sequentially with water (25 mL x 3). The organic layer was dried over Na ₂ S04, filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C 18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing % NH4HCO3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford a colourless liquid which was purified by preparative chiral-HPLC on a ChiralCel IC column, eluting isocratically with 50% heptane in MeCN as eluent. The fractions containing the desired compounds were evaporated to dryness to afford 2 enantiomeric products of undefined absolute stereochemistry. 1 ^st eluting product (Example 71a), retention time: 3.1 1 mins: (R or 5)-3-(methoxymethyl)-3-methyl-7-(5- methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2- yl)methyl)-3 ,4-dihydropyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one (58 mg, 29%) as a white solid. ^! H NMR (400 MHz, DMSO, 20 °C) 1.27 (3H, s), 2.34 (3H, s), 2.46 (3H, s), 3.18 (3H, s), 3.31 - 3.39 (2H, m), 3.69 (3H, s), 4.21 (1H, d), 4.41 (1H, d), 4.60 (1H, d), 4.94 (1H, d), 6.27 (1H, s), 7.1 1 - 7.17 (2H, m), 7.25 (1H, s), 7.34 (1H, s), 7.60 - 7.64 (1H, m), 7.67 (1H, s), 8.26 (1H, s), 9.13 (1H, s). ES+ [M+H]+ = 487. 2 ^nd eluting product (Example 71b), retention time: 4.51 mins: (R or 5)-3-(methoxymethyl)-3-methyl-7-(5-methyl-2-((l- methyl-lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6-methylpyr idin-2-yl)methyl)-3,4- dihydropyrrolo[l ,2-a]pyrazin-l(2H)-one (80 mg, 40%) as a white solid. ^l H NMR (DMSO, 20 °C, 400Hz) 1.27 (3H, s), 2.34 (3H, s), 2.46 (3H, s), 3.18 (3H, s), 3.31 - 3.39 (2H, m), 3.69 (3H, s), 4.21 (1H, d), 4.41 (1H, d), 4.60 (1H, d), 4.94 (1H, d), 6.27 (1H, s), 7.1 1 - 7.17 (2H, m), 7.25 (1H, s), 7.34 (1H, s), 7.60 - 7.64 (1H, m), 7.67 (1H, s), 8.26 (1H, s), 9.13 (1H, s). m/z (ES+), [M+H]+ = 487. (+/-)-Methyl l-(3-methoxy-2-methyl-2-(((6-methylpyridm^

(5 -methyl-2-((l -methyl- lH-pyrazol-5-yl)am

Sodium borohydride (157 mg, 4.16 mmol) was added to methyl l-(2-amino-3-methoxy-2- methylpropyl)-4-(5 -methyl -2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)- 1H- pyrrole-2-carboxylate (860 mg, 2.08 mmol) and 6-methylpicolinaldehyde (252 mg, 2.08 mmol) in MeOH (15 mL) at 20 °C under nitrogen. The reaction mixture was diluted with DCM (50 mL), and washed with water (2 x 25 mL). The organic layer was dried over Na ₂ S04, filtered and evaporated to afford crude product which was used in the next stage without further purification, m/z (ES+), [M+H]+ = 518.

(+/ -)- Methyl 1 -(2-amino-3 -methoxy-2-methylpropyl)- 4-(5 -methyl-2-(( 1 -methyl- 1 H- pyrazol-5-yl)amino)pyrimidin-4-yl)-lH-pyrrole-2-carboxylate

(+/-)-Methyl l-(2-((tert-butoxycarbonyl)amino)-3-methoxy-2-methylpropyl)- 4-(5-methyl- 2-((l -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-lH-pyrrole-2-carboxyl ate (900 mg, 1.75 mmol) was added to hydrogen chloride (excess) in MeOH (10 mL) at 20 °C under nitrogen. The resulting solution was stirred at 20 °C for 12 hours. The solvent was removed under reduced pressure, saturated NaHC0 ₃ was added and the resulting solution was stirred for 20 minutes and then extracted with DCM (50 mL). The organic layer was washed with water (2 x 20 mL), dried over Na ₂ S04, filtered and evaporated to afford (+/-)- methyl 1 -(2-amino-3 -methoxy-2-methylpropyl)-4-(5 -methyl -2-(( 1 -methyl- 1 H-pyrazol-5 - yl)amino)pyrimidin-4-yl)-lH-pyrrole-2-carboxylate (860 mg) as white solid which was used in the next stage without further purification, m/z (ES+), [M+H]+ = 414.

(+/-)-Methyl l-(2-((tert-butoxycarbonyl)amino)-3-methoxy-2-methylpropyl)- 4-(5-methyl- 2-((l-methyl-lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-lH-pyrrol e-2-carboxylate

3rd Generation BrettPhos precatalyst (0.125 g, 0.14 mmol) was added to (+/-)-methyl l-(2- ((tert-butoxycarbonyl)amino)-3-methoxy-2-methylpropyl)-4-(2- chloro-5-methylpyrimidin- 4-yl)-lH-pyrrole-2-carboxylate (1.25 g, 2.76 mmol), 1 -methyl- 1 H-pyrazol-5 -amine (0.536 g, 5.52 mmol) and Cs ₂ C0 ₃ (2.70 g, 8.28 mmol) in 1,4-dioxane (20 mL) at 25°C under nitrogen and stirred at 80°C for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with DCM (3 x 50 mL), the organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated to afford yellow residue. The crude product was purified by flash silica chromatography, elution gradient 0 to 4% MeOH in DCM. Pure fractions were evaporated to dryness to afford (+/-)-methyl l-(2-((tert-butoxycarbonyl)amino)-3- methoxy-2-methylpropyl)-4-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4- yl)-lH-pyrrole-2-carboxylate (0.90 g, 64 %) as a yellow solid, m/z: ES+ [M+H]+ = 514. (+/-)-Methyl l -(2-((tert-butoxycarbonyl)amino)-3-methoxy-2-methylpropyl)-4 -(2-chloro- 5-methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate

(+/-)-tert-Butyl 4-(methoxymethyl)-4-methyl-l ,2,3-oxathiazolidine-3-carboxylate 2,2- dioxide (2g, 7.1 1 mmol) was added to methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-lH- pyrrole-2-carboxylate (1.5 g, 5.96 mmol), K2CO3 (2.471 g, 17.88 mmol) and 18-crown-6 (1.575 g, 5.96 mmol) in 1 ,4-dioxane (30 mL) at 25°C under nitrogen. The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into water (50 mL), extracted with EtOAc (3 x 75 mL), the organic layer was dried over Na ₂ S04, filtered and evaporated to afford yellow residue. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford (+/-)-methyl l-(2-((tert-butoxycarbonyl)amino)-3- methoxy-2-methylpropyl)-4-(2-chloro-5 -methylpyrimidin-4-yl)- 1 H-pyrrole-2-carboxylate (1.25 g, 46%) as a yellow solid, m/z (ES+), [M+H]+ = 453.

(+/-)-fert-Butyl 4-(methoxymethyl)-4-methyl-l ,2,3-oxathiazolidine-3-carboxylate 2,2- dioxide

Ruthenium (III) chloride (0.191 g, 0.85 mmol) was added to (+/-)-tert-butyl 4- (methoxymethyl)-4-methyl-l ,2,3-oxathiazolidine-3-carboxylate 2-oxide (4.5 g, 16.96 mmol) in acetonitrile (40mL) and water (20 mL) cooled to 0°C under nitrogen. A solution of Sodium metaperiodate (4.53 g, 21.20 mmol) in water (50mL) was added dropwise maintaining the temperature below 10 °C. The resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with EtOAc (300 mL), and washed sequentially with water (200 mL) and saturated brine (400 mL). The organic layer was dried over Na ₂ S04, filtered and evaporated to afford desired product {+l-)-tert- vXy\ 4- (methoxymethyl)-4-methyl-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (4.23 g, 89%) as a white solid. ¹ H NMR (DMSO, 25 °C, 300Hz) 1.41 (3H, s), 1.45(9H, s), 3.31 (3H, s), 3.44 (1H, d), 3.66 (1H, d), 4.43 (1H, d), 4.57 (1H, d).

(+/-)-tert-Butyl 4-(methoxymethyl)-4-methyl-l ,2,3-oxathiazolidine-3-carboxylate 2-oxide

(l-hydroxy-3-methoxy-2-methylpropan-2-yl)carbamate (4g, 18.24 mmol) in DCM (40mL) was added dropwise to a stirred mixture of sulfurous dichloride (2.496 g, 20.98 mmol), lH-imidazole (4.97 g, 72.97 mmol) and triethylamine (5.85 mL, 41.96 mmol) in DCM (50 mL) at -60 °C, over a period of 20 minutes under nitrogen. The resulting mixture was stirred at -60 °C to room temperature for 16 hours. The reaction mixture was quenched with water (100 mL), extracted with DCM (400 mL), the organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated to afford colourless residue. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford (+/- 4-(methoxymethyl)-4-methyl- 1 ,2,3-oxathiazolidine-3-carboxylate 2-oxide

(4.50 g, 93 %) as a colourless oil. ¹ HNMR (DMSO, 25°C, 300Hz) δ 1.40 and 1.60 (3H,2 x s),1.51(9H,s),3.34 and 3.35(3H,2 x s),3.40 and 3.65(1H,2 x d),3.52 and 3.82(1H,2 x d),4.39 and 4.70 (1H,2 x d),4.71 and 5.05 (1H,2 x d). (+/ -)- fert-Butyl ( 1 -hydroxy-3 -methoxy-2-methylpropan-2-yl)carbamate

Di-tert-butyldicarbonate (5.61 mL, 24.17 mmol) was added to (+/-)-2-amino-3-methoxy-2- methylpropan-l-ol (2.4 g, 20.14 mmol) and diisopropylethylamine (3.52 mL, 20.14 mmol) in MeOH (30 mL) at 25°C under nitrogen. The resulting solution was stirred at 60 °C for 12 hours. The reaction mixture was diluted with DCM (150 mL), and washed with water (100 mL). The organic layer was dried over Na ₂ S04, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford (+/-)-tert-butyl (l-hydroxy-3-methoxy-2-methylpropan-2-yl)carbamate (4 g, 91%) as a colourless liquid. 'H NMR (300HZ, CDCb, 25 °C) 1.25 (3H, s), 1.47 (9H, s), 3.39 (3H, s), 3.49 - 3.70 (4H, s), 4.10 (1H, m), 5.14 (1H, s). m/z (ES+), [M-Boc]+ = 120.

The following examples were prepared in analogous manner to Examples 71a and 71b using the appropriate commercially available aldehyde and sulfamidate, the synthesis of which immediately follows the example. Chiral purification was performed; the conditions and elution order of the examples are captured in the Compound Name column.

Example No Compound Name 'H-NMR Mass Spectrum m/z

71c (3R,4S)-3- (400 MHz, DMSO, ES+ [M+H]+ = 487

(methoxymethyl)-4- 2FC) 1.23 (3H, d), methyl-7-(5 -methyl- 2.32 (3H, s), 2.47

2-((l-methyl-lH- (3H, s), 3.24 (3H,

pyrazol-5- s), 3.45 (1H, dd),

yl)amino)pyrimidin- 3.69 (3H, s), 3.80 -

4-yl)-2-((6- 3.88 (lH, m), 4.25

methylpyridin-2- (1H, d), 4.62 (1H, yl)methyl)-3,4- q), 5.24 (lH, d),

dihydropyrrolo[ 1 ,2- 6.27 (1H, d), 7.16 - ajpyrazin- 1 (2H)-one. 7.26 (3H, m), 7.34

(chiral-HPLC on a (1H, d), 7.65 - 7.75

ChiralCel IC column, (2H, m), 8.24 (1 H, eluting isocratically s), 9.12 (1H, s)

with 50% EtOH in

Hex (modified with

0.2% DEA) as

eluent. 1 ^st eluting

component.

71d (3R,4R)-3- (400 MHz, DMSO, ES+ [M+H]+ = 487

(methoxymethyl)-4- 2FC) 1.60 (3H, d), methyl-7-(5 -methyl- 2.35 (3H, s), 2.47

2-((l-methyl-lH- (3H, s), 3.18 (3H, pyrazol-5- s), 3.39 (1H, dd),

yl)amino)pyrimidin- 3.56 (1H, dd), 3.69

4-yl)-2-((6- (3H, s), 3.93 (1H, methylpyridin-2- q), 4.35 (1H, d),

yl)methyl)-3,4- 4.73 (1H, dd), 5.26 dihydropyrrolo[ 1 ,2- (1H, d), 6.26 (1H, ajpyrazin- 1 (2H)-one d), 7.18 (2H, t),

(chiral-HPLC on a 7.25 (1H, d), 7.34

ChiralCel IC column, (1H, d), 7.59 (1H, eluting isocratically d), 7.67 (lH, t),

with 50% EtOH in 8.25 (1H, s), 9.13

Hex (modified with (1H, s).

0.2% DEA) as

eluent. 2nd eluting

component. Sulfamidate intermediate for Examples 71c and 71d

(4S, 5R/S)-tert-Butyl 4-(methoxymethyl)-5-methyl-l,2,3-oxathiazolidine-3-carboxyla te 2,2-dioxide

A solution of tert-butyl ((2S, 3R/S)-3-hydroxy-l-methoxybutan-2-yl)carbamate (8 g, 36.48 mmol) in DCM (80 mL) was added dropwise to a stirred mixture of sulfurous dichloride (4.99 g, 41.96 mmol), lH-imidazole (9.93 g, 145.93 mmol) and TEA (11.70 mL, 83.91 mmol) in DCM (100 mL) at -60°C, over a period of 20 minutes under nitrogen. The resulting mixture was stirred at -60 °C to room temperature for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were dried over Na ₂ S04, filtered and evaporated to afford colourless residue. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford (4S, 5R/S)-tert-butyl 4-(methoxymethyl)-5-methyl-l,2,3-oxathiazolidine-3- carboxylate 2-oxide (8.20 g, 85 %) as a colourless oil which was used directly in the next stage. Ruthenium (III) chloride (0.348 g, 1.55 mmol) was added to (4S, 5R/S)-tert-butyl 4- (methoxymethyl)-5-methyl-l,2,3-oxathiazolidine-3-carboxylate 2-oxide (8.2 g, 30.91 mmol) in acetonitrile (100 mL) and water (50 mL) cooled to 0°C under nitrogen. A solution of Sodium metaperiodate (8.26 g, 38.63 mmol) in water (50 mL) was added dropwise maintaining the temperature below 10 °C. The resulting mixture was then stirred at 25 °C for 12 hours. The reaction mixture was diluted with EtOAc (300 mL), and the organic phase was then washed sequentially with water (200 mL) and saturated brine (2 x 200 mL). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and evaporated to afford desired product (4S, 5R/S)-tert-butyl 4-(methoxymethyl)-5-methyl-l ,2,3- oxathiazolidine-3-carboxylate 2,2-dioxide (8.00 g, 92 %) as a white solid. ^! H NMR (400 MHz, CDCb, 24 °C); 1.58 (9H, s), 1.61 - 1.70 (1H, m), 3.41 (4H, d), 3.59 (1H, dd), 3.61 - 3.73 (1 H, m), 3.78 (1H, dd), 4.30 (1H, ddd), 5.03 - 5.15 (1H, m). tert-Butyl (Y2S, 3R/S)-3-hvdroxy-l-methoxybutan-2-yl)carbamate

NaBH ₄ (2.79 g, 73.64 mmol) was added to (S)-tert-Butyl (1 -methoxy-3 -oxobutan-2- yl)carbamate (8 g, 36.82 mmol) in MeOH (50 mL) at 20°C . The resulting mixture was stirred at 25 °C for 30 minutes. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and evaporated to afford the desired product tert-butyl ((2S, 3R/S)-3-hydroxy-l- methoxybutan-2-yl)carbamate (8.00 g, 99 %) as a colourless oil. m/z (ES+), [M-tBu]+ = 164.

(S)-tert-Butyl ( 1 -methoxy-3 -oxobutan-2-yl)carbamate

CH3L1 (59.6 mL, 1.6M in ether, 95.31 mmol) was added dropwise to (S)-tert-butyl (3- methoxy-l-(methoxy(methyl)amino)-l-oxopropan-2-yl)carbamate (10 g, 38.12 mmol) in THF (150 mL) cooled to -78°C over a period of 30 minutes under nitrogen. The resulting mixture was allowed to warm to ambient temperature and stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated NH ₄ C1 (50 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers was dried over Na ₂ S0 ₄ , filtered and

evaporated to afford the desired product (S)-tert-butyl (1 -methoxy-3 -oxobutan-2- yl)carbamate (8.00 g, 97 %) as a colourless oil. ^l H NMR (400 MHz, CDCI3, 22 °C) δ 1.47 (9 H, s), 2.26 (3 H, s), 3.35 (3 H, s), 3.61 (1 H, dd), 3.86 (1 H, dd), 4.32 - 4.38 (1 H, m), 5.53 (1 H, d). m/z (ES+), [M-tBu]+ = 162. (S)-tert-butyl 3 -methoxy- 1 -(methoxy(methyl)amino)- 1 -oxopropan-2- vDcarbamate

—

N, O-dimethylhydroxylamine hydrochloride (13.35 g, 136.84 mmol) was added to (S)-2- ((tert-butoxycarbonyl)amino)-3-methoxypropanoic acid (20 g, 91.23 mmol), HATU (38.2 g, 100.35 mmol) and DIPEA (47.8 mL, 273.68 mmol) in DMF (100 mL) at 25°C under air. The resulting mixture was then stirred at 25 °C for 12 hours. The reaction mixture was then concentrated and diluted with EtOAc (500 mL), and the organic phases washed sequentially with water (150 mL) and saturated brine (2 x 200 mL). The organic layers were dried over Na ₂ S04, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% THF in petroleum ether. Pure fractions were evaporated to dryness to afford (S)-tert-butyl (3- methoxy-l-(methoxy(methyl)amino)-l -oxopropan-2-yl)carbamate (24 g, 100 %) as a colourless oil. ^l H NMR (400 MHz, CDCb, 22°C) δ 1.46 (9 H, s), 3.25 (3 H, s), 3.37 (3 H, s), 3.62 (2 H, ddd), 3.72 - 3.82 (3 H, m), 4.86 (1 H, s), 5.43 (1 H, d). m/z (ES+), [M+H]+ =

263.

Example 72

7'-(5-Methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2 ^, -((6-methylpyridin-2- vDmethvD^'^'-dihvdro- 1 'H-spiroroxetane-SJ'-pyrrolor 1 ,2-alpyrazinl-l '-one

Methyl 4-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)- 1 -((3-(((6- methylpyridin-2-yl)methyl)amino)oxetan-3 -yl)methyl)- 1 H-pyrrole-2-carboxylate (100 mg, 0.20 mmol) in 7M NH ₃ in ethanol (20 mL) at 25 °C under air was stirred at 45 °C for 3 days. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (XSelect CSH Prep C18 OBD column, 5μ silica, 19 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.01% NH ₄ HC0 ₃ ) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 7'-(5-methyl-2-((l-methyl-lH-pyrazol-5-yl)amino)pyrimidin-4- yl)-2'-((6- methylpyridin-2-yl)methyl)-2',4'-dihydro- 1 'H-spiro[oxetane-3,3'-pyrrolo[ 1 ,2-a]pyrazin]- 1 '- one (36.5 mg, 39.0 %) as a white solid. ^! H NMR (300 MHz, DMSO, 25.6 °C) 2.33 (3H, s), 2.46 (3H, s), 3.68 (3H, s), 4.39 - 4.42 (2H, d), 4.78 - 4.80 (4H, m), 5.12 (2H, s), 6.26 - 6.27 (1H, d), 7.13 - 7.17 (2H, t), 7.25 - 7.26 (1H, d), 7.33 - 7.34 (1H, d), 7.61 - 7.66 (1H, t), 7.79 - 7.80 (1H, d), 8.25(1H, s), 9.13 (1H, s).m/z (ES+), [M+H]+ = 471.

Methyl 4-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)- 1 -((3-(((6- methylpyridin-2-yl)methyl)amino)oxetan-3 -yDmethyl)- 1 H-pyrrole-2-carboxylate

6-Methylpicolinaldehyde (251 mg, 2.08 mmol) was added to methyl l-((3-aminooxetan-3- yl)methyl)-4-(5 -methyl -2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)- 1 H-pyrrole- 2-carboxylate (550 mg, 1.38 mmol) in THF (10 mL) at 25°C under nitrogen. The resulting solution was stirred at 70 °C for 1 hour. NaBH ₄ (209 mg, 5.54 mmol) was added to reaction mixture at 25°C and the resulting solution stirred at 25 °C for 12 hours. The reaction mixture was quenched with water (10 mL) and filtered washing with EtOAc, the organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated to afford a yellow oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 4% MeOH in DCM. Pure fractions were evaporated to dryness to afford methyl 4-(5-methyl-2-((l- methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)- 1 -((3-(((6-methylpyridin-2- yl)methyl)amino)oxetan-3-yl)methyl)-lH-pyrrole-2-carboxylate (155 mg, 22.29 %) as a white foam, m/z (ES+), [M+H]+ = 503.

Methyl 1 -((3 -aminooxetan-3-yl)methyl)-4-(5-methyl-2-((l -methyl- lH-pyrazol-5- yl)amino)pyrimidin-4-yl)- 1 H-pyrrole-2-carboxylate

Methyl 1 -((3 -(((benzyloxy)carbonyl)amino)oxetan-3 -yl)methyl)-4-(5 -methyl-2-(( 1 -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-lH-pyrrole-2-carboxyla te (84 mg, 0.16 mmol) and Pd-C (16.82 mg, 0.02 mmol) in MeOH (3 mL) was stirred under an atmosphere of hydrogen at 25 °C for 12 hours. The reaction mixture was filtered through celite. The solvent was removed by distillation under vacuum to afford methyl l-((3-aminooxetan-3- yl)methyl)-4-(5 -methyl -2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)- 1 H-pyrrole- 2-carboxylate (60.0 mg, 96 %) as a yellow oil. m/z (ES+), [M+H]+ = 398.

Methyl 1 -((3 -(((benzyloxy)carbonyl)amino)oxetan-3 -yl)methyl)-4-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-lH-pyrrole-2-carboxylate

Methyl l-((3-(((benzyloxy)carbonyl)amino)oxetan-3-yl)methyl)-4-(2-c hloro-5- methylpyrimidin-4-yl)-lH-pyrrole-2-carboxylate (1.34 g, 2.85 mmol), 1-methyl-lH- pyrazol-5 -amine (0.829 g, 8.54 mmol), CS2CO3 (2.318 g, 7.11 mmol) and 3rd Generation BrettPhos precatalyst (0.258 g, 0.28 mmol) in 1,4-dioxane (100 mL) was stirred under an atmosphere of nitrogen at 90 °C for 2 hours. The reaction mixture was poured into EtOAc (100 mL), washed with water (3 x 100 mL), the organic layer was dried over Na ₂ S04, filtered and evaporated to afford yellow oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford methyl l-((3-(((benzyloxy)carbonyl)amino)oxetan-3- yl)methyl)-4-(5 -methyl -2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)- 1 H-pyrrole- 2-carboxylate (1.07 g, 70.7 %) as a white foam, m/z (ES+), [M+H]+ = 532.

Methyl l-((3-(((benzyloxy)carbonyl)amino)oxetan-3-yl)methyl)-4-(2-c hloro-5- methylp yrimidin-4- yl)- 1 H-p yrrole-2-carboxylate

CS2CO3 (5.42 g, 16.65 mmol) was added to methyl 4-(2-chloro-5-methylpyrimidin-4-yl)- lH-pyrrole-2-carboxylate (1.397 g, 5.55 mmol) and (3-

(((benzyloxy)carbonyl)amino)oxetan-3-yl)methyl methanesulfonate (2.1 g, 6.66 mmol) in acetonitrile (80 mL) at 25 °C . The resulting mixture was stirred at 60 °C for 30 minutes. The crude product was purified by flash silica chromatography, elution gradient 40 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 1 - ((3 -(((benzyloxy)carbonyl)amino)oxetan-3 -yl)methyl)-4-(2-chloro-5 -methylpyrimidin-4- yl)-lH-pyrrole-2-carboxylate (1.44 g, 55.1%) as a white foam. ^! H NMR (400 MHz,

DMSO, 25. FC) 2.38 (3H, s), 3.77 (3H, s), 4.46-4.48 (2H, d), 4.53 - 4.55 (2H, d), 5.00 (4H, s), 7.33 - 7.34 (5H, d), 7.48 (1H, s), 7.78 (1H, s), 8.02 (1H, s), 8.52 (1H, s). m/z (ES+), [M+H]+ = 471. (3 -(((Benzyloxy)carbonyl)amino)oxetan-3 - vDmethyl methanesulfonate

Cbz

A solution of methanesulfonyl chloride (1.931 g, 16.86 mmol) in DCM (2 mL) was added dropwise to a stirred mixture of benzyl (3-(hydroxymethyl)oxetan-3-yl)carbamate (2.0 g, 8.43 mmol) and TEA (3.52 mL, 25.29 mmol) in DCM (2mL) at 0 °C, over a period of 20 minutes under nitrogen. The resulting mixture was stirred at 0 °C to room temperature for 16 hours. The reaction mixture was then washed with water (100 mL) and saturated brine (100 mL). The organic layer was dried over Na ₂ S04, filtered and evaporated to afford (3- (((benzyloxy)carbonyl)amino)oxetan-3-yl)methyl methanesulfonate (2.85 g) as yellow solid which was used without further purification. ^l H NMR (400 MHz, CDCb, 24.8 °C) 2.98 (3H, s), 4.54 - 4.57 (2H, d), 4.67-4.72 (4H, m), 5.12 (2H, s), 5.41 (1H, s), 7.37 - 7.41 (5H, m). m/z (ES+), [M+H]+ = 316.

Benzyl (3-(hydroxymethyl)oxetan-3-yl)carbamate

Benzyl chloroformate (7.48 mL, 52.37 mmol) was added to (3-aminooxetan-3-yl)methanol (4.5 g, 43.64 mmol) and sodium bicarbonate (11.00 g, 130.92 mmol) in DCM (180 mL)and water (180 mL) at 25°C under nitrogen. The resulting solution was stirred at 25 °C for 16 hours. The reaction mixture extracted with DCM (3 x 20 mL) and the organic layer dried over Na ₂ S0 ₄ , filtered and evaporated to afford colourless oil. The crude product was purified by flash silica chromatography, elution gradient 40 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford benzyl (3- (hydroxymethyl)oxetan-3-yl)carbamate (6.79 g, 65.6 %) as a white solid. ^! H NMR (400 MHz, CDCb, 24.4 °C) 2.59 (1H, s), 4.04 (2H, s), 4.53 - 4.55 (2H, d), 4.71 - 4.73 (2H, d), 5.12 (2H, s), 5.41 (1H, s), 7.31 - 7.41 (5H, m). m/z (ES+), [M+H]+ = 238. Example 73 exemplifying General Preparation Method B

(S)-3 -Methyl-7-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((2- meth l-2H-l ,2J-triazol-4-yl)methyl)-3^-dihydropyrrolo[l ,2-alpyrazin-l(2H)-one

(5)-7-(2-chloro-5-methylpyrimidin-4-yl)-3-methyl-2-((2-methy l-2H-l ,2,3-triazol-4- yl)methyl)-3,4-dihydropyrrolo[l ,2-a]pyrazin-l(2H)-one (190 mg, 0.51 mmol), 1-methyl- lH-pyrazol-5-amine (54.6 mg, 0.56 mmol), cesium carbonate (333 mg, 1.02 mmol) and BrettPhos 3rd generation pre-catalyst (23.16 mg, 0.03 mmol) were suspended in tert- butanol (6mL) and de-gassed for 10 minutes. The reaction was heated to 80 °C for 18 hours under nitrogen. Reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (25 mL), dried over sodium sulfate and concentrated in vacuo to give a yellow solid. The crude product was dissolved in DMSO (5 mL), filtered and purified by preparative HPLC (Waters XBridge Prep C 18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% N¾) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (5)-3- methyl-7-(5 -methyl-2-(( 1 -methyl- 1 H-pyrazol-5 -yl)amino)pyrimidin-4-yl)-2-((2-methyl- 2H-l ,2,3-triazol-4-yl)methyl)-3,4-dihydropyrrolo[ l ,2-a]pyrazin-l(2H)-one (102 mg, 46.2

%) as a white solid. ^l H NMR (500 MHz, DMSO, 30 °C) 1.15 (3H, d), 2.33 (3H, s), 3.70 (3H, s), 3.9 - 4.01 (IH, m), 4.12 (3H, d), 4.14 - 4.32 (2H, m), 4.35 (IH, d), 5.08 (IH, d), 6.27 (IH, d), 7.26 (IH, d), 7.34 (IH, d), 7.64 (IH, d), 7.69 (IH, s), 8.24 (IH, s), 9.08 (IH, s). m/z: ES+ [M+H]+ = 433.

yl)methyl)-3 ,4-dihydropyrrolor 1 ,2-alpyrazin- 1 (2H)-one

General Preparation Method B: Mesylate alkylation

Sodium hydride (22 mg) was added to (S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3-methyl- 3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (265 mg, 0.96 mmol) in DMF (15 mL) at 20 °C under nitrogen. The resulting suspension was stirred at 20 °C for 30 minutes. (2- methyl-2H-l,2,3-triazol-4-yl)methyl methanesulfonate (183 mg, 0.96 mmol) in DMF (2 mL) was added followed by tetrabutylammonium iodide (70.7 mg, 0.19 mmol) and the resulting solution stirred at 20 °C for 18 hours. It was diluted with saturated aqueous ammonium chloride (75 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organics dried over sodium sulfate and concentrated in vacuo then adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (S)-7-(2-chloro-5- methylpyrimidin-4-yl)-3-methyl-2-((2-methyl-2H-l,2,3-triazol -4-yl)methyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (243 mg, 68.2 %) as a white solid. ^l H NMR (400 MHz, DMSO, 30°C) 1.14 (3H, d), 2.42 - 2.45 (3H, m), 3.98 (IH, ddd), 4.12 (3H, s), 4.20 (IH, dd), 4.29 (IH, dd), 4.36 (IH, d), 5.07 (IH, d), 7.29 (IH, d), 7.69 (IH, s), 7.84 (IH, d), 8.51 (IH, d). m/z: ES+ [M+H]+ = 372.

General Preparation Method B: Alkyl halide alkylation

Sodium hydride (22 mg) was added to (S)-7-(2-chloro-5-methylpyrimidin-4-yl)-3-methyl- 3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (150 mg, 0.54 mmol) in DMF (15 mL) at 20 °C under nitrogen. The resulting suspension was stirred at 20 °C for 30 minutes. 4- (Bromomethyl)-2-methyl-2H-l,2,3-triazole (MFCD20637449; 105 mg, 0.60 mmol) was added followed by tetrabutylammonium iodide (40.0 mg, 0.11 mmol) and the resulting solution stirred at 20 °C for 18 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride (75 mL) and extracted with ethyl acetate (2 x 75 mL), the combined organics dried over sodium sulfate and concentrated in vacuo to give (S)-7-(2- chloro-5-methylpyrimidin-4-yl)-3-methyl-2-((2-methyl-2H-l ,2,3-triazol-4-yl)methyl)-3,4- dihydropyrrolo[l ,2-a]pyrazin-l(2H)-one (192 mg, 95 %) as a pale yellow solid, m/z: ES+ [M+H]+ = 372.

(2 -methyl -2H- 1 ,2,3-triazol-4-yl)methyl methanesulfonate

Methanesulfonyl chloride (0.081 mL, 1.04 mmol) was added to (2-methyl-2H-l ,2,3- triazol-4-yl)methanol (1 18 mg, 1.04 mmol) and triethylamine (0.435 mL, 3.13 mmol) in DCM (10 mL) at 0°C over a period of 2 minutes under nitrogen. The resulting solution was stirred at 0 °C for 30 minutes, diluted with DCM (50 mL) and washed with 50% brine (lOmL), dried (sodium sulfate) then concentrated in vacuo to give (2-methyl-2H-l ,2,3- triazol-4-yl)methyl methanesulfonate (185 mg, 93 %) as a colourless oil. ^! H NMR (400 MHz, DMSO, 32°C) 3.23 (3H, s), 4.17 (3H, s), 5.33 (2H, s), 7.88 (1H, s).

(2 -methyl -2H- 1 ,2,3-triazol-4-yl)methanol

Borane-THF (1M in THF) (12.59 mL, 12.59 mmol) was added to 2-methyl-2H-l ,2,3- triazole-4-carboxylic acid (400 mg, 3.15 mmol) in THF (10 mL) at 0 °C over a period of 10 minutes under nitrogen. The resulting solution was stirred and allowed to warm to ambient temperature over 18 hours. It was re-cooled to 0 °C and quenched with water (6 mL). The resulting mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (30 mL). The organic portion was dried over sodium sulphate and concentrated in vacuo to a yellow gum (446 mg). The crude product was dissolved in minimum volume of DCM, concentrated in vacuo and adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in iso-hexane. Pure fractions were evaporated to dryness to afford (2- methyl-2H-l,2,3-triazol-4-yl)methanol (276 mg, 78 %) as a colourless oil. ^! H NMR (400 MHz, DMSO, 30 °C) 4.10 (3H, s), 4.50 (2H, d), 5.17 (1H, t), 7.61 (1H, s).

The following examples were made by the analogous synthesis route as that described for the preparation of Example 73 using General Preparation Method B. In this general method the appropriate lactam is alkylated with the either an alkyl halide or mesylate, following by a palladium catalysed cross coupling to incorporate the appropriate amino heterocycle at the C2 position of the pyrimidine. Where the alkyl halide, mesylate or amino-heterocycle are not commercially available the appropriate preparation is included immediately following the table below, or are well known in the art. Where chiral separation has been performed to isolate pure disateromers or enantiomers, of undefined absolute stereochemistry, the chiral purification method, elution order and retention time is recorded under the chemical name in the table.

Example Alkylating Example Chemical Name Ή-ΝΜΡν Mass Number agent Spectrum

Br, CI or m/z

OMs

74 CI (S)-2-((3-fiuoro-6- (400 MHz, DMSO, ES+

methylpyridin-2- 30°C) 1.18 (3H, d), [M+H]+ = yl)methyl)-3 -methyl-7- 2.32 (3H, s), 2.43 (3H, 461 (5 -methyl -2-(( 1 -methyl- s), 3.68 (3H, s), 3.98 - lH-pyrazol-5- 4.04 (lH, m), 4.20 (1H,

yl)amino)pyrimidin-4- dd), 4.29 - 4.37 (2H,

yi)-3,4- m), 5.31 (1H, d), 6.25 dihydropyrrolo[ 1 ,2- (1H, d), 7.21 - 7.27

ajpyrazin- 1 (2H)-one (2H, m), 7.32 (1H, d),

7.54 - 7.61 (lH, m),

7.63 (1H, d), 8.23 (1H,

s), 9.06 (1H, s).

CI (S)-7-(2-((l,3-dimethyl- (400 MHz, DMSO, ES+

1 H-pyrazol-4-yl)amino)- 30°C) 1.21 (3H, d), [M+H]+ =

5 -methylpyrimidin-4-yl)- 2.12 (3H, s), 2.31 (3H, 458

3-methyl-2-((6- s), 2.46 (3H, s), 3.75

methylpyrimidin-4- (3H, s), 3.95 - 4.07 (1H, yl)methyl)-3,4- m), 4.32 (2H, d), 4.48

dihydropyrrolo[ 1 ,2- (lH, d), 5.12 (lH, d),

ajpyrazin- 1 (2H)-one 7.28 (1H, d), 7.39 (1H,

s), 7.68 (1H, d), 7.80

(1H, s), 8.17 (lH, s),

8.32 (1H, s), 8.97 (1H,

d).

Br (R)-2- (400Hz , DMSO, 24°C) ES+

(cyclopropylmethyl)-3 - 0.27 - 0.35 (2H, d), [M+H]+ =

(methoxymethyl)-7-(5 - 0.47 - 0.53 (2H, m), 422 methyl-2-(( 1 -methyl- 1 H- 1.10 (1H, s), 2.40 (3H,

pyrazol-5- s), 3.09 - 3.14 (lH, m),

yl)amino)pyrimidin-4- 3.19 - 3.25 (1H, s), 3.30

yi)-3,4- (3H, s), 3.45 - 3.49 (1H, dihydropyrrolo[ 1 ,2- m), 3.64 - 3.69 (4H, m),

ajpyrazin- 1 (2H)-one 4.10 - 4.12 (lH ,m),

4.24 - 4.29 (1H, m),

4.41 . 4.44 (lH, d),

6.27 (1H, s), 7.20 (1H,

s), 7.34 (1H, s), 7.66 (1H, s), 8.24 (1H, s),

9.10 (1H, s).

78 CI (S)-2-(( 1,3 -dimethyl- 1 H- (500 MHz, DMSO, ES+

l,2,4-triazol-5- 30°C) 0.95 (3H, d), [M+H]+ = yl)methyl)-3 -methyl-7- 1.98 (3H, s), 2.11 (3H, 446

(5 -methyl -2-(( 1 -methyl- s), 3.47 (3H, s), 3.58

lH-pyrazol-5- (3H, s), 3.80 (1H, ddd),

yl)amino)pyrimidin-4- 3.97 (1H, dd), 4.07

yi)-3,4- (1H, dd), 4.20 (1H, d),

dihydropyrrolo[ 1 ,2- 4.92 (1H, d), 6.05 (1H,

ajpyrazin- 1 (2H)-one d), 7.04 (lH, d), 7.12

(1H, d), 7.43 (1H, d),

8.03 (1H, s), 8.86 (1H,

s).

79 CI (S)-7-(2-((l,3-dimethyl- (500 MHz, DMSO, ES+

1 H-pyrazol-4-yl)amino)- 30°C) 1.18 (3H, d), [M+H]+ =

5 -methylpyrimidin-4-yl)- 2.09 (3H, s), 2.29 (3H, 458

3-methyl-2-((2- s), 2.59 (3H, s), 3.72

methylpyrimidin-4- (3H, s), 3.95 - 4.02 (1H, yl)methyl)-3,4- m), 4.21 (1H, dd), 4.31

dihydropyrrolo[ 1 ,2- (1H, d), 4.45 (1H, dd),

ajpyrazin- 1 (2H)-one 5.08 (1H, d), 7.22 - 7.31 (2H, m), 7.66 (1H,

d), 7.78 (1H, s), 8.14

(1H, s), 8.30 (1H, s),

8.60 (1H, d).

80 Br 2-((6- (400 MHz, DMSO, ES+

(fluoromethyl)pyridin-2- 30°C) 2.33 (3H, s), 3.69 [M+H]+ = yl)methyl)-7-(5 -methyl- (3H, s), 3.74 - 3.88 (2H, 447

2-((l -methyl- 1 H-pyrazol- m), 4.25 - 4.37 (2H, m),

5 -yl)amino)pyrimidin-4- 4.79 (2H, s), 5.40 (1H, yi)-3,4- s), 5.52 (1H, s), 6.27

dihydropyrrolo[ 1 ,2- (1H, d), 7.26 (1H, d),

ajpyrazin- 1 (2H)-one 7.33 (2H, d), 7.41 (1H,

d), 7.66 (1H, d), 7.87

(lH, t), 8.24 (lH, d),

9.06 (1H, s).

81 CI (R)-2-((5-fluoro-6- (400 MHz, DMSO, ES+

methylpyridin-2- 30°C) 1.15 (3H, d), [M+H]+ = yl)methyl)-3 -methyl-7- 2.33 (3H, s), 2.44 (3H, 461

(5 -methyl -2-(( 1 -methyl- d), 3.69 (3H, s), 3.92 -

1 H-pyrazol-5 - 4.02 (lH, m), 4.20 (1H,

yl)amino)pyrimidin-4- dd), 4.27 - 4.39 (2H,

yi)-3,4- m), 5.11 (1H, d), 6.26

dihydropyrrolo[ 1 ,2- (1H, d), 7.26 (1H, d),

ajpyrazin- 1 (2H)-one 7.28 (1H, d), 7.33 (1H,

d), 7.54 - 7.62 (1H, m),

7.65 (1H, d), 8.24 (1H,

s), 9.07 (1H, s).

82 CI (S)-2- (400 MHz, DMSO, ES+

(cyclopropylmethyl)-3 - 30°C) 0.19 - 0.39 (2H, [M+H]+ = methyl-7-(5-methyl-2- m), 0.48 (2H, ddt), 1.08 391

(( 1 -methyl- 1 H-pyrazol-5 - (1H, dd), 1.16 (3H, d),

yl)amino)pyrimidin-4- 2.31 (3H, s), 3.07 (1H,

yi)-3,4- dd), 3.57 (1H, dd), 3.68

dihydropyrrolo[ 1 ,2- (3H, s), 4.06 (1H, d),

ajpyrazin- 1 (2H)-one 4.15 - 4.34 (2H, m),

6.25 (1H, d), 7.19 (1H,

d), 7.33 (1H, d), 7.61

(1H, d), 8.22 (1H, s),

9.05 (1H, s). 83 CI 2-((5-fiuoro-6- (400 MHz, DMSO, ES+

methylpyridin-2- 30°C) 2.39 (3H, s), 2.43 [M+H]+ = yl)methyl)-7-(5 -methyl- (3H, d), 3.79 (2H, t), 445

2-(pyrimidin-4- 4.34 (2H, t), 4.73 (2H,

ylamino)pyrimidin-4-yl)- s), 7.24 (1H, dd), 7.34

3 ,4-dihydropyrrolo [ 1 ,2- (1H, s), 7.60 (1H, d),

ajpyrazin- 1 (2H)-one 7.78 (1H, s), 8.32 (1H,

d), 8.41 (1H, s), 8.54

(1H, d), 8.74 (1H, s),

10.15 (1H, s).

84 CI (S)-3-methyl-7-(5- (400 MHz, DMSO, ES+

methyl-2-(pyrimidin-4- 30°C) 1.21 (3H, d), [M+H]+ = ylamino)pyrimidin-4-yl)- 2.41 (3H, s), 2.59 (3H, 442

2-((3 -methylpyrazin-2- s), 3.98 (1H, dd), 4.23

yl)methyl)-3,4- (1H, dd), 4.31 - 4.46

dihydropyrrolo[ 1 ,2- (2H, m), 5.36 (1H, d),

ajpyrazin- 1 (2H)-one 7.35 (1H, d), 7.80 (1H,

d), 8.33 (1H, dd), 8.34 - 8.5 (3H, m), 8.56 (1H,

d), 8.76 (1H, s), 10.16

(1H, s).

85 CI (R)-7-(2-((l,3-dimethyl- (400 MHz, DMSO, ES+

1 H-pyrazol-4-yl)amino)- 20°C) 2.12 (3H, s), 2.29 [M+H]+ =

5 -methylpyrimidin-4-yl)- (3H, s), 3.23 (3H, s), 479

3 -(methoxymethyl)-2- 3.26 - 3.30 (lH, m),

(thiazol-4-ylmethyl)-3 ,4- 3.49 (1H, d), 3.75 (3H,

dihydropyrrolo [ 1 ,2- s), 4.05 (1H, s), 4.27

ajpyrazin- 1 (2H)-one (1H, d), 4.40 (1H, dd),

4.46 (1H, d), 5.26 (1H,

d), 7.26 (1H, s), 7.66

(2H, d), 7.81 (lH, s), 8.16 (1H, s), 8.44 (1H,

s), 9.11 (1H, s).

86 CI (S)-2-((4- (400 MHz, DMSO, ES+

(difluoromethyl)pyridin- 30°C) 1.18 (3H, d), [M+H]+ =

2-yl)methyl)-3 -methyl-7- 2.33 (3H, s), 3.69 (3H, 479

(5 -methyl -2-(( 1 -methyl- s), 4.02 (lH, m), 4.21

lH-pyrazol-5- (1H, dd), 4.38 (1H, dd),

yl)amino)pyrimidin-4- 4.45 (1H, d), 5.21 (1H,

yi)-3,4- d), 6.27 (lH, d), 7.10 - dihydropyrrolo[ 1 ,2- 7.25 (lH, t), 7.27 (1H,

ajpyrazin- 1 (2H)-one d), 7.33 (1H, d), 7.49

(1H, d), 7.55 (1H, s),

7.66 (1H, d), 8.24 (1H,

s), 8.71 (1H, d), 9.07

(1H, s).

86a Br (R or S)-2-(2- (400 MHz, DMSO, ES+

methoxyethyl)-3 - 30°C) 2.32 (3H, s), 3.15 [M+H]+ =

(methoxymethyl)-7-(5 - - 3.23 (lH, m), 3.25 426 methyl-2-(( 1 -methyl- 1 H- (3H, s), 3.30 (4H, d),

pyrazol-5- 3.43 (1H, dd), 3.48 - yl)amino)pyrimidin-4- 3.62 (2H, m), 3.69 (3H,

yi)-3,4- s), 3.97 - 4.1 (2H, m),

dihydropyrrolo[ 1 ,2- 4.23 (1H, dd), 4.33 - ajpyrazin- 1 (2H)-one. 4.44 (1H, m), 6.27 (1H,

(Chiral Technolgies IA d), 7.20 (1H, d), 7.34

column, 20 μιη silica, 50 (1H, d), 7.64 (1H, d),

mm diameter, 250 mm 8.11 - 8.37 (lH, m),

length), eluting with IP A 9.07 (1H, s).

100%. lst eluted,

retention time 0.71 mins). 86b Br (R or S)-2-(2- (400 MHz, DMSO, ES+

methoxyethyl)-3 - 30°C) 2.32 (3H, s), 3.15 [M+H]+ =

(methoxymethyl)-7-(5 - - 3.23 (lH, m), 3.25 426. methyl-2-(( 1 -methyl- 1 H- (3H, s), 3.30 (4H, d),

pyrazol-5- 3.43 (1H, dd), 3.48 - yl)amino)pyrimidin-4- 3.62 (2H, m), 3.69 (3H,

yi)-3,4- s), 3.97 - 4.1 (2H, m),

dihydropyrrolo[ 1 ,2- 4.23 (1H, dd), 4.33 - ajpyrazin- 1 (2H)-one. 4.44 (1H, m), 6.27 (1H,

(Chiral Technolgies IA d), 7.20 (1H, d), 7.34

column, 20 μιη silica, 50 (1H, d), 7.64 (1H, d),

mm diameter, 250 mm 8.11 - 8.37 (lH, m),

length), eluting with IP A 9.07 (1H, s).

100%. 2nd eluted,

retention time 1.53 mins).

87 Br or OMs (S)-7-(2-((l,3-dimethyl- (400 MHz, DMSO, ES+

lH-pyrazol-5-yl)amino)- 30°C) 1.15 (3H, d), [M+H]+ =

5 -methylpyrimidin-4-yl)- 2.12 (3H, s), 2.32 (3H, 447

3 -methyl-2 -((2 -methyl- s), 3.60 (3H, s), 3.96

2H-l,2,3-triazol-4- (1H, ddd), 4.12 (3H, s),

yl)methyl)-3,4- 4.17 (1H, dd), 4.23 - dihydropyrrolo[ 1 ,2- 4.41 (2H, m), 5.08 (1H,

ajpyrazin- 1 (2H)-one d), 6.03 (1H, s), 7.26

(1H, d), 7.62 (1H, d),

7.69 (1H, s), 8.22 (1H,

s), 8.96 (1H, s).

88 Br (S)-7-(2-((l,3-dimethyl- (400 MHz, DMSO, ES+

1 H-pyrazol-4-yl)amino)- 30°C) 1.18 (3H, d), [M+H]+ =

5 -methylpyrimidin-4-yl)- 2.12 (3H, s), 2.31 (3H, 475

2-((6- s), 3.75 (3H, s), 3.9 -

(fluoromethyl)pyridin-2- 4.07 (lH, m), 4.21 (1H, yl)methyl)-3 -methyl-3 ,4- dd), 4.3 - 4.52 (2H, m),

dihydropyrrolo[ 1 ,2- 5.20 (1H, d), 5.42 (1H,

ajpyrazin- 1 (2H)-one s), 5.54 (1H, s), 5.75

(1H, s), 7.28 (1H, d),

7.40 (2H, t), 7.66 (1H,

d), 7.80 (1H, s), 7.87

(lH, t), 8.12 - 8.2 (1H,

m), 8.30 (1H, s).

89 Br (S)-2-((2,5-dimethyl-2H- (400 MHz, DMSO, ES+

l,2,3-triazol-4- 23°C) 1.19 (3H, d), [M+H]+ yl)methyl)-3 -methyl-7- 2.26 (3H, s), 2.37 (3H, 447

(5 -methyl -2-(( 1 -methyl- s), 3.74 (3H, s), 3.92

lH-pyrazol-5- (1H, d), 4.09 (3H, s),

yl)amino)pyrimidin-4- 4.22 (2H, d), 4.29 (1H,

yi)-3,4- d), 5.15 (1H, d), 6.32

dihydropyrrolo[ 1 ,2- (1H, d), 7.30 (1H, d),

ajpyrazin- 1 (2H)-one 7.40 (1H, d), 7.68 (1H,

d), 8.16 - 8.38 (lH, m),

9.16 (1H, s).

90 Br (S)-7-(2-((l,3-dimethyl- (400 MHz, DMSO, ES+

lH-pyrazol-5-yl)amino)- 32°C) 1.18 (3H, d), [M+H]+ =

5 -methylpyrimidin-4-yl)- 2.12 (3H, s), 2.33 (3H, 475

2-((6- s), 3.60 (3H, s), 3.99

(fluoromethyl)pyridin-2- (1H, ddd), 4.22 (1H,

yl)methyl)-3 -methyl-3 ,4- dd), 4.31 - 4.46 (2H,

dihydropyrrolo[ 1 ,2- m), 5.19 (lH, d), 5.42

ajpyrazin- 1 (2H)-one (1H, s), 5.54 (1H, s),

6.04 (1H, s), 7.27 (1H,

d), 7.35 - 7.46 (2H, m),

7.66 (1H, d), 7.87 (1H, t), 8.23 (1H, s), 8.98

(1H, s).

91 Br 7-(5-methyl-2-((l- (400 MHz, DMSO, ES+

methyl-1 H-pyrazol-5 - 30°C) 2.32 (3H, s), 3.68 [M+H]+ = yl)amino)pyrimidin-4- (3H, s), 3.81 - 3.88 (2H, 483 yl)-2-((6- m), 4.28 - 4.39 (2H, m),

(trifluoromethyl)pyridin- 4.86 (2H, s), 6.26 (1H,

2-yl)methyl)-3,4- d), 7.26 (1H, d), 7.32

dihydropyrrolo[ 1 ,2- (1H, d), 7.67 (2H, d),

ajpyrazin- 1 (2H)-one 7.80 (1H, d), 8.07 (1H,

t), 8.23 (1H, s), 9.07

(1H, s).

92 CI (R)-2-((l,3-dimethyl-lH- (500 MHz, DMSO, ES+

pyrazol-5 -yl)methyl)-3 - 30°C) 1.08 (3H, d), [M+H]+ = methyl-7-(5 -methyl-2- 2.10 (3H, s), 2.32 (3H, 446

(( 1 -methyl- 1 H-pyrazol-5 - s), 3.69 (6H, d), 3.79 - yl)amino)pyrimidin-4- 3.88 (lH, m), 4.15 - 4.2

yi)-3,4- (lH, m), 4.21 - 4.27

dihydropyrrolo[ 1 ,2- (1H, m), 4.30 (1H, d),

ajpyrazin- 1 (2H)-one 5.05 (1H, d), 6.07 (1H,

s), 6.26 (1H, d), 7.26

(1H, d), 7.33 (1H, d),

7.63 (1H, d), 8.24 (1H,

s), 9.07 (1H, s).

93 Br 7-(5-methyl-2- (400 MHz, DMSO, ES+

(pyridazin-4- 30°C) 2.39 (3H, s), 2.45 [M+H]+ = ylamino)pyrimidin-4-yl)- (3H, s), 3.71 - 3.86 (2H, 427

2-((6-methylpyridin-2- m), 4.29 - 4.44 (2H, m),

yl)methyl)-3,4- 4.74 (2H, s), 7.14 (2H,

dihydropyrrolo[ 1 ,2- dd), 7.35 (1H, s), 7.65

ajpyrazin- 1 (2H)-one (lH, t), 7.78 (lH, s), 8.14 (1H, dd), 8.41

(1H, s), 8.89 (1H, d),

9.45 (lH, d), 10.13

(1H, s).

94 CI (R)-2-((l- (400 MHz, DMSO, ES+

(difluoromethyl)- 1 H- 30°C) 1.11 (3H, d), [M+H]+ = pyrazol-5 -yl)methyl)-3 - 2.33 (3H, s), 3.68 (3H, 468 methyl-7-(5-methyl-2- s), 3.88 - 4.02 (lH, m),

(( 1 -methyl- 1 H-pyrazol-5 - 4.13 - 4.40 (2H, m),

yl)amino)pyrimidin-4- 4.54 (1H, d), 5.22 (1H,

yi)-3,4- d), 6.26 (1H, d), 6.56

dihydropyrrolo[ 1 ,2- (1H, d), 7.28 (1H, d),

ajpyrazin- 1 (2H)-one 7.33 (1H, d), 7.66 (1H,

d), 7.73 (1H, d), 7.73 - 8.05 (lH, t), 8.24 (1H,

s), 9.07 (1H, s).

95 CI (R)-2-((6- (400 MHz, DMSO, ES+

(difluoromethyl)pyridin- 30°C) 1.17 (3H, d), [M+H]+ =

2-yl)methyl)-3 -methyl-7- 2.32 (3H, s), 3.68 (3H, 479

(5 -methyl -2-(( 1 -methyl- s), 4.00 (1H, m), 4.22

1 H-pyrazol-5 - (1H, dd), 4.36 - 4.48

yl)amino)pyrimidin-4- (2H, m), 5.20 (1H, d),

yi)-3,4- 6.26 (1H, d), 6.80 - dihydropyrrolo[ 1 ,2- 7.08 (lH, t), 7.26 (1H,

ajpyrazin- 1 (2H)-one d), 7.32 (1H, d), 7.58

(2H, dd), 7.66 (1H, d),

7.97 (lH, t), 8.23 (1H,

s), 9.07 (1H, s).

96 Br 7-(2-((l,5-dimethyl-lH- (400 MHz, DMSO, ES+

pyrazol-4-yl)amino)-5- 30°C) 2.18 (3H, s), 2.29 [M+H]+ methylpyrimidin-4-yl)-2- (3H, s), 2.46 (3H, s), = 443 ((6-methylpyridin-2- 3.71 (3H, s), 3.78 (2H,

yl)methyl)-3,4- dd), 4.19 - 4.36 (2H,

dihydropyrrolo[ 1 ,2- m), 4.73 (2H, s), 7.07 - ajpyrazin- 1 (2H)-one 7.18 (2H, m), 7.26 (IH,

d), 7.56 (IH, s), 7.61

(IH, d), 7.65 (IH, t),

8.12 (IH, s), 8.27 (IH,

s).

97 CI (S)-7-(2-((l,3-dimethyl- (500 MHz, DMSO, ES+

1 H-pyrazol-5 -yl)amino)- 30°C) 1.20 (3H, d), [M+H]+ =

5 -methylpyrimidin-4-yl)- 2.12 (3H, s), 2.34 (3H, 458

3-methyl-2-((6- s), 2.47 (3H, s), 3.60

methylpyrimidin-4- (3H, s), 4.01 (IH, dt),

yl)methyl)-3,4- 4.23 (IH, dd), 4.32

dihydropyrrolo[ 1 ,2- (IH, d), 4.50 (IH, dd),

ajpyrazin- 1 (2H)-one 5.11 (IH, d), 6.04 (IH,

s), 7.28 (IH, d), 7.39

(IH, s), 7.68 (IH, d),

8.24 (IH, s), 8.91 - 9.07

(2H, m).

98 CI (S)-7-(2-((2- (400 MHz, DMSO, ES+

methoxypyridin-4- 30°C) 1.18 (3H, d), [M+H]+ = yl)amino)-5- 2.37 (3H, s), 2.47 (3H, 470 methylpyrimidin-4-yl)-3 - s), 3.82 (3H, s), 3.99

methyl-2-((6- (IH, m), 4.23 (IH, dd),

methylpyridin-2- 4.30 (IH, d), 4.40 (IH,

yl)methyl)-3,4- dd), 5.16 (IH, d), 7.12 - dihydropyrrolo[ 1 ,2- 7.2 (2H, m), 7.30 (IH,

ajpyrazin- 1 (2H)-one dd), 7.37 (IH, d), 7.41

(IH, d), 7.65 (IH, t),

7.73 (IH, d), 7.93 (IH, d), 8.36 (1H, s), 9.77

(1H, s).

99 CI (R)-3-(methoxymethyl)- (500 MHz, DMSO, ES+

7-(5-methyl-2-((l- 30°C) 2.33 (3H, s), 3.22 [M+H]+ methyl- 1 H-pyrazol-5 - (3H, d), 3.27 - 3.31 465 yl)amino)pyrimidin-4- (lH, m), 3.40 (1H, dd),

yl)-2-(thiazol-2- 3.70 (3H, d), 4.1 - 4.16

ylmethyl)-3,4- (1H, m), 4.29 (1H, dd),

dihydropyrrolo[ 1 ,2- 4.44 (1H, d), 4.73 (1H,

ajpyrazin- 1 (2H)-one d), 5.31 (1H, d), 6.27

(1H, d), 7.28 (1H, d),

7.35 (1H, d), 7.69 (1H,

d), 7.7 - 7.72 (1H, m),

7.76 - 7.79 (1H, m),

8.25 (1H, s), 9.10 (1H,

s).

100 CI (S)-7-(2-((l,3-dimethyl- (500 MHz, DMSO, ES+

1 H-pyrazol-5 -yl)amino)- 30°C) 1.17 (3H, d), [M+H]+ =

5 -methylpyrimidin-4-yl)- 2.12 (3H, s), 2.33 (3H, 457

3-methyl-2-((6- s), 2.47 (3H, s), 3.60

methylpyridin-2- (3H, s), 3.98 (1H, d),

yl)methyl)-3,4- 4.19 - 4.34 (2H, m),

dihydropyrrolo[ 1 ,2- 4.38 (1H, dd), 5.15

ajpyrazin- 1 (2H)-one (1H, d), 6.04 (1H, s),

7.16 (2H, t), 7.27 (1H,

d), 7.61 - 7.71 (2H, m),

8.23 (1H, s), 8.99 (1H,

s).

101 CI (S)-7-(2-((l,3-dimethyl- (500 MHz, DMSO, ES+

1 H-pyrazol-4-yl)amino)- 30°C) 1.18 (3H, d), [M+H]+ =

5 -methylpyrimidin-4-yl)- 2.12 (3H, s), 2.31 (3H, 457 3-methyl-2-((6- s), 2.48 (3H, s), 3.75

methylpyridin-2- (3H, s), 3.98 (IH, dq),

yl)methyl)-3,4- 4.18 - 4.42 (3H, m),

dihydropyrrolo[ 1 ,2- 5.16 (IH, d), 7.17 (2H,

ajpyrazin- 1 (2H)-one t), 7.28 (IH, s), 7.62 -

7.7 (2H, m), 7.81 (IH,

s), 8.17 (IH, s), 8.32

(IH, s).

102 CI (S)-2-((6- (400 MHz, DMSO, ES+

(difluoromethyl)pyridin- 30°C) 1.17 (3H, d), [M+H]+ =

2-yl)methyl)-3 -methyl-7- 2.33 (3H, s), 3.68 (3H, 479

(5 -methyl -2-(( 1 -methyl- s), 3.96 - 4.03 (lH, m),

lH-pyrazol-5- 4.22 (IH, dd), 4.38 - yl)amino)pyrimidin-4- 4.47 (2H, m), 5.20 (IH,

yi)-3,4- d), 6.26 (IH, d), 6.80 - dihydropyrrolo[ 1 ,2- 7.08 (lH, t), 7.26 (IH,

ajpyrazin- 1 (2H)-one d), 7.32 (IH, d), 7.56

(IH, d), 7.60 (IH, d),

7.66 (IH, d), 7.97 (IH,

t), 8.24 (IH, s), 9.07

(IH, s).

103 CI (S)-3-methyl-7-(5- (400 MHz, DMSO, ES+

methyl-2-(pyridazin-4- 30°C) 1.18 (3H, d), [M+H]+ ylamino)pyrimidin-4-yl)- 2.40 (3H, s), 2.47 (3H, 441

2-((6-methylpyridin-2- s), 4.00 (IH, m), 4.25

yl)methyl)-3,4- (IH, dd), 4.31 (IH, d),

dihydropyrrolo[ 1 ,2- 4.41 (IH, dd), 5.16

ajpyrazin- 1 (2H)-one (IH, d), 7.17 (2H, dd),

7.36 (IH, d), 7.66 (IH,

t), 7.79 (lH, d), 8.15

(IH, dd), 8.42 (IH, s), 8.91 (IH, d), 9.43 -

9.49 (lH, m), 10.14

(IH, s).

Br (R)-2- (400 MHz, DMSO, ES+

(cyclopropylmethyl)-3 - 24°C) 0.28 - 0.35 (2H, [M+H]+ =

(methoxymethyl)-7-(5 - d), 0.48 - 0.54 (2H, m), 420 methyl-2-(pyrimidin-4- 1.10 (IH, s), 2.40 (3H,

ylamino)pyrimidin-4-yl)- s), 3.09 - 3.14 (lH, m),

3 ,4-dihydropyrrolo [ 1 ,2- 3.21 - 3.26 (IH, s), 3.30

ajpyrazin- 1 (2H)-one (3H, s), 3.47 - 3.51 (IH,

m), 3.64 - 3.70 (lH, m),

4.12 - 4.14 (lH,m),

4.28 - 4.32 (IH, m),

4.47 (IH, d), 7.31 (IH,

s), 7.80 (IH, s), 8.32

(IH, d), 8.34 (IH, s),

8.56 (IH, d), 8.76 (IH,

s), 10.20 (IH, s).

Br 7-(5-methyl-2-((5- (400 MHz, DMSO, ES+

methyl- 1 H-imidazol-4- 30°C) 2.03 (3H, s), 2.28 [M+H]+ = yl)amino)pyrimidin-4- (3H, s), 2.46 (3H, s), 429 yl)-2 -((6 -methylpyridin- 3.73 - 3.8 (2H, m), 4.26

2-yl)methyl)-3,4- - 4.32 (2H, m), 4.72

dihydropyrrolo[ 1 ,2- (2H, s), 7.13 (2H, dd),

ajpyrazin- 1 (2H)-one 7.21 (IH, d), 7.37 (IH,

s), 7.57 (IH, d), 7.65

(lH, t), 8.08 (IH, s),

8.15 (IH, s), 11.80 (IH,

s). 106 CI (R)-3-methyl-2-((l- (400 MHz, DMSO, ES+

methyl-1 H-pyrazol-5 - 30°C) 1.07 (3H, d), [M+H]+ = yl)methyl)-7-(5 -methyl- 2.32 (3H, s), 3.68 (3H, 432

2-((l -methyl- 1 H-pyrazol- s), 3.79 (3H, s), 3.83 -

5 -yl)amino)pyrimidin-4- 3.87 (lH, m), 4.18 (1H,

yi)-3,4- dd), 4.25 (1H, dd), 4.39

dihydropyrrolo[ 1 ,2- (lH, d), 5.11 (lH, d),

ajpyrazin- 1 (2H)-one 6.26 (1H, d), 6.30 (1H,

d), 7.27 (1H, d), 7.33

(1H, d), 7.35 (1H, d),

7.64 (1H, d), 8.21 - 8.25 (lH, m), 9.07 (1H,

s).

107 CI (R)-3-(methoxymethyl)- (400 MHz, CD30D, ES+

7-(5-methyl-2-((l- 23°C) 2.40 (3H, s), [M+H]+ = methyl- 1 H-pyrazol-5 - 2.72 (3H, s), 3.35 (3H, 493 yl)amino)pyrimidin-4- s), 3.37 - 3.46 (lH, m),

yl)-2-((2-methylthiazol- 3.48 - 3.50 (lH, m),

4-yl)methyl)-3,4- 3.76 (3H, s), 4.07 - 4.11

dihydropyrrolo[ 1 ,2- (lH, m), 4.28 - 4.32

ajpyrazin- 1 (2H)-one (lH, m), 4.41 - 4.48

(lH, m), 5.28 (1H, d),

6.34(1H, s), 7.33 (1H,

s), 7.44 (1H, s), 7.48

(1H, s), 7.60 (1H, s),

8.18 (1H, s).

108 CI (S)-7-(2-((l,3-dimethyl- (500 MHz, DMSO, ES+

1 H-pyrazol-4-yl)amino)- 30°C) 1.20 (3H, d), [M+H]+ =

5 -methylpyrimidin-4-yl)- 2.12 (3H, s), 2.31 (3H, 458

3-methyl-2-((3- s), 2.58 (3H, s), 3.75

methylpyrazin-2- (3H, s), 3.95 (1H, s), yl)methyl)-3,4- 4.19 (1H, d), 4.31 - dihydropyrrolo[ 1 ,2- 4.44 (2H, m), 5.36 (1H, ajpyrazin- 1 (2H)-one d), 7.26 (1H, s), 7.65

(1H, s), 7.81 (lH, s),

8.16 (1H, s), 8.32 (1H,

s), 8.43 (2H, d).

CI (R)-7-(2-((l,3-dimethyl- (500 MHz, DMSO, ES- [M-

1 H-pyrazol-4-yl)amino)- 30°C) 1.18 (3H, d), H]- = 455

5 -methylpyrimidin-4-yl)- 2.12 (3H, s), 2.31 (3H,

3-methyl-2-((6- s), 2.47 (3H, s), 3.75

methylpyridin-2- (3H, s), 3.95 - 4.00 (1H, yl)methyl)-3,4- m), 4.21 (1H, dd), 4.30

dihydropyrrolo[ 1 ,2- (1H, d), 4.38 (1H, dd),

ajpyrazin- 1 (2H)-one 5.16 (1H, d), 7.16 (2H,

t), 7.28 (1H, s), 7.64 - 7.68 (2H, m), 7.81 (1H,

s), 8.17 (1H, s), 8.32

(1H, s).

CI 7-(5-methyl-2-((l- (500 MHz, DMSO, ES+

methyl-1 H-pyrazol-5 - 30°C) 2.34 (3H, s), 2.60 [M+H]+ = yl)amino)pyrimidin-4- (3H, s), 3.69 (3H, s), 430 yi)-2-((2- 3.8 - 3.89 (2H, m), 4.33

methylpyrimidin-4- - 4.41 (2H, m), 4.73

yl)methyl)-3,4- (2H, s), 6.27 (1H, d),

dihydropyrrolo[ 1 ,2- 7.24 - 7.3 (2H, m), 7.34

ajpyrazin- 1 (2H)-one (1H, d), 7.68 (1H, d),

8.25 (1H, s), 8.63 (1H,

d), 9.09 (1H, s).

OMs (R)-3-(methoxymethyl)- (500 MHz, DMSO, ES+

7-(5-methyl-2-((l- 30°C) 2.32 (3H, s), 2.61 [M+H]+ = methyl-1 H-pyrazol-5 - (3H, s), 3.22 (3H, s), 479 yl)amino)pyrimidin-4- 3.32 - 3.37 (2H, m),

yl)-2-((2-methylthiazol- 3.69 (3H, s), 3.98 - 4.08

5-yl)methyl)-3,4- (lH, m), 4.18 (lH, dd),

dihydropyrrolo[ 1 ,2- 4.39 (lH, d), 4.56 (1H,

ajpyrazin- 1 (2H)-one d), 5.12 (lH, d), 6.27

(1H, d), 7.25 (1H, d),

7.35 (1H, d), 7.65 (2H,

d), 8.25 (1H, s), 9.08

(1H, s).

112 CI 2-((6-methoxypyridin-2- (500 MHz, DMSO, ES+

yl)methyl)-7-(5 -methyl- 27°C) 2.32 (3H, s), 3.68 [M+H]+ =

2-((l -methyl- 1 H-pyrazol- (3H, s), 3.80 (3H, s), 445

5 -yl)amino)pyrimidin-4- 3.82 - 3.86 (2H, m),

yi)-3,4- 4.28 - 4.37 (2H, m),

dihydropyrrolo[ 1 ,2- 4.68 (2H, s), 6.26 (1H,

ajpyrazin- 1 (2H)-one d), 6.70 (1H, dd), 6.92

(1H, dd), 7.25 (1H, d),

7.33 (1H, d), 7.64 - 7.7

(2H, m), 8.24 (1H, d),

9.09 (1H, s).

113 CI (R)-3-(methoxymethyl)- (400MHz, DMSO, ES+

7-(5-methyl-2-((l- 24°C) 2.33 (3H, s), 3.23 [M+H]+ = methyl- 1 H-pyrazol-5 - (3H, s), 3.22 (lH, m), 465 yl)amino)pyrimidin-4- 3.27 - 3.33 (lH, m),

yl)-2-(thiazol-4- 3.39 - 3.43 (lH, m),

ylmethyl)-3,4- 3.69 (3H, s), 4.04 (1H,

dihydropyrrolo[ 1 ,2- s), 4.27 - 4.31 (lH, m),

ajpyrazin- 1 (2H)-one 4.39 - 4.50 (2H, m),

5.25 (1H, d), 6.27 (1H,

s), 7.25 (1H, s), 7.34

(1H, s), 7.65 (2H, d), 8.24 (1H, s), 9.11 (1H,

s).

114 CI 2-((6- (500 MHz, DMSO, ES+

(difluoromethyl)pyridin- 30°C) 1.28 (6H, s), 2.35 [M+H]+ =

2-yl)methyl)-3,3- (3H, s), 3.70 (3H, s), 493 dimethyl-7-(5 -methyl-2- 4.27 (2H, s), 4.85 (2H,

(( 1 -methyl- 1 H-pyrazol-5 - s), 6.27 (1H, d), 6.85 - yl)amino)pyrimidin-4- 7.05 (lH, t), 7.28 (1H,

yi)-3,4- d), 7.34 (1H, d), 7.57

dihydropyrrolo[ 1 ,2- (1H, s), 7.59 (1H, s),

ajpyrazin- 1 (2H)-one 7.66 (1H, d), 7.96 (1H,

t), 8.26 (1H, s), 9.09

(1H, s).

115 CI (R)-2-((4,6- (400 MHz, DMSO, ES+

dimethylpyridin-2- 30°C) 1.20 (3H, d), [M+H]+ = yl)methyl)-3 -methyl-7- 2.30 (3H, s), 2.37 (3H, 458

(5 -methyl -2-(( 1 -methyl- s), 2.45 (3H, s), 3.73

1 H-pyrazol-5 - (3H, s), 3.98 (1H, ddd),

yl)amino)pyrimidin-4- 4.19 - 4.30 (2H, m),

yi)-3,4- 4.41 (1H, dd), 5.16

dihydropyrrolo[ 1 ,2- (1H, d), 6.31 (1H, d),

ajpyrazin- 1 (2H)-one 7.02 (2H, d), 7.30 (1H,

d), 7.37 (1H, d), 7.69

(1H, d), 8.28 (1H, s),

9.11 (1H, s).

116 CI 2-(cyclopropylmethyl)-7- (400 MHz, DMSO, ES+

(5 -methyl -2-(( 1 -methyl- 30°C) 0.26 (2H, d), [M+H]+ =

1 H-pyrazol-5 - 0.46 (2H, dd), 1.02 378 yl)amino)pyrimidin-4- (1H, s), 2.31 (3H, s),

yi)-3,4- 3.33 (2H, d), 3.68 (3H,

s), 3.73 - 3.81 (2H, m), dihydropyrrolo[ 1 ,2- 4.2 - 4.35 (2H, m), 6.25

ajpyrazin- 1 (2H)-one (1H, d), 7.20 (1H, d),

7.32 (1H, d), 7.61 (1H,

d), 8.22 (1H, s), 9.06

(1H, s).

117 Br (S)-3-methyl-7-(5- (400 MHz, DMSO, ES+

methyl-2-(( 1 -methyl- 1 H- 30°C) 1.14 (3H, d), [M+H]+ = pyrazol-5- 1.96 (3H, d), 2.32 (3H, 432 yl)amino)pyrimidin-4- s), 3.68 (3H, s), 3.83 - yl)-2-((4-methylisoxazol- 3.93 (lH, m), 4.11 -

3-yl)methyl)-3,4- 4.28 (2H, m), 4.33 (1H,

dihydropyrrolo[ 1 ,2- d), 5.15 (1H, d), 6.25

ajpyrazin- 1 (2H)-one (1H, d), 7.26 (1H, d),

7.33 (1H, d), 7.63 (1H,

d), 8.23 (1H, s), 8.64

(1H, s), 9.06 (1H, s).

118 Br (+/-)-2-(2-methoxyethyl)- (400 MHz, DMSO, ES+

3-(methoxymethyl)-7-(5- 30°C) 2.32 (3H, s), 3.15 [M+H]+ = methyl-2-(( 1 -methyl- 1 H- - 3.23 (lH, m), 3.25 426 pyrazol-5- (3H, s), 3.30 (4H, d),

yl)amino)pyrimidin-4- 3.43 (1H, dd), 3.48 - yi)-3,4- 3.62 (2H, m), 3.69 (3H,

dihydropyrrolo[ 1 ,2- s), 3.97 - 4.1 (2H, m),

ajpyrazin- 1 (2H)-one 4.23 (1H, dd), 4.33 -

4.44 (1H, m), 6.27 (1H,

d), 7.20 (1H, d), 7.34

(1H, d), 7.64 (1H, d),

8.11 - 8.37 (lH, m),

9.07 (1H, s). 119 CI (S)-3-methyl-7-(5- (400 MHz, DMSO, ES+

methyl-2-(( 1 -methyl- 1 H- 30°C) 1.14 (3H, d), [M+H]+ = pyrazol-5- 2.32 (3H, s), 2.63 (3H, 472 yl)amino)pyrimidin-4- s), 3.68 (3H, s), 3.98

yl)-2-((2-methylthiazol- (1H, d), 4.18 (lH, dd),

4-yl)methyl)-3,4- 4.30 (2H, td), 5.10 (1H,

dihydropyrrolo[ 1 ,2- d), 6.25 (1H, d), 7.24

ajpyrazin- 1 (2H)-one (1H, d), 7.32 (1H, d),

7.35 (1H, s), 7.63 (1H,

d), 8.23 (1H, s), 9.06

(1H, s).

120 CI (R)-3-methyl-7-(5- (500 MHz, DMSO, ES+

methyl-2-(( 1 -methyl- 1 H- 30°C) 1.14 (3H, d), [M+H]+ = pyrazol-5- 2.32 (3H, s), 2.64 (3H, 449 yl)amino)pyrimidin-4- s), 3.69 (3H, s), 3.94 - yl)-2-((2-methylthiazol- 4.02 (lH, m), 4.19 (1H,

4-yl)methyl)-3,4- dd), 4.26 - 4.35 (2H,

dihydropyrrolo[ 1 ,2- m), 5.11 (1H, d), 6.26

ajpyrazin- 1 (2H)-one (1H, d), 7.25 (1H, d),

7.33 (1H, d), 7.36 (1H,

s), 7.63 (1H, d), 8.24

(1H, s), 9.07 (1H, s).

121 Br (R)-3-methyl-7-(5- (500 MHz, DMSO, ES+

methyl-2-(( 1 -methyl- 1 H- 30°C) 1.14 (3H, d), [M+H]+ = pyrazol-5- 1.95 - 1.99 (3H, m), 433 yl)amino)pyrimidin-4- 2.32 (3H, s), 3.68 (3H,

yl)-2-((4-methylisoxazol- s), 3.84 - 3.92 (lH, m),

3-yl)methyl)-3,4- 4.15 - 4.25 (2H, m),

dihydropyrrolo[ 1 ,2- 4.34 (1H, d), 5.16 (1H,

ajpyrazin- 1 (2H)-one d), 6.26 (1H, d), 7.27

(1H, d), 7.33 (1H, d), 7.64 (1H, d), 8.24 (1H,

s), 8.63 - 8.66 (1H, m),

9.07 (1H, s).

122 OMs 3,3-dimethyl-7-(5- (500 MHz, DMSO, ES+

methyl-2-(( 1 -methyl- 1 H- 30°C) 1.17 (6H, s), 2.2 [M+H]+ = pyrazol-5- - 2.24 (3H, m), 3.58 446 yl)amino)pyrimidin-4- (3H, s), 3.99 (3H, s),

yl)-2-((2-methyl-2H- 4.07 (2H, s), 4.60 (2H,

l,2,3-triazol-4- s), 6.15 (lH, d), 7.14

yl)methyl)-3,4- (1H, d), 7.22 (1H, d),

dihydropyrrolo[ 1 ,2- 7.47 - 7.52 (2H, m),

ajpyrazin- 1 (2H)-one 8.13 (1H, d), 8.96 (1H,

s).

123 CI (S)-7-(2-((l,3-dimethyl- (500 MHz, DMSO, ES+

1 H-pyrazol-5 -yl)amino)- 30°C) 1.20 (3H, d), [M+H]+ =

5 -methylpyrimidin-4-yl)- 2.12 (3H, s), 2.34 (3H, 458

3-methyl-2-((2- s), 2.62 (3H, s), 3.60

methylpyrimidin-4- (3H, s), 4.02 (1H, d),

yl)methyl)-3,4- 4.24 (1H, dd), 4.34

dihydropyrrolo[ 1 ,2- (1H, d), 4.48 (1H, dd),

ajpyrazin- 1 (2H)-one 5.10 (1H, d), 6.04 (1H,

s), 7.21 - 7.38 (2H, m),

7.68 (1H, d), 8.24 (1H,

s), 8.63 (1H, d), 9.00

(1H, s).

124 CI (S)-3-methyl-7-(5- (400 MHz, DMSO, ES+

methyl-2-((5- 30°C) 1.17 (3H, d), [M+H]+ = methylpyridazin-4- 2.31 (3H, s), 2.39 (3H, 455 yl)amino)pyrimidin-4- s), 2.46 (3H, s), 3.98

yl)-2 -((6 -methylpyridin- (1H, m), 4.22 (1H, dd),

2-yl)methyl)-3,4- 4.30 (lH, d), 4.39 (1H, dihydropyrrolo[ 1 ,2- dd), 5.14 (lH, d), 7.16

ajpyrazin- 1 (2H)-one (2H, t), 7.34 (lH, d),

7.65 (lH, t), 7.73 (1H,

d), 8.38 (1H, s), 8.87

(1H, s), 9.00 (1H, s),

9.89 (1H, s).

125 CI (R)-2-((4- (400 MHz, DMSO, ES+

(difluoromethyl)pyridin- 30°C) 1.18 (3H, d), [M+H]+ =

2-yl)methyl)-3 -methyl-7- 2.34 (3H, s), 3.69 (3H, 479

(5 -methyl -2-(( 1 -methyl- s), 4.02 (lH, m), 4.21

lH-pyrazol-5- (1H, dd), 4.38 (1H, dd),

yl)amino)pyrimidin-4- 4.46 (1H, d), 5.22 (1H,

yi)-3,4- d), 6.27 (1H, d), 7.00 - dihydropyrrolo[ 1 ,2- 7.25 (lH, t), 7.27 (1H,

ajpyrazin- 1 (2H)-one d), 7.34 (1H, d), 7.49

(1H, d), 7.55 (1H, s),

7.67 (1H, d), 8.25 (1H,

s), 8.71 (1H, d), 9.08

(1H, s).

126 CI (R)-2-((l- (500 MHz, DMSO, ES+

(difluoromethyl)- 1 H- 30°C) 2.33 (3H, s), 3.22 [M+H]+ = pyrazol-3 -yl)methyl)-3 - (3H, s), 3.26 (1H, dd), 498

(methoxymethyl)-7-(5 - 3.37 (1H, dd), 3.70

methyl-2-(( 1 -methyl- 1 H- (3H, s), 3.93 - 4.00 (1H, pyrazol-5- m), 4.26 (1H, dd), 4.36

yl)amino)pyrimidin-4- - 4.43 (2H, m), 5.10

yi)-3,4- (1H, d), 6.27 (1H, d),

dihydropyrrolo[ 1 ,2- 6.51 (1H, d), 7.26 (1H,

ajpyrazin- 1 (2H)-one d), 7.34 (1H, d), 7.67

(1H, d), 7.67 - 7.90

(1H, t), 8.20 (1H, d), 8.25 (1H, s), 9.09 (1H,

s).

127 CI (S)-3-methyl-7-(5- (400 MHz, DMSO, ES+

methyl-2-(( 1 -methyl- 1 H- 30°C) 1.15 (3H, d), [M+H]+ = pyrazol-5- 2.33 (3H, s), 3.69 (3H, 434 yl)amino)pyrimidin-4- s), 4.02 (lH, d), 4.19

yl)-2-(thiazol-4- (1H, dd), 4.34 (1H, d),

ylmethyl)-3,4- 4.45 (1H, s), 5.20 (1H,

dihydropyrrolo[ 1 ,2- d), 6.27 (1H, d), 7.26

ajpyrazin- 1 (2H)-one (1H, d), 7.34 (1H, d),

7.63 (2H, dd), 8.24

(1H, s), 9.05 (1H, s),

9.09 (1H, d).

128 CI (S)-3-methyl-7-(5- (400 MHz, DMSO, ES+

methyl-2-(pyrimidin-4- 30°C) 1.18 (3H, d), [M+H]+ = ylamino)pyrimidin-4-yl)- 2.40 (3H, s), 2.47 (3H, 441

2-((6-methylpyridin-2- s), 4.00 (1H, m), 4.24

yl)methyl)-3,4- (1H, dd), 4.31 (1H, d),

dihydropyrrolo[ 1 ,2- 4.40 (1H, dd), 5.15

ajpyrazin- 1 (2H)-one (lH, d), 7.16 (2H, t),

7.36 (1H, d), 7.65 (1H,

t), 7.79 (1H, d), 8.33

(1H, dd), 8.42 (1H, s),

8.55 (1H, d), 8.75 (1H,

s), 10.15 (1H, s).

129 CI (R)-3-methyl-7-(5- (400 MHz, DMSO, ES+

methyl-2-(pyrimidin-4- 30°C) 1.24 (3H, d), [M+H]+ = ylamino)pyrimidin-4-yl)- 2.47 (3H, s), 2.53 (3H, 441

2-((6-methylpyridin-2- s), 4.02 - 4.09 (1H, m),

yl)methyl)-3,4- 4.30 (lH, d), 4.38 (1H,

d), 4.47 (1H, dd), 5.22 dihydropyrrolo[ 1 ,2- (lH, d), 7.23 (2H, t),

ajpyrazin- 1 (2H)-one 7.43 (1H, s), 7.72 (1H,

t), 7.86 (1H, s), 8.39

(1H, d), 8.49 (1H, s),

8.62 (1H, d), 8.81 (1H,

s), 10.20 (1H, s).

130 CI 2-((6- (400 MHz, DMSO, ES+

(difluoromethyl)pyridin- 30°C) 2.33 (3H, s), 3.69 [M+H]+ =

2-yl)methyl)-7-(5- (3H, s), 3.83 (2H, dd), 465 methyl-2-(( 1 -methyl- 1 H- 4.29 - 4.39 (2H, m),

pyrazol-5- 4.84 (2H, s), 6.27 (1H,

yl)amino)pyrimidin-4- d), 6.80 - 7.08 (1H, t),

yi)-3,4- 7.27 (1H, d), 7.33 (1H,

dihydropyrrolo[ 1 ,2- d), 7.54 (1H, d), 7.61

ajpyrazin- 1 (2H)-one (1H, d), 7.66 (1H, d),

7.99 (lH, t), 8.17 - 8.3

(1H, m), 9.06 (1H, s).

131 CI (R)-3-methyl-7-(5- (500 MHz, DMSO, ES+

methyl-2-(( 1 -methyl- 1 H- 30°C) 1.20 (3H, d), [M+H]+ = pyrazol-5- 2.34 (3H, s), 2.47 (3H, 444 yl)amino)pyrimidin-4- s), 3.70 (3H, s), 3.96 - yl)-2-((6- 4.05 (lH, m), 4.23 (1H,

methylpyrimidin-4- dd), 4.33 (1H, d), 4.50

yl)methyl)-3,4- (1H, dd), 5.11 (1H, d),

dihydropyrrolo[ 1 ,2- 6.28 (1H, d), 7.27 (1H,

ajpyrazin- 1 (2H)-one d), 7.34 (1H, d), 7.39

(1H, s), 7.69 (1H, d),

8.25 (1H, s), 8.97 (1H,

d), 9.09 (1H, s). 132 CI (S)-2-((5-fluoro-4- (400 MHz, DMSO, ES+

methylpyridin-2- 30°C) 1.15 (3H, d), [M+H]+ = yl)methyl)-3 -methyl-7- 2.28 (3H, s), 2.33 (3H, 461

(5 -methyl -2-(( 1 -methyl- s), 3.69 (3H, s), 3.96

lH-pyrazol-5- (lH, m), 4.18 (lH, dd),

yl)amino)pyrimidin-4- 4.28 (lH, d), 4.36 (1H,

yi)-3,4- dd), 5.13 (1H, d), 6.26

dihydropyrrolo[ 1 ,2- (1H, d), 7.26 (1H, d),

ajpyrazin- 1 (2H)-one 7.31 - 7.39 (2H, m),

7.65 (1H, d), 8.24 (1H,

s), 8.39 (1H, s), 9.07

(1H, s).

133 CI (R)-3-methyl-7-(5- (500 MHz, DMSO, ES+

methyl-2-(( 1 -methyl- 1 H- 30°C) 1.15 (3H, d), [M+H]+ = pyrazol-5- 2.33 (3H, s), 2.55 (3H, 443 yl)amino)pyrimidin-4- s), 3.69 (3H, s), 3.76 - yl)-2 -((2 -methylpyridin- 3.85 (lH, m), 4.16 -

3-yl)methyl)-3,4- 4.26 (2H, m), 4.35 (1H,

dihydropyrrolo[ 1 ,2- dd), 5.13 (1H, d), 6.27

ajpyrazin- 1 (2H)-one (1H, d), 7.20 (1H, dd),

7.28 (1H, d), 7.33 (1H,

d), 7.62 (1H, d), 7.66

(1H, d), 8.24 (1H, s),

8.34 - 8.38 (lH, m),

9.08 (1H, s).

134 CI 7-(5-methyl-2-((l- (500 MHz, DMSO, ES+

methyl- 1 H-pyrazol-5 - 30°C) 2.40 (3H, s), 3.25 [M+H]+ = yl)amino)pyrimidin-4- (2H, d), 3.69 - 3.75 428 yl)-2 -((2 -methylpyridin- (2H, m), 3.76 (3H, s),

3-yl)methyl)-3,4- 4.14 (1H, q), 4.34 - 4.4

(2H, m), 4.77 (2H, s), dihydropyrrolo[ 1 ,2- 6.34 (IH, d), 7.28 (IH,

ajpyrazin- 1 (2H)-one dd), 7.35 (IH, d), 7.41

(IH, d), 7.64 (IH, d),

7.72 (IH, d), 8.32 (IH,

s), 8.43 (IH, dd), 9.15

(IH, s).

135 CI (R)-3-methyl-7-(5- (500 MHz, DMSO, ES- [M- methyl-2-((2- 30°C) 1.19 (3H, d), H]- = 452 methylpyridin-4- 2.39 (3H, s), 2.42 (3H,

yl)amino)pyrimidin-4- s), 2.48 (3H, s), 3.96 - yl)-2 -((6 -methylpyridin- 4.04 (IH, m), 4.25 (IH,

2-yl)methyl)-3,4- dd), 4.31 (IH, d), 4.41

dihydropyrrolo[ 1 ,2- (IH, dd), 5.17 (IH, d),

ajpyrazin- 1 (2H)-one 7.16 (IH, d), 7.19 (IH,

d), 7.39 (IH, d), 7.61

(IH, dd), 7.66 (IH, t),

7.71 (IH, d), 7.76 (IH,

d), 8.22 (IH, d), 8.37

(IH, s), 9.73 (IH, s).

136 CI (S)-7-(2-((l,3-dimethyl- (500 MHz, DMSO, ES+

1 H-pyrazol-5 -yl)amino)- 30°C) 1.19 (3H, d), [M+H]+ =

5 -methylpyrimidin-4-yl)- 2.12 (3H, s), 2.33 (3H, 458

3-methyl-2-((3- s), 2.58 (3H, s), 3.60

methylpyrazin-2- (3H, s), 3.95 (IH, dt),

yl)methyl)-3,4- 4.19 (IH, dd), 4.31 - dihydropyrrolo[ 1 ,2- 4.44 (2H, m), 5.36 (IH,

ajpyrazin- 1 (2H)-one d), 6.04 (IH, s), 7.26

(IH, d), 7.65 (IH, d),

8.23 (IH, s), 8.38 - 8.48

(2H, m), 8.99 (IH, s). CI 2-((5-fluoro-6- (400 MHz, DMSO, ES+ methylpyridin-2- 30°C) 2.33 (3H, s), 2.44 [M+H]+ = yl)methyl)-7-(5 -methyl- (3H, d), 3.69 (3H, s), 447

2-((l -methyl- 1 H-pyrazol- 3.73 - 3.82 (2H, m), 4.2

5 -yl)amino)pyrimidin-4- - 4.38 (2H, m), 4.72

yi)-3,4- (2H, s), 6.27 (1H, d),

dihydropyrrolo[ 1 ,2- 7.18 - 7.28 (2H, m),

ajpyrazin- 1 (2H)-one 7.33 (1H, d), 7.52 - 7.63 (lH, m), 7.65 (1H,

d), 8.24 (1H, s), 9.06

(1H, s).

Br 7-(2-((l,3-dimethyl-lH- (500 MHz, DMSO, ES+

pyrazol-5 -yl)amino)-5 - 30°C) 1.19 (6H, s), 2.02 [M+H]+ = methylpyrimidin-4-yl)- (3H, s), 2.23 (3H, s), 461

3,3-dimethyl-2-((2- 3.49 (3H, s), 4.00 (3H,

methyl-2H- 1 ,2,3-triazol- s), 4.08 (2H, s), 4.61

4-yl)methyl)-3,4- (2H, s), 5.93 (1H, s),

dihydropyrrolo[ 1 ,2- 7.16 (1H, d), 7.51 (2H,

ajpyrazin- 1 (2H)-one d), 8.13 (1H, s), 8.90

(1H, s).

CI (R)-2-((6- (500 MHz, DMSO, ES+

methoxypyrimidin-4- 30°C) 1.20 (3H, d), [M+H]+ = yl)methyl)-3 -methyl-7- 2.34 (3H, s), 3.70 (3H, 460

(5 -methyl -2-(( 1 -methyl- s), 3.93 (3H, s), 3.97 - lH-pyrazol-5- 4.05 (1H, m), 4.22 (1H,

yl)amino)pyrimidin-4- dd), 4.31 (1H, d), 4.45

yi)-3,4- (1H, dd), 5.06 (1H, d),

dihydropyrrolo[ 1 ,2- 6.27 (1H, d), 6.87 (1H,

ajpyrazin- 1 (2H)-one s), 7.26 (1H, d), 7.34

(1H, d), 7.67 (1H, d), 8.25 (1H, s), 8.75 (1H,

s), 9.08 (1H, s).

141 Br (R)-2-(2-methoxyethyl)- (400 MHz, DMSO, ES+

3 -methyl-7 -(5 -methyl-2- 30°C) 1.13 (3H, d), [M+H]+ =

(( 1 -methyl- 1 H-pyrazol-5 - 2.32 (3H, s), 3.13 - 3.25 396 yl)amino)pyrimidin-4- (lH, m), 3.28 (3H, s),

yi)-3,4- 3.4 - 3.61 (2H, m), 3.68

dihydropyrrolo[ 1 ,2- (3H, s), 3.87 - 4.06 (2H, ajpyrazin- 1 (2H)-one m), 4.12 - 4.35 (2H, m),

6.26 (1H, d), 7.20 (1H,

s), 7.33 (1H, d), 7.61

(1H, s), 8.23 (1H, s),

9.06 (1H, s).

142 CI (S)-3-methyl-2-((l- (500 MHz, DMSO, ES+

methyl- 1 H- 1 ,2,3-triazol- 30°C) 1.15 (3H, d), [M+H]+ =

4-yl)methyl)-7-(5- 2.33 (3H, s), 3.69 (3H, 433 methyl-2-(( 1 -methyl- 1 H- s), 3.98 - 4.02 (lH, m),

pyrazol-5- 4.02 (3H, s), 4.17 (lH,

yl)amino)pyrimidin-4- dd), 4.25 (1H, dd), 4.37

yi)-3,4- (1H, d), 5.04 (1H, d),

dihydropyrrolo[ 1 ,2- 6.27 (1H, d), 7.25 (1H,

ajpyrazin- 1 (2H)-one d), 7.34 (1H, d), 7.63

(1H, d), 8.02 (1H, s),

8.24 (1H, s), 9.08 (1H,

s).

143 CI (R)-2-((l- (400 MHz, DMSO, ES+

(difluoromethyl)- 1 H- 30°C) 1.12 (3H, d), [M+H]+ = pyrazol-3 -yl)methyl)-3 - 2.32 (3H, s), 3.68 (3H, 468 methyl-7-(5-methyl-2- s), 3.87 - 4.01 (lH, m),

(( 1 -methyl- 1 H-pyrazol-5 - 4.04 - 4.5 (3H, m), 5.03

yl)amino)pyrimidin-4- (1H, d), 6.26 (1H, d), yi)-3,4- 6.48 (1H, d), 7.26 (1H,

dihydropyrrolo[ 1 ,2- s), 7.33 (1H, d), 7.54 - ajpyrazin- 1 (2H)-one 7.98 (2H, m), 8.18 (1H,

d), 8.24 (1H, s), 9.07

(IH, s).

144 Br (R)-3-methyl-7-(5- (500 MHz, DMSO, ES+

methyl-2-(( 1 -methyl- 1 H- 30°C) 1.14 (3H, d), [M+H]+ = pyrazol-5- 2.32 (3H, s), 2.54 (3H, 433 yl)amino)pyrimidin-4- s), 3.68 (3H, s), 3.9 - yl)-2-((2-methyl-2H- 3.99 (lH, m), 4.17 (IH,

l,2,3-triazol-4- dd), 4.27 (IH, dd), 4.33

yl)methyl)-3,4- (IH, d), 5.07 (IH, d),

dihydropyrrolo[ 1 ,2- 6.26 (IH, d), 7.25 (IH,

ajpyrazin- 1 (2H)-one d), 7.31 - 7.35 (lH, m),

7.63 (IH, d), 7.68 (IH,

s), 8.23 (IH, s), 9.07

(IH, s).

145 CI (R)-2- (500 MHz, DMSO, ES+

(cyclopropylmethyl)-3 - 30°C) 0.23 - 0.37 (2H, [M+H]+ = methyl-7-(5-methyl-2- m), 0.43 - 0.57 (2H, m), 392

(( 1 -methyl- 1 H-pyrazol-5 - 1.00- 1.12 (lH, m),

yl)amino)pyrimidin-4- 1.17 (3H, d), 2.33 (3H,

yi)-3,4- s), 3.08 (IH, dd), 3.59

dihydropyrrolo[ 1 ,2- (IH, dd), 3.69 (3H, s),

ajpyrazin- 1 (2H)-one 4.03 - 4.12 (lH, m),

4.21 (IH, d), 4.26 -

4.32 (lH, m), 6.27 (IH,

d), 7.21 (IH, d), 7.34

(IH, d), 7.62 (IH, d),

8.24 (IH, s), 9.07 (IH,

s). 146 CI (R)-3-methyl-7-(5- (500 MHz, DMSO, ES+

methyl-2-(( 1 -methyl- 1 H- 30°C) 1.18 (3H, d), [M+H]+ = pyrazol-4- 2.31 (3H, s), 2.47 (3H, 443 yl)amino)pyrimidin-4- s), 3.81 (3H, s), 3.98

yl)-2 -((6 -methylpyridin- (1H, dt), 4.22 (1H, dd),

2-yl)methyl)-3,4- 4.30 (lH, d), 4.39 (1H,

dihydropyrrolo[ 1 ,2- dd), 5.15 (1H, d), 7.16

ajpyrazin- 1 (2H)-one (2H, dd), 7.30 (1H, d),

7.54 (1H, s), 7.65 (1H,

t), 7.69 (1H, s), 7.83

(1H, s), 8.20 (1H, s),

9.05 (1H, s).

147 Br (R)-7-(5-chloro-2-((l- (400 MHz, DMSO, ES+

methyl- 1 H-pyrazol-5 - 30°C) 1.06 - 1.19 (3H, [M+H]+ = yl)amino)pyrimidin-4- m), 3.04 - 3.26 (lH, m), 416 yl)-2-(2-methoxyethyl)- 3.28 (3H, d), 3.40 -

3-methyl-3,4- 3.57 (2H, m), 3.68 (3H,

dihydropyrrolo[ 1 ,2- s), 3.86 - 4.06 (2H, m),

ajpyrazin- 1 (2H)-one 4.23 (2H, t), 6.25 (1H,

d), 7.35 (2H, dd), 7.91

(1H, d), 8.44 (1H, s),

9.44 (1H, s).

148 CI (R)-7-(2-((l,3-dimethyl- (400 MHz, DMSO, ES+

1 H-pyrazol-5 -yl)amino)- 23°C) 2.12 (3H, s), [M+H]+ =

5 -methylpyrimidin-4-yl)- 2.32 (3H, s), 3.26 (4H, 479

3 -(methoxymethyl)-2- d), 3.42 (1H, dd), 3.60

(thiazol-4-ylmethyl)-3 ,4- (3H, s), 4.05 (1H, s),

dihydropyrrolo[ 1 ,2- 4.29 (1H, dd), 4.44

ajpyrazin- 1 (2H)-one (2H, dd), 5.26 (1H, d),

6.04 (1H, s), 7.26 (1H,

s), 7.66 (2H, d), 8.23 (1H, s), 9.03 (1H, s),

9.11 (1H, s).

149 Br 7-(5-methyl-2- (400 MHz, DMSO, ES+

(pyrimidin-4- 30°C) 2.41 (3H, s), 2.46 [M+H]+ = ylamino)pyrimidin-4-yl)- (3H, s), 3.76 - 3.85 (2H, 427

2-((6-methylpyridin-2- m), 4.31 - 4.4 (2H, m),

yl)methyl)-3,4- 4.75 (2H, s), 7.12 - 7.18

dihydropyrrolo[ 1 ,2- (2H, m), 7.36 (1H, d),

ajpyrazin- 1 (2H)-one 7.66 (lH, t), 7.79 (1H,

d), 8.33 (1H, dd), 8.41 - 8.44 (lH, m), 8.56 (1H,

d), 8.73 - 8.77 (1H, m),

10.13 (1H, s).

150 CI (S)-2-((6- (400 MHz, DMSO, ES+

methoxypyrimidin-4- 30°C) 1.18 (3H, d), [M+H]+ = yl)methyl)-3 -methyl-7- 2.32 (3H, s), 3.68 (3H, 459

(5 -methyl -2-(( 1 -methyl- s), 3.91 (3H, s), 3.95 - lH-pyrazol-5- 4.05 (1H, m), 4.20 (1H,

yl)amino)pyrimidin-4- dd), 4.29 (1H, d), 4.43

yi)-3,4- (1H, dd), 5.04 (1H, d),

dihydropyrrolo[ 1 ,2- 6.26 (1H, d), 6.85 (1H,

ajpyrazin- 1 (2H)-one s), 7.25 (1H, d), 7.32

(1H, d), 7.65 (1H, d),

8.23 (1H, s), 8.73 (1H,

d), 9.07 (1H, s).

151 OMs (R)-7-(2-((l,3-dimethyl- (500 MHz, DMSO, ES+

lH-pyrazol-5-yl)amino)- 30°C) 2.12 (3H, s), 2.32 [M+H]+ =

5 -methylpyrimidin-4-yl)- (3H, s), 3.24 (3H, s), 477

3 -(methoxymethyl)-2- 3.28 (1H, dd), 3.42

((2-methyl-2H- 1,2,3- (1H, dd), 3.60 (3H, s),

triazol-4-yl)methyl)-3 ,4- 3.96 - 4.03 (lH, m), dihydropyrrolo[ 1 ,2- 4.13 (3H, s), 4.25 (1H,

ajpyrazin- 1 (2H)-one dd), 4.35 - 4.42 (2H,

m), 5.15 (1H, d), 6.03

(1H, s), 7.25 (1H, d),

7.65 (1H, d), 7.71 (1H,

s), 8.23 (1H, s), 8.99

(1H, s).

152 CI 2-((5-methoxy-6- (500 MHz, DMSO, ES+

methylpyridin-2- 27°C) 2.32 (3H, s), 2.34 [M+H]+ = yl)methyl)-7-(5 -methyl- (3H, s), 3.68 (3H, s), 459

2-((l -methyl- 1 H-pyrazol- 3.73 (2H, t), 3.79 (2H,

5 -yl)amino)pyrimidin-4- s), 4.28 (2H, t), 4.57 - yi)-3,4- 4.70 (3H, m), 6.26 (1H,

dihydropyrrolo[ 1 ,2- d), 7.14 (lH, d), 7.25

ajpyrazin- 1 (2H)-one (1H, d), 7.27 - 7.39

(2H, m), 7.63 (1H, d),

8.24 (1H, s), 9.09 (1H,

s).

153 CI (R)-3-methyl-7-(5- (500 MHz, DMSO, ES+

methyl-2-(( 1 -methyl- 1 H- 30°C) 1.19 (3H, d), [M+H]+ = pyrazol-5- 2.34 (3H, s), 2.58 (3H, 444 yl)amino)pyrimidin-4- s), 3.70 (3H, s), 3.91 - yl)-2-((3 -methylpyrazin- 3.99 (lH, m), 4.19 (1H,

2-yl)methyl)-3,4- dd), 4.31 - 4.41 (2H,

dihydropyrrolo[ 1 ,2- m), 5.35 (1H, d), 6.27

ajpyrazin- 1 (2H)-one (1H, d), 7.25 (1H, d),

7.34 (1H, d), 7.65 (1H,

d), 8.25 (1H, s), 8.42

(1H, d), 8.44 (1H, d),

9.08 (1H, s). CI 2-((l,3-dimethyl-lH- (500 MHz, DMSO, ES+ pyrazol-5 -yl)methyl)-7- 30°C) 1.98 (3H, s), 2.20 [M+H]+ =

(5 -methyl -2-(( 1 -methyl- (3H, s), 3.48 - 3.55 (2H, 431

1 H-pyrazol-5 - m), 3.57 (3H, s), 3.59

yl)amino)pyrimidin-4- (3H, s), 4.1 - 4.17 (2H,

yi)-3,4- m), 4.55 (2H, s), 5.91

dihydropyrrolo[ 1 ,2- (1H, s), 6.14 (lH, d),

ajpyrazin- 1 (2H)-one 7.14 (1H, d), 7.22 (1H,

d), 7.51 (1H, d), 8.12

(1H, s), 8.96 (1H, s).

CI (S)-2-(( 1,3 -dimethyl- 1H- (500 MHz, DMSO, ES+

pyrazol-5 -yl)methyl)-3 - 30°C) 0.95 (3H, d), [M+H]+ = methyl-7-(5-methyl-2- 1.98 (3H, s), 2.20 (3H, 445

(( 1 -methyl- 1 H-pyrazol-5 - s), 3.56 (6H, d), 3.72

yl)amino)pyrimidin-4- (1H, ddd), 4.03 - 4.14

yi)-3,4- (2H, m), 4.17 (lH, d),

dihydropyrrolo[ 1 ,2- 4.93 (1H, d), 5.95 (1H,

ajpyrazin- 1 (2H)-one s), 6.14 (lH, d), 7.14

(1H, d), 7.21 (1H, d),

7.51 (1H, d), 8.11 (1H,

s), 8.94 (1H, s).

Br (S)-3-methyl-7-(5- (400 MHz, DMSO, ES+

methyl-2-(( 1 -methyl- 1 H- 30°C) 1.23 (3H, d), [M+H]+ = pyrazol-5- 2.34 (3H, s), 3.69 (3H, 498 yl)amino)pyrimidin-4- s), 4.01 - 4.11 (lH, m),

yl)-2-((2- 4.27 (1H, dd), 4.50

(trifluoromethyl)pyrimidi (1H, dd), 4.56 (1H, d),

n-4-yl)methyl)-3,4- 5.21 (1H, d), 6.27 (1H,

dihydropyrrolo[ 1 ,2- d), 7.28 (1H, d), 7.33

ajpyrazin- 1 (2H)-one (1H, d), 7.70 (1H, d),

7.84 (1H, d), 8.25 (1H, d), 9.00 (IH, d), 9.06

(IH, s).

157 CI (R)-3-methyl-7-(5- (500 MHz, DMSO, ES+

methyl-2-(( 1 -methyl- 1 H- 30°C) 1.15 (3H, d), [M+H]+ = pyrazol-5- 2.32 (3H, s), 3.68 (3H, 435 yl)amino)pyrimidin-4- s), 3.96 - 4.04 (lH, m),

yl)-2-(thiazol-4- 4.19 (IH, dd), 4.28 - ylmethyl)-3,4- 4.34 (lH, m), 4.42 (IH,

dihydropyrrolo[ 1 ,2- d), 5.19 (lH, d), 6.26

ajpyrazin- 1 (2H)-one (IH, d), 7.25 (IH, d),

7.33 (IH, d), 7.61 (IH,

d), 7.63 (IH, d), 8.23

(IH, s), 9.07 (IH, s),

9.09 (IH, d).

158 CI (S)-3-methyl-7-(5- (400 MHz, DMSO, ES+

methyl-2-((3- 30°C) 1.16 (3H, d), [M+H]+ = methylisothiazol-4- 2.35 (3H, s), 2.44 (3H, 460 yl)amino)pyrimidin-4- s), 2.46 (3H, s), 3.94 - yl)-2 -((6 -methylpyridin- 4.00 (lH, m), 4.21 (IH,

2-yl)methyl)-3,4- dd), 4.29 (IH, d), 4.38

dihydropyrrolo[ 1 ,2- (IH, dd), 5.14 (IH, d),

ajpyrazin- 1 (2H)-one 7.15 (2H, t), 7.29 (IH,

d), 7.64 (IH, t), 7.73

(IH, d), 8.28 (IH, s),

8.90 (IH, s), 8.97 (IH,

s).

159 CI (S)-3-methyl-7-(5- (400 MHz, DMSO, ES+

methyl-2-((3- 30°C) 1.17 (3H, d), [M+H]+ = methylpyridazin-4- 2.40 (3H, s), 2.47 (3H, 455 yl)amino)pyrimidin-4- s), 2.70 (3H, s), 3.92 - yl)-2 -((6 -methylpyridin- 4.04 (lH, m), 4.19 - 2-yl)methyl)-3,4- 4.27 (lH, m), 4.31 (1H,

dihydropyrrolo[ 1 ,2- d), 4.39 (lH, dd), 5.15

ajpyrazin- 1 (2H)-one (lH, d), 7.16 (2H, t),

7.35 (1H, d), 7.65 (1H,

t), 7.78 (1H, s), 8.38

(1H, d), 8.41 (1H, s),

8.76 (1H, s), 8.86 (1H,

d).

CI (S)-3-methyl-2-((l- (400 MHz, DMSO, ES+

methyl- 1 H-pyrazol-5 - 30°C) 1.07 (3H, d), [M+H]+ = yl)methyl)-7-(5 -methyl- 2.32 (3H, s), 3.68 (3H, 432

2-((l -methyl- 1 H-pyrazol- s), 3.79 (3H, s), 3.81 -

5 -yl)amino)pyrimidin-4- 3.89 (lH, m), 4.18 (1H, yi)-3,4- d), 4.25 (1H, dd), 4.38

dihydropyrrolo[ 1 ,2- (1H, d), 5.10 (1H, d),

ajpyrazin- 1 (2H)-one 6.25 (1H, d), 6.30 (1H,

d), 7.26 (1H, d), 7.33

(1H, d), 7.35 (1H, d),

7.63 (1H, d), 8.23 (1H,

s), 9.06 (1H, s).

OMs (S)-3-methyl-2-((l- (400 MHz, DMSO, ES+

methyl- 1 H- 1 ,2,3-triazol- 30°C) 1.13 (3H, d), [M+H]+ =

5-yl)methyl)-7-(5- 2.33 (3H, s), 3.69 (3H, 433 methyl-2-(( 1 -methyl- 1 H- s), 4.02 (3H, s), 4.05

pyrazol-5- (1H, d), 4.20 (1H, dd),

yl)amino)pyrimidin-4- 4.26 - 4.36 (lH, m),

yi)-3,4- 4.44 (1H, d), 5.18 (1H,

dihydropyrrolo[ 1 ,2- d), 6.27 (1H, d), 7.28

ajpyrazin- 1 (2H)-one (1H, d), 7.34 (1H, d),

7.65 (1H, d), 7.74 (1H, s), 8.19 - 8.29 (lH, m),

9.06 (1H, s).

162 CI (S)-2-((3,5- (400 MHz, DMSO, ES+

dimethylisoxazol-4- 30°C) 1.12 (3H, d), [M+H]+ = yl)methyl)-3 -methyl-7- 2.18 (3H, s), 2.32 (3H, 447

(5 -methyl -2-(( 1 -methyl- s), 2.42 (3H, s), 3.69

lH-pyrazol-5- (3H, s), 3.71 - 3.83 (1H, yl)amino)pyrimidin-4- m), 4.03 (1H, d), 4.18

yi)-3,4- (2H, d), 4.89 (1H, d),

dihydropyrrolo[ 1 ,2- 6.27 (1H, d), 7.26 (1H,

ajpyrazin- 1 (2H)-one d), 7.34 (1H, d), 7.63

(1H, d), 8.24 (1H, s),

9.05 (1H, s).

163 Br 7-(2-((2-fluoropyridin-3 - (400 MHz, DMSO, ES+

yl)amino)-5- 30°C) 2.36 (3H, s), 2.46 [M+H]+ = methylpyrimidin-4-yl)-2- (3H, s), 3.79 (2H, dd), 444

((6-methylpyridin-2- 4.29 - 4.39 (2H, m),

yl)methyl)-3,4- 4.73 (2H, s), 7.14 (2H,

dihydropyrrolo[ 1 ,2- t), 7.29 (1H, d), 7.34

ajpyrazin- 1 (2H)-one (1H, ddd), 7.65 (1H, d),

7.69 (1H, d), 7.82 - 7.88 (lH, m), 8.29 (1H,

d), 8.49 (1H, ddd), 8.90

(IH, s).

164 OMs (R)-3-(methoxymethyl)- (500 MHz, DMSO, ES+

7-(5-methyl-2-((l- 30°C) 2.32 (3H, s), 3.23 [M+H]+ = methyl- 1 H-pyrazol-5 - (3H, s), 3.27 (IH, dd), 463 yl)amino)pyrimidin-4- 3.41 (IH, dd), 3.69

yl)-2-((2-methyl-2H- (3H, s), 3.96 - 4.04 (IH, l,2,3-triazol-4- m), 4.13 (3H, s), 4.25

yl)methyl)-3,4- (IH, dd), 4.38 (2H, d), dihydropyrrolo[ 1 ,2- 5.15 (1H, d), 6.27 (1H,

ajpyrazin- 1 (2H)-one d), 7.25 (1H, d), 7.34

(1H, d), 7.66 (1H, d),

7.71 (1H, s), 8.25 (1H,

s), 9.09 (1H, s).

165 CI 7-(5-methyl-2-((l- (400 MHz, DMSO, ES+

methyl-1 H-pyrazol-5 - 30°C) 2.31 (3H, s), 2.62 [M+H]+ = yl)amino)pyrimidin-4- (3H, s), 3.68 (3H, s), 435 yl)-2-((2-methylthiazol- 3.69 - 3.79 (2H, m),

4-yl)methyl)-3,4- 4.28 (2H, s), 4.70 (2H,

dihydropyrrolo[ 1 ,2- s), 6.25 (1H, s), 7.17 - ajpyrazin- 1 (2H)-one 7.27 (1H, m), 7.32 (2H,

s), 7.62 (1H, s), 8.23

(1H, s), 9.07 (1H, s).

166 CI (S)-2-((5-fluoro-6- (400 MHz, DMSO, ES+

methylpyridin-2- 30°C) 1.15 (3H, d), [M+H]+ = yl)methyl)-3 -methyl-7- 2.32 (3H, s), 2.44 (3H, 461

(5 -methyl -2-(( 1 -methyl- d), 3.68 (3H, s), 3.92 -

1 H-pyrazol-5 - 4 (lH, m), 4.19 (lH, d),

yl)amino)pyrimidin-4- 4.30 (1H, d), 4.33 - yi)-3,4- 4.38 (lH, m), 5.10 (1H,

dihydropyrrolo[ 1 ,2- d), 6.26 (1H, d), 7.22 - ajpyrazin- 1 (2H)-one 7.29 (2H, m), 7.32 (1H,

d), 7.58 (1H, t), 7.64

(1H, s), 8.23 (1H, s),

9.06 (1H, s).

167 CI (R)-2-((5-fluoro-4- (400 MHz, DMSO, ES+

methylpyridin-2- 30°C) 1.15 (3H, d), [M+H]+ = yl)methyl)-3 -methyl-7- 2.28 (3H, s), 2.33 (3H, 461

(5 -methyl -2-(( 1 -methyl- s), 3.69 (3H, s), 3.96

1 H-pyrazol-5 - (lH, m), 4.18 (lH, dd), yl)amino)pyrimidin-4- 4.28 (lH, d), 4.36 (1H,

yi)-3,4- dd), 5.13 (1H, d), 6.26

dihydropyrrolo[ 1 ,2- (1H, d), 7.26 (1H, d),

ajpyrazin- 1 (2H)-one 7.31 - 7.38 (2H, m),

7.65 (1H, d), 8.24 (1H,

s), 8.39 (1H, s), 9.07

(1H, s).

CI (R)-7-(2-((l,5-dimethyl- (400 MHz, DMSO, ES+

1 H-pyrazol-3 -yl)amino)- 30°C) 1.17 (3H, d), [M+H]+ =

5 -methylpyrimidin-4-yl)- 2.24 (3H, s), 2.31 (3H, 457

3-methyl-2-((6- s), 2.47 (3H, s), 3.61

methylpyridin-2- (3H, s), 3.97 (1H, dt),

yl)methyl)-3,4- 4.21 (1H, dd), 4.30

dihydropyrrolo[ 1 ,2- (1H, d), 4.38 (1H, dd),

ajpyrazin- 1 (2H)-one 5.15 (1H, d), 6.46 (1H,

s), 7.16 (2H, t), 7.31

(1H, d), 7.64 (1H, d),

7.67 (lH, d), 8.16 - 8.2

(1H, m), 9.07 (1H, s).

Br 7-(2-((3-methoxy-l- (400 MHz, DMSO, ES+

methyl- 1 H-pyrazol-4- 30°C) 2.29 (3H, s), 2.46 [M+H]+ = yl)amino)-5- (3H, s), 3.68 (3H, s), 459 methylpyrimidin-4-yl)-2- 3.80 (5H, s), 4.28 - 4.34

((6-methylpyridin-2- (2H, m), 4.73 (2H, s),

yl)methyl)-3,4- 7.14 (2H, t), 7.26 (1H,

dihydropyrrolo[ 1 ,2- d), 7.62 - 7.7 (3H, m),

ajpyrazin- 1 (2H)-one 7.84 (1H, s), 8.12 (1H,

s).

CI (S)-3-methyl-7-(5- (400 MHz, DMSO, ES+

methyl-2-((2- 30°C) 1.17 (3H, d), [M+H]+ = methylpyrimidin-4- 2.39 (3H, s), 2.46 (3H, 455 yl)amino)pyrimidin-4- s), 3.40 (3H, s), 3.91 - yl)-2 -((6 -methylpyridin- 4.04 (IH, m), 4.23 (IH,

2-yl)methyl)-3,4- dd), 4.31 (IH, d), 4.39

dihydropyrrolo[ 1 ,2- (IH, dd), 5.14 (IH, d),

ajpyrazin- 1 (2H)-one 7.16 (2H, t), 7.35 (IH,

d), 7.65 (IH, t), 7.78

(IH, d), 8.15 (IH, d),

8.39 (IH, s), 8.45 (IH,

d), 9.97 (IH, s).

Example 80, 88, 90, 137 Akyl Bromide Intermediate

-(bromomethyl)-6-(fluoromethyl)pyridine

To a suspension of (6-(bromomethyl)pyridin-2-yl)methanol (0.250 g, 1.24 mmol) in DCM (10 mL) under nitrogen at 0°C was added diethylaminosulfur trifluoride (0.163 mL, 1.24 mmol) and the resulting reaction mixture stirred for 2 hrs. Additional diethylaminosulfur trifluoride (0.163 mL, 1.24 mmol) was added and the reaction mixture stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the reaction mixture and the organics extracted, washed with saturated brine and dried by passing through a phase seperating cartridge to afford a gum after evaporation. The crude product was dissolved in minimum volume of DCM and purified by suction column eluting with 0- 10% diethylether/DCM. Pure fractions were evaporated to afford 2-(bromomethyl)-6- (fluoromethyl)pyridine (0.152 g, 60%) as a clear oil. ^! H NMR (400 MHz, DMSO, 30°C) 4.70 (2H, s), 5.41 (IH, s), 5.53 (IH, s), 7.44 (IH, d), 7.55 (IH, d), 7.91 (IH, t). m/z: ES+ [M+H]+ = 204. Example 111 Mesylate Intermdiate

( -methylthiazol-5 - vDmethyl methanesulfonate

Methanesulfonyl chloride (0.066 mL, 0.85 mmol) was added to (2-methylthiazol-5- yl)methanol (100 mg, 0.77 mmol) and triethylamine (0.215 mL, 1.55 mmol) in DCM (3 mL) at 0°C over a period of 1 minute under nitrogen. The resulting solution was stirred at 0 °C for 1 hour, then evaporated, redissolved in DCM (5ml) and washed with water (5ml). The organic phase was dried using a phase separator cartridge, evaporated and dried under vacuum to give (2-methylthiazol-5-yl)methyl methanesulfonate (124 mg, 77 %) as an impure colourless gum which was used crude in the next stage, m/z: ES+ [M+H]+ not seen.

Example 161 Mesylate Intermediate

(l-methyl-lH-l,2,3-triazol-5-yl)methyl methanesulfonate

Methanesulfonyl chloride (1.129 mL, 14.59 mmol) was added to (l-methyl-lH-1,2,3- triazol-5-yl)methanol (MFCD 19273577; 1.65 g, 14.59 mmol) and triethylamine (4.05 mL, 29.17 mmol) in DCM (30 mL) at 0°C over a period of 2 minutes under nitrogen. The resulting solution was stirred at 0 °C for 30 minutes and evaporated. Residue was dissolved in DCM (100 mL), washed with water and dried by passing through a phase separator cartridge to afford an oil after evaporation (l-methyl-lH-l,2,3-triazol-5-yl)methyl methanesulfonate (2.58 g, 93 %). IH NMR (400 MHz, CDC13, 30°C) 3.01 (3H, s), 4.13 (3H, s), 5.32 (2H, s), 7.78 (1H, s).