TYROSINE KINASE 2 INHIBITORS AND USES THEREOF

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 63/389,038, filed on July 14, 2022, The entire contents of the foregoing application are expressly incorporated herein by reference.

FIELD OF THE INVENTION

The present disclosure relates to inhibitors of Tyrosine kinase 2 (TYK2), and pharmaceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, their use in the treatment of diseases, their use in optional combination with a pharmaceutically acceptable carrier for the manufacture of pharmaceutical preparations, the use of the pharmaceutical preparations in the treatment of diseases, and methods of treating diseases comprising administering the TYK2 inhibitor to a warm-blooded animal, especially a human.

BACKGROUND OF THE INVENTION

Cytokines are small secreted proteins released by cells and have a specific effect on the interactions and communications between cells. Cytokine pathways mediate a broad range of biological functions including many aspects of inflammation and immunity through mostly extracellular signaling.

Tyrosine kinase 2 (TYK2) is a member of Janus kinases (JAK) that are cytoplasmic protein kinases associated with cytokine receptors and play a central role in mediating cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1; and Yamaoka et al. Genome Biology 2004, 5, 253). The JAK family also includes JAK1, JAK2 and JAK3. More specifically, cytokine’s engagement with cognate receptors triggers activation of receptors associate with JAK, which leads to JAK mediated tyrosine phosphorylation of signal transducer and activator of transcription (STAT) proteins and ultimately transcriptional activation of specific gene sets (Schindler et al, 2007, J. Biol. Chem. 282: 20059-63). Numerous cytokines known to activate the JAK family include the interferon (IFN) family (IFN-alpha, IFN-beta, IFN-omega, Limitin, IFN-gamma, IL-10, IL-19, IL-20, IL-22), the glycoprotein (gp) 130 family (IL-6, IL-11, OSM, L1F, CNTF, NNT-l/BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23), the gamma C family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family (IL-3, IL-5, GM-CSF), the single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and G-protein coupled receptors (ATI).

TYK2 is important in the signaling of the type I interferons (e.g., IFN-alpha), IL-6, IL- 10, IL-12 and IL-23 (Liang, Y. et al., Expert Opinion on Therapeutic Targets, 2014, 18,5, 571- 580; Kisseleva et al., 2002, Gene 285: 1-24; and Watford, W.T. & O’Shea, J. J., 2006, Immunity 25:695-697). Consistent with this, primary cells derived from a TYK2 deficient human are defective in type I interferon, IL-6, IL- 10, IL- 12 and IL-23 signaling. TYK2 signals with other members of the JAK family in the following combinations: TYK2/JAK1, TYK2/JAK2, TYK2/JAK1/JAK2.

Studies have shown that inappropriate JAK activities can arise from mutation, overexpression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines, and therefore trigger a variety of biological cellular responses relating to cell growth, cell differentiation, cell function, survival, apoptosis, and cell mobility. The inappropriate JAK activities are implicated in many diseases that include but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease.

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. To date, all known small molecule JAK inhibitors that have progressed into development are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain (also referred to as the JH1 or “Janus Homology 1” domain) of the JAK protein, which prevents catalytic activity of the kinase by blocking ATP, downstream phosphorylation, and resulting pathway signal transduction (Bryan et al., J. Med. Chem. 2018, 61, 9030-9058).

Because of the high homology of the ATP active site across the kinome and especially within the JAK family, it is a significant challenge to achieve high selectivity for a specific JAK family member while also maintaining selectivity within the kinome. As a result, many JAK inhibitors that have been developed are pan-JAK inhibitors or are modestly selective for one or more JAK family members. While these inhibitors have shown encouraging results in treating autoimmune diseases, undesirable side effects leading to a narrow therapeutic index have been observed and suggest the need for improved treatments.

TYK2 has been shown to be important in the differentiation and function of multiple cell types important in inflammatory disease and autoimmune disease including natural killer cells, B cells, and T helper cell types. Aberrant TYK2 expression is associated with multiple autoimmune or inflammatory conditions.

There remains a need for potent compounds that demonstrate high selectivity for TYK2 over other members of the JAK family as potential therapeutic agents for treating diseases or disorders that are responsive to TYK2 inhibition.

SUMMARY OF THE INVENTION

The present disclosure provides compounds that are TYK2 inhibitors. In a first aspect, the present disclosure relates to compounds having the Formula I: or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is H, Ci-6 alkyl, -OR ^la , -NR ^lb R ^lc , 3 to 7 membered monocyclic carbocyclyl, or 4 to 7 membered monocyclic heterocyclyl, wherein the Ci-6 alkyl, 3 to 7 membered monocyclic carbocyclyl and 4 to 7 membered monocyclic heterocyclyl represented by R ¹ are each optionally substituted by one or more R ^ld ;

R ^la , R ^lb , and R ^lc are each independently H, Ci.4alkyl, or 3 to 4 membered monocyclic carbocyclyl; each R ^ld is independently halo, oxo, -CN, -OR ^la , -NR ^lb R ^lc , Ci-6 alkyl, Ci-4 haloalkyl, phenyl, 5 to 6 membered heteroaryl, 3 to 7 membered monocyclic carbocyclyl or 4 to 7 membered monocyclic heterocyclyl;

R ² is selected from H, halo, Ci-ealkyl, C3-7cycloalkyl, -OR ^2a , -N(R ^2b )2, 4- to 11- membered monocyclic or bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the Ci-ealkyl, C3-7cycloalkyl, 5- to 11-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl represented by R ² are each optionally substituted by 1 to 3 R ²⁰ ; R ^2a is selected from H, Ci-ealkyl, C3-7cycloalkyl, 5-or 6-membered heteroaryl, and 4- to 7-membered monocyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the Ci-ealkyl, C3-7cycloalkyl, 5-or 6- membered heteroaryl, and 4- to 7-membered monocyclic heterocyclyl represented by R ^2a are optionally substituted with 1 to 3 R ²⁰ ; each R ^2b is independently H, Ci-4alkyl, Ci-3alkyl-Ci-3alkoxy, Ci.4alkoxy, or 4- to 6-membered monocyclic heterocyclyl;

R ²⁰ , for each occurrence, is independently selected from halo, -CN, Ci-4alkyl, Ci- ₄ haloalkyl, -OR ^20c -C(O)R ^20b , -C(O)N(R ^20b ) ₂ , -N(R ^20b ) ₂ , -SO ₂ R ^20b , -P(O)(Ci- ₃ alkyl) ₂ , phenyl, C3-7cycloalkyl, 5- to 10-membered bicyclic carbocycle, 4- to 10-membered monocyclic or bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the Ci-4alkyl, phenyl, C3-7cycloalkyl, 5- to 10-membered bicyclic carbocycle, 4- to 10-membered monocyclic or bicyclic heterocyclyl and 5- to 6-membered monocyclic heteroaryl represented by R ²⁰ are each optionally substituted with 1 to 3 R ²⁰⁰ ; each R ^20b is independently H, Ci.4alkyl or Ci.4alkoxy;

R ^20C is H, Ci-4alkyl, Ci.4haloalkyl, C3-6cycloalkyl, or 4- to 6-membered monocyclic heterocyclcyl, wherein the Ci.4alkyl is optionally substituted by Ci-3alkoxy;

R ²⁰⁰ , for each occurrence, is independently selected from halo, -CN, Ci-4alkyl, Ci-3alkyl-Ci-3alkoxy, Ci-4haloalkyl, -OH, -N(R ^20b ) ₂ , Ci.3alkoxy, Ci-3haloalkoxy, C3- 7cycloalkyl, and 5- to 10-membered monocyclic or bicyclic heterocyclyl optionally substituted with 1 to 3 Ci.3alkyl or Ci.3alkoxy;

Ring B is phenyl, 5 to 10 membered monocyclic or bicyclic heteroaryl, 3 to 7 membered monocyclic carbocyclyl or 4 to 7 membered monocyclic heterocyclyl, each of which is optionally substituted by one or more R ^B ; each R ^B is independently selected from halo, -CN, -OR ^Ba , -N(R ^Bb ) ₂ , -C(O)R ^Bc , -C(O)OR ^Ba , -SO ₂ R ^BC , Ci-ealkyl, C ₂ .ealkyenyl, phenyl, 3 to 7 membered monocyclic carbocyclyl, 4- to 7-membered monocyclic or bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5 to 10 membered monocyclic or bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the Ci-ealkyl, C ₂ .ealkyenyl, phenyl, 3 to 7 membered monocyclic carbocyclyl, 4- to 7-membered monocyclic heterocyclyl and 5 to 10 membered monocyclic or bicyclic heteroaryl represented by R ^B are each optionally substituted by one or more R ^B1 ; each R ^B1 is independently seleted from halo, oxo, -CN, -OR ^Ba , -N(R ^Bb )2, Ci- 4alkyl, Ci-4alkyl-R ^Bd , Ci.4haloalkyl, -C(O)OR ^Ba , phenyl, 5 to 6 membered heteroaryl, 3 to 7 membered monocyclic carbocyclyl, and 4 to 8 membered monocyclic heterocyclyl;

R ^Ba is independently H, Ci.4alkyl, Cs-vcycloalkyl, or 4- to 8- membered monocyclic or bicycle heterocyclyl, wherein the Ci-4alkyl, C3-7cycloalkyl and 4- to 8- membered monocyclic or bicycle heterocyclyl represented by R ^Ba are each optionally substituted with 1 or 2 R ^B0 ; each R ^BO is independently halo, -CN, -OH, Ci.4alkyl or Ci.4alkoxy; each R ^Bb is independently H, Ci.4alkyl, Ci.4alkoxy or C3-7cycloalkyl;

R ^BC is Ci-ealkyl or C3-7cycloalkyl;

R ^Bd is -C(O)OR ^Ba , -N(R ^Bb )2, -OR ^Ba , 3 to 7 membered monocyclic carbocyclyl, or 4 to 8 membered monocyclic heterocyclyl; and

R ^N1 and R ^N2 are each independently H or Ci-4alkyl.

Another aspect of the disclosure relates to pharmaceutical compositions comprising compounds of Formula (I) or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

In yet another aspect, the present disclosure provides a method of treating a disease or disorder that is responsive to inhibition of TYK2 in a subject comprising administering to said subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to the use of at least one compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder responsive to inhibition of TYK2. Also provided is a compound described herein or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder responsive to inhibition of TYK2. Use of a compound described herein or a pharmaceutically acceptable salt thereof for treating a disease or disorder responsive to inhibition of TYK2 is also included in the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure provides compounds and pharmaceutical compositions thereof that may be useful in the treatment of diseases or disorders through mediation of TYK2. In some embodiments, the compounds of present disclosure are TYK2 inhibitors.

COMPOUNDSAND COMPOSITIONS In a first embodiment, the present disclosure relates to compounds having the Formula or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is H, Ci-6 alkyl, -OR ^la , -NR ^lb R ^lc , 3 to 7 membered monocyclic carbocyclyl, or 4 to 7 membered monocyclic heterocyclyl, wherein the Ci-6 alkyl, 3 to 7 membered monocyclic carbocyclyl and 4 to 7 membered monocyclic heterocyclyl represented by R ¹ are each optionally substituted by one or more R ^ld ;

R ^la , R ^lb , and R ^lc are each independently H, Ci.4alkyl, or 3 to 4 membered monocyclic carbocyclyl; each R ^ld is independently halo, oxo, -CN, -OR ^la , -NR ^lb R ^lc , Ci-6 alkyl, Ci-4 haloalkyl, phenyl, 5 to 6 membered heteroaryl, 3 to 7 membered monocyclic carbocyclyl or 4 to 7 membered monocyclic heterocyclyl;

R ² is selected from H, Ci-ealkyl, C3-7cycloalkyl, -OR ^2a , -N(R ^2b )2, 4- to 11-membered monocyclic or bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the Ci-ealkyl, C3-7cycloalkyl, 5- to 11 -membered monocyclic or bicyclic heterocyclyl, and 5- to 6- membered monocyclic heteroaryl represented by R ² are each optionally substituted by 1 to 3 R ²⁰ ;

R ^2a is selected from H, Ci-ealkyl, C3-7cycloalkyl and 4- to 7-membered monocyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the Ci-ealkyl, C3-7cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R ^2a are optionally substituted with 1 to 3 R ²⁰ ; each R ^2b is independently H, Ci.4alkyl or Ci.4alkoxy;

R ²⁰ , for each occurrence, is independently selected from halo, -CN, Ci-4alkyl, Ci-4 haloalkyl, Ci.4alkoxy, -N(R ^20b )2, phenyl, C3-7cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl, C3-7cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclyl and 5- to 6-membered monocyclic heteroaryl represented by R ²⁰ are each optionally substituted with 1 to 3 R ²⁰⁰ ; each R ^20b is independently H, Ci.4alkyl or Ci.4alkoxy;

R ²⁰⁰ , for each occurrence, is independently selected from halo, -CN, Ci.4alkyl, Ci-4haloalkyl, Ci.salkoxy and C3-7cycloalkyl;

Ring B is phenyl, 5 to 10 membered monocyclic or bicyclic heteroaryl, 3 to 7 membered monocyclic carbocyclyl or 4 to 7 membered monocyclic heterocyclyl, each of which is optionally substituted by one or more R ^B ; each R ^B is independently selected from halo, -CN, -OR ^Ba , -N(R ^Bb )2, -C(O)R ^Bc , -C(O)OR ^Ba , -SO2R ^BC , Ci-ealkyl, phenyl, 3 to 7 membered monocyclic carbocyclyl 4- to 7- membered monocyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5 to 10 membered monocyclic or bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the Ci- ealkyl, phenyl, 3 to 7 membered monocyclic carbocyclyl, 4- to 7-membered monocyclic heterocyclyl and 5 to 10 membered monocyclic or bicyclic heteroaryl represented by R ^B are each optionally substituted by one or more R ^B1 ; each R ^B1 is independently seleted from halo, oxo, -CN, -OR ^Ba , -N(R ^Bb )2, Ci- 4alkyl, Ci-4alkyl-R ^Bd , Ci-4haloalkyl, -C(O)OR ^Ba , phenyl, 5 to 6 membered heteroaryl, 3 to 7 membered monocyclic carbocyclyl, and 4 to 8 membered monocyclic heterocyclyl;

R ^Ba is independently H, Ci.4alkyl or C3-7cycloalkyl, wherein the Ci.4alkyl and C3-7cycloalkyl represented by R ^Ba are each optionally substituted with 1 or 2 R ^B0 ; each R ^BO is independently halo, -CN, -OH, Ci.4alkyl or Ci.4alkoxy; each R ^Bb is independently H, Ci.4alkyl, Ci.4alkoxy or C3-7cycloalkyl;

R ^BC is Ci-ealkyl or C3-7cycloalkyl;

R ^Bd is -C(O)OR ^Ba , -N(R ^Bb )2, -OR ^Ba , 3 to 7 membered monocyclic carbocyclyl, or 4 to 8 membered monocyclic heterocyclyl; and

R ^N1 and R ^N2 are each independently H or Ci-4alkyl.

In a second embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is selected from phenyl, pyridinyl, pyrimidinyl and thiazolyl, each of which is substituted with one to three R ^B ; and the remaining variables are as described in the first aspect or the first embodiment. In a third embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, R ^N1 and R ^N2 are each independently H or -CH3; and the remaining variables are as described in the first aspect or the first aspect or or second embodiment.

In a fourth embodiment, the compound of the present disclosure is represented by Formula (II) or (III): or a pharmaceutically acceptable salt thereof, wherein:

A ¹ is N or CR ⁵ , A ² is N or CR ⁶ , and A ³ is N or CR ³ , provided no more than one of A ¹ , A ² , and A ³ is N;

R ³ is selected from H, -OR ^3a , -N(R ^3b )2, Ci-ealkyl, Ci.4haloalkyl, C3-7cycloalkyl, phenyl, and 5 to 10 membered monocyclic or bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl and 5 to 10 membered monocyclic or bicyclic heteroaryl are each optionally substituted by 1 to 3 R ^3c ;

R ^3a is H, Ci-4alkyl or C3-7cycloalkyl, each of which is optionally substituted with 1 or 2 R ³⁰ ; each R ³⁰ is independently halo, -CN, -OH, Ci.4alkyl or Ci.4alkoxy; each R ^3b is independently H, Ci.4alkyl, Ci.4alkoxy or C3-7cycloalkyl; each R ^3C is independently selected from halo, oxo, -CN, -OR ^3a , -N(R ^3b )2, Ci-

4alkyl, Ci-4alkyl-R ^3d , Ci-4haloalkyl, -C(O)OR ^3a , phenyl, 5 to 6 membered heteroaryl, 3 to 7 membered monocyclic carbocyclyl, and 4 to 8 membered monocyclic heterocyclyl;

R ^3d is -C(O)OR ^3a , -N(R ^3b )2, -OR ^3a , 3 to 7 membered monocyclic carbocyclyl, or 4 to 8 membered monocyclic heterocyclyl;

R ⁴ is selected from H, Ci^alkyl, Ci-ehaloalkyl, Ci.4alkoxy, -SO2R ^4a , 4- to 6-membered monocyclic heterocyclyl having 1 to 2 heteroatoms selected from nitrogen and oxygen and

C3-7cycloalkyl optionally substituted with 1 to 3 substituents independently halo or Ci.4alkyl; R ^4a is Ci-ealkyl;

R ⁵ is H, halo, Ci-salkyl, Ci-shaloalkyl or 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the 5- to 6- membered heteroaryl represented by R ⁵ is optionally substituted by 1 to 3 R ⁵⁰ ; and

R ⁵⁰ , for each occurrence, is independently halo, Ci-4alkyl or Ci.4haloalkyl; and

R ⁶ is H, halo, Ci-salkyl, Ci-shaloalkyl or Ci.4alkoxy; and the remaining variables are as described in the first aspect or the first, second, or third embodiment. In an alternative fourth embodiment, the compound of the present disclosure is represented by Formula (II), (IF), or (III):

(III), or a pharmaceutically acceptable salt thereof, wherein:

A ¹ is N or CR ⁵ , A ² is N or CR ⁶ , and A ³ is N or CR ³ , provided no more than one of A ¹ , A ² , and A ³ is N;

R ³ is selected from H, halo, -OR ^3a , -N(R ^3b )2, Ci-ealkyl, Ci.4haloalkyl, Ci-salkyl-Ci- salkoxy, C2alkeneyl, Cs-vcycloalkyl, phenyl, and 5 to 10 membered monocyclic or bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl and 5 to 10 membered monocyclic or bicyclic heteroaryl are each optionally substituted by 1 to 3 R ^3c ; R ^3a is H, Ci-4alkyl, 4- to 8- membered monocyclic or bicycle heterocyclyl, or C3-7cycloalkyl, each of which is optionally substituted with 1 or 2 R ³⁰ ; each R ³⁰ is independently halo, -CN, -OH, Ci.4alkyl or Ci.4alkoxy; each R ^3b is independently H, Ci.4alkyl, Ci.4alkoxy or C3-7cycloalkyl; each R ^3C is independently selected from halo, oxo, -CN, -OR ^3a , -N(R ^3b )2, Ci- 4alkyl, Ci-4alkyl-R ^3d , Ci-4haloalkyl, -C(O)OR ^3a , phenyl, 5 to 6 membered heteroaryl, 3 to 7 membered monocyclic carbocyclyl, and 4 to 8 membered monocyclic heterocyclyl;

R ^3d is -C(O)OR ^3a , -N(R ^3b )2, -OR ^3a , 3 to 7 membered monocyclic carbocyclyl, or 4 to 8 membered monocyclic heterocyclyl;

R ⁴ is selected from H, Ci^alkyl, Ci-ehaloalkyl, Ci.4alkoxy, Ci-3alkoxy-Ci-3alkoxy, Ci- shaloalkoxy, -C2haloalkenyl, -SO2R ^4a , 4- to 8-membered monocyclic or bicyclic heterocyclyl having 1 to 2 heteroatoms selected from nitrogen and oxygen, and C3-7cycloalkyl, wherein the 4- to 8-membered monocyclic or bicyclic heterocyclyl and C3-6cycloalkyl are each optionally substituted with 1 to 3 substituents independently selected from halo, Ci.4alkyl, Ci- shaloalkyl, and Ci-3alkyl-Ci-3alkoxy;

R ^4a is Ci-ealkyl;

R ⁵ is H, halo, Ci-salkyl, Ci.shaloalkyl or 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the 5- to 6- membered heteroaryl represented by R ⁵ is optionally substituted by 1 to 3 R ⁵⁰ ; and

R ⁵⁰ , for each occurrence, is independently halo, Ci-4alkyl or Ci.4haloalkyl; and

R ⁶ and R ⁷ are each, independently, H, halo, Ci-salkyl, Ci.shaloalkyl or Ci.4alkoxy; and the remaining variables are as described in the first aspect or the first, second, or third embodiment.

In a fifth embodiment, the compound of the present disclosure is represented by Formula (IV), (V), (VI), or (VII):

or a pharmaceutically acceptable salt thereof, wherein the variables in Formula (IV),

(V), (VI), or (VII) are as defined in the first, second, or third embodiment. In an alternative fifth embodiment, the compound of the present disclosure is represented by Formula (IV), (V),

(VI), (VII), (VIII), or (IX):

(VIII), (IX), or a pharmaceutically acceptable salt thereof, wherein the variables in Formula (IV), (V), (VI),

(VII), (VIII), or (IX) are as defined in the first, second, or third embodiment.

In a sixth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or a pharmaceutically acceptable salt thereof, R ¹ is Ci.4alkyl or C3- ecycloalkyl, wherein the Ci-4alkyl is optionally substituted with Ci-salkoxy; and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment. In an alternative sixth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ¹ is H, Ci-4alkyl, -OR ^la , -NR ^lb R ^lc , or Cs-ecycloalkyl, wherein the Ci.4alkyl is optionally substituted with Ci-3alkoxy; R ^la is Ci-salkyl; R ^lb and R ^lc are each, independently, H or Ci-salkyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment.

In a seventh embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ¹ is selected from - CH3, -CH2CH3, -CH2OCH3, -CH2CH2OCH3 and cyclopropyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment. In an alternative seventh embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ¹ is selected from H, -CH ₃ , -CH2CH3, -CH2OCH3, -CH2CH2OCH3, -OCH3, -NH ₂ , -NHCH3 and cyclopropyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment.

In an eighth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof;

R ² is selected from H, Ci.4alkyl, -OR ^2a , and -N(R ^2b )2, wherein the Ci-4alkyl represented by R ² is optionally substituted with 1 to 3 R ²⁰ ; R ^2a is H, Ci-4alkyl, Cs-ecycloalkyl or 4- to 6-membered monocyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the Ci- 4alkyl, Cs-ecycloalkyl and 4- to 6-membered monocyclic heterocyclyl represented by R ^2a are each optionally substituted with 1 to 3 R ²⁰ ;

R ²⁰ is independently selected from halo, Ci-salkyl, Ci.3alkoxy, -N(R ^20b )2, phenyl, C3- ecycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl, C3-6cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 R ²⁰⁰ ;

R ^2b , for each occurrence, is independently H or Ci-3alkyl;

R ^20b , for each occurrence, is independently H or Ci-salkyl; and

R ²⁰⁰ , for each occurrence, is independently selected from halo, Ci.4alkyl, Ci-4haloalkyl, Ci-2alkoxy and Cs-scycloalkyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, or seventh embodiment.

In an alternative eighth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof;

R ² is selected from H, halo, Ci^alkyl, -OR ^2a , and -N(R ^2b )2, wherein the Ci.4alkyl represented by R ² is optionally substituted with 1 to 3 R ²⁰ ;

R ^2a is H, Ci-4alkyl, C3-6cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered monocyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the Ci.4alkyl, C3-6cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered monocyclic heterocyclyl represented by R ^2a are each optionally substituted with 1 to 3 R ²⁰ ;

R ²⁰ is independently selected from halo, Ci.4alkyl, Ci.4alkoxy, -C(O)R ^20b , - C(O)N(R ^20b )2, -N(R ^20b )2, phenyl, C3-6cycloalkyl, 5- to 10-membered bicyclic carbocycle, 4- to 10-membered monocyclic or bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the Ci- 4alkyl, phenyl, C3-6cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 R ²⁰⁰ ;

R ^2b , for each occurrence, is independently H or Ci-3alkyl;

R ^20b , for each occurrence, is independently H or Ci-salkyl; and R ²⁰⁰ , for each occurrence, is independently selected from halo, Ci^alkyl, Ci-salkyl-Ci- salkoxy, Ci.4haloalkyl, Ci.2alkoxy, and Cs-scycloalkyl.

In a ninth embodiment, for the compounds of Formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ² is H, Ci.4alkyl, - OR ^2a or -N(R ^2b )2, wherein the Ci.4alkyl represented by R ² is optionally substituted with 1 to 3 substituents independently selected from halo, Ci.salkoxy and -N(R ^20b )2; and R ^2a is H or Ci- 4alkyl optionally substituted with 1 to 3 substituents independently selected from halo, Ci- salkoxy and -N(R ^20b )2; and the remaining variables are as described in the eighth embodiment.

In a tenth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ² is -OR ^2a ; R ^2a is C3- ecycloalkyl or 4- to 6-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, wherein the C3-6cycloalkyl or 4- to 6- membered monocyclic heterocyclyl represented by R ^2a are each optionally substituted with 1 to 3 substituents independently selected from halo, Ci.3alkyl and Ci.3alkoxy; and the remaining variables are as described in the eighth embodiment. In an alternative tenth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), R ² is - OR ^2a ; R ^2a is C3-6cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, wherein the C3-6cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered monocyclic heterocyclyl represented by R ^2a are each optionally substituted with 1 to 3 substituents independently selected from halo, Ci.3alkyl and Ci.3alkoxy; and the remaining variables are as described in the eighth embodiment.

In an eleventh embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV),

(V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ^2a is cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl or pyrrolidinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, Ci.3alkyl and Ci-3alkoxy; and the remaining variables are as described in the tenth embodiment. In an alternative eleventh embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V),

(VI), (VII), (VIII), or (IX), R ^2a is cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl pyrrolidinyl, pyrazinyl, pyridazinyl, or pyrazoyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, Ci.3alkyl and Ci.3alkoxy; and the remaining variables are as described in the tenth embodiment. In a twelfth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ^2a is represented by the following: halo, Ci-3alkyl and Ci.salkoxy; and the remaining variables are as described in the tenth embodiment. In an alternative twelfth embodiment, for the compounds of Formula (I), (II),

(IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ^2a is represented by the following:

1, 2 or 3; and each R ²⁰ is independently halo, Ci-salkyl and Ci.salkoxy; and the remaining variables are as described in the tenth embodiment. In some embodiments, R ^2a is represented by the following:

In a thirteenth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ^2a is represented by the following: the remaining variables are as described in the twelfth embodiment. In an alternative thirteenth embodiment, for the compounds of Formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ^2a is represented by the following: described in the twelfth embodiment.

In a fourteenth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ² is -OR ^2a and R ^2a is Ci-4alkyl substituted with one R ²⁰ ; and R ²⁰ is phenyl, Cs-ecycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl, Cs-ecycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclyl and 5- to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R ²⁰⁰ ; and the remaining variables are as described in the eighth embodiment. In an alternative fourteenth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ² is -OR ^2a and R ^2a is Ci.4alkyl substituted with one R ²⁰ ; and R ²⁰ is phenyl, C3-6cycloalkyl, 5- to 10-membered bicyclic carbocycle, 4- to 10- membered monocyclic or bicyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl, Cs-ecycloalkyl, 5- to 10-membered bicyclic carbocycle, 4- to 10-membered monocyclic or bicyclic heterocyclyl and 5- to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R ²⁰⁰ ; and the remaining variables are as described in the eighth embodiment. In a fifteenth embodiment, for the compounds of Formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ²⁰ is independently selected from azetindinyl, benzo[d][l,3]dioxolyl, cyclobutyl, cyclopropyl, dihydrofuranonyl, imidazolyl, isoxazolyl, morpholinyl, oxabicyclo[2.2.1]hexanyl, oxadiazolyl, oxetanyl, oxazolyl, phenyl, pyrazolyl, pyridinyl, pyrrolidinyl and tetrahydrofuranyl, each of which is optionally substituted with 1 to 3 R ²⁰⁰ ; and the remaining variables are as described in the fourteenth embodiment. In an alternative fifteenth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ²⁰ is independently selected from azetindinyl, benzo[d][l,3]dioxolyl, cyclobutyl, cyclopropyl, spiro[2.2]pentanyl, bicyclo[l. l.l]pentanyl, 2-oxabicyclo[2.1.1]hexanyl, 5- oxaspiro[2.4]heptanyl, 6-oxaspiro[3.4]octanyl, dihydrofuranonyl, 1,3-dioxolanyl, morpholinyl, piperazinyl, 1,4-dioxanyl, 5,8-dioxaspiro[3.5]nonanyl, tetrahydropyranyl, 3- oxabicyclo[3.1.1]heptanyl, 2-oxabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptanyl, imidazolyl, isoxazolyl, morpholinyl, oxabicyclo[2.2.1]hexanyl, oxadiazolyl, oxetanyl, oxazolyl, phenyl, furanyl, thiazoyl, isothiazolyl, thiadiazolyl, triazoyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl and tetrahydrofuranyl, each of which is optionally substituted with 1 to 3 R ²⁰⁰ ; and the remaining variables are as described in the fourteenth embodiment.

In a sixteenth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ²⁰ is independently selected from:

and the remaining variables are as described in the fourteenth embodiment. In an alternative sixteenth embodiment, for the compounds of Formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ²⁰ is independently selected from:

wherein m is 0, 1 or 2 as valence permits; and the remaining variables are as described in the fourteenth embodiment. In a seventeenth embodiment, for the compounds of Formula (I), (II), (II’), (III), (IV),

(V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ² is selected from H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ OCH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ , cyclopropyl, -CH ₂ OCH ₃ , OH, -OCH ₃ , -OCD ₃ , -OCHF ₂ , -OCH ₂ CH ₃ , -OCD ₂ CH ₃ , -OCD ₂ CD ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , -OCH(CH ₃ ) ₂ , -OCH ₂ CH ₂ OCH ₃ , -OCH ₂ CH ₂ OCF ₂ H, -OCH ₂ CH ₂ CH ₂ OCH ₃ , -OCH ₂ CH(CH ₃ )OCH ₃ , -OCH(CH ₃ )CH ₂ OCH ₃ , -OCH ₂ C(CH ₃ ) ₂ OCH ₃ , -OCH ₂ CH ₂ OCH ₂ CH ₃ , -OCH ₂ CH ₂ OCH(CH ₃ ) ₂ , -OCH ₂ CH ₂ N(CH ₃ ) ₂ , remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, or seventh embodiment. In an alternative seventeenth embodiment, for the compounds of Formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ² is selected from H, -F, -CH3, -CH2CH3, -CH2CH2CH3, -CF2CH2CH3, -CH2CH2CH2OCH3, -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ N(CH3)2, -CF ₂ -cyclopropyl, cyclopropyl, -CH2OCH3, -OH, -OCH3, -OCD3, -OCHF ₂ , -OCH2CH3, -OCD2CH3, -OCD2CD3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CH2F, -OCH ₂ CH ₂ CH(CH ₃ )F, -OCH(CH ₃ ) ₂ , -OCH ₂ CF(CH ₃ )2, -OCH2CH2CH2CH3, -OCH ₂ CHFCH(CH ₃ )2,

-OCH2CHF -cyclobutyl, -OCH2CH2OH, -OCH ₂ CH(OCH3)CH ₂ CH3, -OCH2CH2OCH3, -OCH2CH2OCF2H, -OCH2CH2OCH2CH3, -OCH2CH2CH2OCH3, -OCH ₂ CH(CH ₃ )OCH3, -OCH ₂ CH(CH3)CH ₂ OCH3, -OCH(CH ₃ )CH ₂ OCH3, -OCH ₂ CH(CH3)OC(CH ₃ )3, -OCH ₂ CH ₂ CH(CH3)OCH3, -OCH ₂ C(CH3) ₂ OCH3, -OCH2CH2OCH2CH3, -OCH ₂ CH ₂ OCH(CH3)2, -OCH ₂ CH ₂ OC(CH3)3, -OCH ₂ CH ₂ O-cyclopropyl, -OCH ₂ CH ₂ N(CH3)2, -OCH ₂ C(O)NHCH ₃ , -OCH ₂ C(O)N(CH ₃ )2, -NH ₂ , -N(CH ₃ ) ₂ , and and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, or seventh embodiment.

In an eighteenth embodiment, for the compounds of Formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ²⁰⁰ , for each occurrence, is independently selected from F, -CN, -CH3, -CF3, -CH2CH3, -CH(CH3)2, - OCH3 and cyclopropyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment. In an alternative eighteenth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ²⁰⁰ , for each occurrence, is independently selected from F, -CN, -CH3, -CH2F, -CF3, -CH2CH3, -CH(CH3)2, - CH2OCH3, -OCH3, cyclobutyl, and cyclopropyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment.

In a nineteenth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ² is C3- ecycloalkyl, 4- to 6-membered monocyclic heterocyclyl, 7- to 10-membered bicyclic heterocyclyl or 5- to 6-membered monocyclic heteroaryl, each of which is optionally substituted with 1 to 2 R ²⁰ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, or seventh embodiment.

In a twentieth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ² is selected from azetidinyl, cyclopropyl, dioxino[2,3- ]pyridinyl, isoxazolyl, isothiazolyl, morpholinyl, oxaazabicyclo[3.1.1]heptanyl, oxazolyl, pyradazinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, triazoyl, oxazoyl, isoxazoyl, oxadiazoyl, thiadiazolyl and thiazolyl, each of which is optionally substituted with 1 to 2 R ²⁰ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, or seventh embodiment. In an alternative twentieth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ² is selected from azetidinyl, cyclopropyl, tetrahydropyranyl, dioxino[2,3-t/]pyridinyl, pyridazinonyl, pyrimidinonyl, pyrazinonyl, isoxazolyl, isothiazolyl, morpholinyl, oxaazabicyclo[3.1.1]heptanyl, oxazolyl, pyradazinyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, pyrimidinyl, triazoyl, imidazolyl, oxazoyl, isoxazoyl, oxadiazoyl, pyrrolidinyl, thiadiazolyl, thiazolyl, 6,7-dihydro-[l,2,4]triazolo[l,5-a]pyrazin-8(5H)-onyl,

6.7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazinyl, 5,6-dihydro-8H-imidazo[2,l-c][l,4]oxazinyl,

6.7-dihydro-5H-pyrazolo[5,l-b][l,3]oxazinyl, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridinyl,

3.4.6.7-tetrahydropyrano[3,4-d]imidazolyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl,

4.5.6.7-tetrahydropyrazolo[l,5-a]pyrimidinyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazinyl,

5.6.7.8-tetrahydro-[l,2,4]triazolo[l,5-a]pyrazine, 5,6-dihydro-8H-[l,2,4]triazolo[5,l- c] [ 1 ,4]oxazinyl, 5,6-dihydro-8H-imidazo[2, 1 -c] [ 1 ,4]oxazinyl, imidazof 1 ,2-a]pyrimidinyl,

[ 1 ,2,4]triazolo[4,3 -a]pyrazinyl, pyrazolof 1 , 5-a]pyrimidinyl, [ 1 , 2, 4]tri azolof 1 , 5-a]pyrimidinyl, imidazof l,2-b]pyridazinyl, 6,7-dihydro-5H-cyclopenta[b]pyridin-5-onyl, furo[3,4- d]pyrimidin-5(7H)-onyl, 5,7-dihydrofuro[3,4-d]pyrimidinyl, 7,8-dihydro-5H-pyrano[4,3- b]pyridinyl, 2,3-dihydro-[l,4]dioxino[2,3-b]pyridinyl, 5,6-dihydro-4H-pyrrolo[3,4- d]thiazolyl, 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, and 2,3-dihydroimidazo[2,l-b]oxazolyl, each of which is optionally substituted with 1 to 2 R ²⁰ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, or seventh embodiment.

In a twenty-first embodiment, for the compounds of Formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ² is selected wherein n is 0, 1 or 2; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, or seventh embodiment. In an alternative twenty-first embodiment, for the compounds of Formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ² is selected from and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, or seventh embodiment.

In a twenty-second embodiment, for the compounds of Formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ²⁰ , for each occurrence, is independently halo, -CN, Ci-salkyl, Ci-43haloalkyl, C1.3 alkoxy or C3- ecycloalkyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, nineteenth, twentieth, or twenty-first embodiment. In an alternative twenty-second embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ²⁰ , for each occurrence, is independently halo, -CN, Ci-4alkyl, Ci.4haloalkyl, OR ^20c , -N(R ^20b )2, -C(O)Ci-3alkyl, -SChCi-salkyl, P(O)(Ci-3alkyl)2, C3-6cycloalkyl, or 5- to 10- membered monocyclic or bicyclic heterocyclyl, wherein the Ci-4alkyl represented by R ²⁰ is optionally substituted by -CN, OH, -N(R ^20b )2, Ci.3alkoxy, Ci-shaloalkoxy, C3-6cycloalkyl, and 5- to 10- membered monocyclic or bicyclic heterocyclyl optionally substituted by Ci.4alkyl, R ^20c is H, Ci-4alkyl, Ci-4haloalkyl, or 4-membered monocyclic heterocyclcyl, wherein the Ci.4alkyl is optionally substituted by Ci.salkoxy; wherein the 5- to 10- membered monocyclic or bicyclic heterocyclyl represented by R ²⁰ is optionally substituted with Ci.4alkyl or Ci-salkoxy; each R ^20b is, independently, H or Ci.4alkyl optionally substituted by Ci.salkoxy; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, nineteenth, twentieth, or twenty -first embodiment.

In a twenty-third embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ²⁰ , for each occurrence, is independently selected from F, -CN, -OCH3, -CH3, -CHF2, cyclopropyl and cyclobutyl; and the remaining variables are as described in the twenty-second embodiment. In an alternative twenty-third embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ²⁰ , for each occurrence, is independently selected from -F, -Cl, -Br, -CN, -OH, -OCH3, -OCHF2, -OCH2CH3, -OCH(CH ₃ ) ₂ , -OCH2CH2OCH3, -CH ₃ , -CD ₃ , -CHF ₂ , -CH2CH3, -CH(CH ₃ ) ₂ , -CF(CH ₃ ) ₂ , -C(CH ₃ )3, -CF2CH3, -CHFCH3, -CH2CH2CH3, -CH(CH ₃ )OH, -CH(CH ₃ )OCH ₃ , -CH ₂ CN, -CH ₂ N(CH ₃ )2, -CH(CH3)N(CH ₃ ) ₂ , -CH2CH2OCH3, -CH2OCH3, -CH2OCHF2, -CH ₂ N(CH ₃ )2, -CH ₂ C(OH)(CH ₃ )2, -CH ₂ C(OCH3)(CH ₃ )2, -CH2CH2OCH2CH3, -C(CH ₃ ) ₂ OH, -C(CH ₃ ) ₂ OCH3, -C(CH ₃ ) ₂ CN, -C(CH3) ₂ N(CH3) ₂ , -NHCH3, -N(CH ₃ ) ₂ , -NHCH(CH ₃ ) ₂ , -NHCH2CH2OCH3, -CH ₂ N(CH3)CH ₂ CH ₂ OCH3, -N(CH3)CH ₂ CH ₂ OCH3, -C(O)CH ₃ , tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, N-methylpiperazinyl, N- methylmorpholinyl, and morpholinyl; and the remaining variables are as described in the twenty-second embodiment. In some embodiments, R ²⁰ , for each occurrence, is independently selected from F, -CN, -OCH3, -CH3, -CHF2, cyclopropyl and cyclobutyl.

In a twenty-fourth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ³ is selected from H, Ci.4alkyl, Ci-shaloalkyl, Cs-ecycloalkyl, -OR ^3a , -N(R ^3b )2 phenyl, pyridinyl, pyrimidinyl, pyrazoyl, thiazoyl, indazoyl, [l,2,4]triazolo[l,5-a]pyridinyl, imidazo[l,2- a]pyridinyl, and imidazo[l,2-b]pyridazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyrazoyl, thiazoyl, indazoyl, [l,2,4]triazolo[l,5-a]pyridinyl, imidazo[l,2-a]pyridinyl, or imidazo[l,2-b]pyridazinyl are each optionally substituted by 1 or 2 R ^3c ; R ^3a is H, Ci.3alkyl or C3-6cycloalkyl, wherein the Ci.3alkyl and C3-6cycloalkyl represented by R ^3a are each optionally substituted with one or two substituents independently selected from halo, -CN, Ci-2alkyl, -OH and Ci.2alkoxy; each R ^3b , for each occurrence, is independently H, Ci-salkyl, or C3-5cycloalkyl; each R ^3c is independently selected from halo, oxo, -CN, -OR ^3a , -N(R ^3b )2, Ci-4alkyl, Ci-4alkyl-R ^3d , Ci.4haloalkyl, -C(O)OR ^3a , phenyl, cyclopropyl, cyclobutyl, oxetanyl, and morpholinyl; R ^3d is -C(O)OR ^3a , -N(R ^3b )2, -OR ^3a , cyclopropyl, or morpholinyl; and the remaining variables are as described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty -third embodiment. In an alternative twenty-fourth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ³ is selected from H, halo, Ci.4alkyl, Ci-3haloalkyl, C3-6cycloalkyl, C2-4alkenyl, Ci-salkyl-Ci- 3alkoxy, -OR ^3a -N(R ^3b )2, phenyl, pyridinyl, pyrimidinyl, pyrazoyl, thiazoyl, indazoyl, [l,2,4]triazolo[l,5-a]pyridinyl, imidazo[l,2-a]pyridinyl, or imidazo[l,2-b]pyridazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyrazoyl, thiazoyl, indazoyl, [l,2,4]triazolo[l,5- a]pyridinyl, imidazo[l,2-a]pyridinyl, or imidazo[l,2-b]pyridazinyl are each optionally substituted by 1 or 2 R ^3c ; R ^3a is H, Ci-salkyl, 4- to 8- membered monocyclic or bicycle heterocyclyl, or C3-6cycloalkyl, wherein the Ci.3alkyl and C3-6cycloalkyl represented by R ^3a are each optionally substituted with one or two substituents independently selected from halo, -CN, Ci-2alkyl, -OH and Ci.2alkoxy; each R ^3b , for each occurrence, is independently H, Ci- 3alkyl, or C3-5cycloalkyl; each R ^3c is independently selected from halo, oxo, -CN, - OR ^3a , -N(R ^3b )2, Ci-4alkyl, Ci-4alkyl-R ^3d , Ci.4haloalkyl, -C(O)OR ^3a , phenyl, cyclopropyl, cyclobutyl, oxetanyl, or morpholinyl; R ^3d is -C(O)OR ^3a , -N(R ^3b )2, -OR ^3a , cyclopropyl, or morpholinyl; and the remaining variables are as described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment.

In a twenty-fifth embodiment, for the compounds of Formula (I), (II), (IF). (Ill), (IV), (V), (VI), (VII), (VIII), (IX), or a pharmaceutically acceptable salt thereof, R ³ is selected from H, -CH ₃ , -CH2CH3, -CF2CH3, -CH(CH ₃ ) ₂ , cyclopropyl, -OCH3, -OCH2CH2OCH3, - wherein n is 0, 1, or 2; and the remaining variables are as described in the twenty-fourth embodiment. In an alternative twenty-fifth embodiment, for the compounds of Formula (I), (IF), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ³ is selected from H, -F, -Cl, -CH ₃ , -CH2CH3, -CF2CH3, -CF ₃ , -CH(CH ₃ ) ₂ , cyclopropyl, -CH=CH ₂ , -CH2OCH3, -OCH3, -OCH2CH3, -OCH(CH ₃ ) ₂ , -OCH2CH2OCH3, - wherein n is 0, 1, or 2; and the remaining variables are as described in the twenty-fourth embodiment.

In a twenty- sixth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, each R ^3c is individually selected from -CN, F, -OCH3, -CH ₃ , -CH2CH3, -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ )2, -

CHF ₂ , -CH2CF3, -CF ₃ ,

-CD3, -CH2CH2OCH3, -CFF-cyclopropyl, -CH ₂ CH ₂ -morpholinyl, cyclopropyl, cyclobutyl, -CH2C(0)0H, -C(O)OC(CH3)3, -CH ₂ CH ₂ N(CH3)2, and morpholinyl; and the remaining variables are as described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth or twenty-fifth embodiment. In an alternative twenty-sixth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, each R ^3c is individually selected from -CN, -F, -Cl, -OCH3, -CH ₃ , -CH2CH3, - CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ )2, -CHF ₂ , -CH2CF3, -CF ₃ , -CD ₃ , -CH2CH2OCH3, -CH ₂ -cyclopropyl, -CFFCFF-morpholinyl, cyclopropyl, cyclobutyl, -CH2C(0)0H, -C(O)OC(CH3)3, - CH ₂ CH ₂ N(CH3) ₂ , oxetanyl, and morpholinyl; and the remaining variables are as described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty- first, twenty- second, twenty-third, twenty-fourth or twenty-fifth embodiment.

In a twenty- seventh embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ⁴ is selected from Ci-4haloalkyl and Cs-ecycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo and Ci. ₃ alkyl; and the remaining variables are as described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment. In an alternative twenty-seventh embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ⁴ is selected from Ci-4haloalkyl, Ci.3alkoxy, Ci-3alkoxy-Ci-3alkoxy, Ci.shaloalkoxy, -C2-4alkenyl, C2-4haloalkenyl, 5- to 7 membered monocyclic or bicyclic heterocyclyl, and C3-6cycloalkyl, wherein the 5- to 7 membered monocyclic or bicyclic heterocyclyl, and C3-6cycloalkyl are each optionally substituted with 1 to 3 substituents independently selected from halo, Ci- shaloalkyl, Ci-3alkyl-Ci-3alkoxy, and Ci-salkyl; and the remaining variables are as described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment..

In a twenty-eighth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ⁴ is selected from the remaining variables are as described in the twenty- seventh embodiment. In an alternative twenty-seventh embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ⁴ is selected from -

CF2CH3, -CF2CFH2, -CFHCFH2, -CF(CH ₃ ) ₂ , -CF(CH ₃ )CFH ₂ , -CH(CH ₃ )CFH ₂ , -CF2CH2CH3, variables are as described in the twenty-seventh embodiment.

In a twenty-ninth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ⁵ is H or 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the 5-membered heteroaryl represented by R ⁵ is optionally substituted by 1 to 3 R ⁵⁰ ; and the remaining variables are as described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty- third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment.

In a thirtieth embodiment, for the compounds of Formula (I), (II), (IF), (III), (IV),

(V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R ⁵ is H or pyrazolyl optional substituted by 1 to 3 R ⁵⁰ ; and the remaining variables are as described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty- first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty- seventh, twentyeighth, or twenty-ninth embodiment.

In some embodiments, for the compounds of Formula (I), (II), (IF), (III), (IV), (V),

(VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ⁶ is H, halo, Ci- salkoxy, and the remaining variables are as described in the first aspect or any of the embodiments described above. Alternatively, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ⁶ is H, -F, or -OCH3, and the remaining variables are as described in the first aspect or any of the embodiments described above.

In some embodiments, for the compounds of Formula (I), (II), (IF), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R ⁷ is H, and the remaining variables are as described in the first aspect or any of the embodiments described above.

In a thirty-first embodiment, the compound of the present disclosure is represented by Formula (IV-1) or (V-l):

(IV- 1) or (V-l), or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is Ci-3alkyl; R ² is -OR ^2a or 5-membered monocyclic heteroaryl optionally substituted with Ci-

3alkyl;

R ^2a is Ci-4alkyl optionally substituted with R ²⁰ ;

R ²⁰ is Ci-3alkoxy or C3-6cycloalkyl optionally substituted with Ci.2alkoxy;

R ³ is selected from H, -OR ^3a , Ci-salkyl, C3-6cycloalkyl, and pyrazoyl, wherein the pyrazoyl is optionally substituted by 1 or 2 R ^3c ;

R ^3a is Ci-3alkyl optionally substituted with Ci.3alkoxy, or C3-6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from Ci.3alkoxy, Ci- 3alkyl and -OH;

R ^3C is Ci-3alkyl; and

R ⁴ is Ci-3haloalkyl; and the remaining variables are as described in the first aspect or the first embodiment.

In a thirty-second embodiment, for the compounds of Formula (I), (IV-1), or (V-l), or a pharmaceutically acceptable salt thereof, R ¹ is -CH3; and the remaining variables are as described in the thirty-first embodiment.

In a thirty-third embodiment, for the compounds of Formula (I), (IV-1), or (V-l), or a pharmaceutically acceptable salt thereof, R ² is selected from -OCH3, -OCD3, and the remaining variables are as described in the thirty-first or thirty-second embodiment.

In a thirty-fourth embodiment, for the compounds of Formula (I), (IV-1), or (V-l), or a pharmaceutically acceptable salt thereof, R ³ is selected from H, -CH3, -CH2CH3, cyclopropyl, - the remaining variables are as described in the thirty-first, thirty-second, or thirty-third embodiment.

In a thirty-fifth embodiment, for the compounds of Formula (I), (IV-1), or (V-l), or a pharmaceutically acceptable salt thereof, R ^3c is -CH3, R ⁴ is -CF2CH3, -CF2CFH2, -CFHCFH2, -CF2CH2CH3, -CF(CH3)2; and the remaining variables are as described in the thirty-first, thirty-second, thirty -third, or thirty-fourth embodiment.

In a thirty-sixth embodiment, the compound of the present disclosure is represented by Formula (III):

(III) or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is Ci-ealkyl;

R ² is Ci-4alkoxy;

R ³ is H or Ci-ealkyl;

R ⁴ is Ci-4haloalkyl or 4- to 6-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen and oxygen; and

R ^N1 and R ^N2 are each independently H or Ci-salkyl; and the remaining variables are as described in the first aspect or the first, second, or third embodiment.

In a thirty-seventh embodiment, for the compounds of Formula (I) or (III), or a pharmaceutically acceptable salt thereof, R ¹ is -CH3; and the remaining variables are as described in the thirty-sixth embodiment.

In a thirty-eighth embodiment, for the compounds of Formula (I) or (III), or a pharmaceutically acceptable salt thereof, R ² is -OCH2CH3 or -OCH2CH2OCH3; and the remaining variables are as described in the thirty-sixth or thirty-seventh embodiment.

In a thirty-ninth embodiment, for the compounds of Formula (I) or (III), or a pharmaceutically acceptable salt thereof, R ³ is H or -CH3; and the remaining variables are as described in the thirty-sixth, thirty-seventh, or thirty-eighth embodiment.

In a fortieth embodiment, for the compounds of Formula (I) or (III), or a pharmaceutically acceptable salt thereof, R ⁴ is C i-shaloalkyl or tetrahydrofuranyl; and the remaining variables are as described in the thirty-sixth, thirty-seventh, thirty-eighth, or thirtyninth embodiment. In a forty-first embodiment, for the compounds of Formula (I) or (III), or a pharmaceutically acceptable salt thereof, R ⁴ is -CF2CH3 or ; and the remaining variables are as described in the fortieth embodiment.

In a forty-second embodiment, the compound of the present disclosure is represented by Formula (X): or a pharmaceutically acceptable salt thereof, wherein:

A ¹ is N or CH;

R ² is -OR ^2a , 5- or 6-membered monocyclic heteroaryl, or 7- to 10-membered bicyclic heterocyclyl, wherein the 5- or 6-membered monocyclic heteroaryl or 7- to 10-membered bicyclic heterocyclyl are each optionally substituted with one or two R ²⁰ ;

R ^2a is Ci-3alkyl optionally substituted with Ci.3alkoxy;

R ²⁰ is Ci-3alkyl optionally substituted by -N(Ci-3alkyl)2;

R ³ is H, Ci-3alkyl, or -OR ^3a ;

R ^3a is C3-4cycloalkyl;

R ⁴ is Ci-4haloalkyl or 5- to 7-membered bicyclic heterocyclyl; and the remaining variables are as described in the first aspect or first embodiment.

In a forty-third embodiment, for the compunds of Formula (I) or (X), or a pharmaceutically acceptable salt thereof, A ¹ is N; and the remaining variables are as described in the forty-second embodiment.

In a forty-fourth embodiment, for the compunds of Formula (I) or (X), or a pharmaceutically acceptable salt thereof, R ² is -OCH3, -OCH2CH3, or -OCH2CH2OCH3; and the remaining variables are as described in the forty-second or forty-third embodiment.

In a forty-fifth embodiment, for the compunds of Formula (I) or (X), or a pharmaceutically acceptable salt thereof, R ² is pyrazoyl pyridinyl, pyrimidinyl, or 4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazinyl, each of which is optionally substituted by one or two R ²⁰ ; and the remaining variables are as described in the forty-second or forty-third embodiment. In a forty-sixth embodiment, for the compunds of Formula (I) or (X), or a pharmaceutically acceptable salt thereof, , wherein n is 0, 1 or 2; and the remaining variables are as described in the forty-fifth embodiment.

In a forty-seventh embodiment, for the compunds of Formula (I) or (X), or a pharmaceutically acceptable salt thereof, R ² is and the remaining variables are as described in the forty- sixth embodiment.

In a forty-eighth embodiment, for the compunds of Formula (I) or (X), or a pharmaceutically acceptable salt thereof, each R ²⁰ is, independently, -CH , -CH2CH3, or - CH2N(CHa)2; and the remaining variables are as described in the forty-second, forty-third, forty -fifth, forty-sixth, or forty-seventh embodiment.

In a forty-ninth embodiment, for the compunds of Formula (I) or (X), or a pharmaceutically acceptable salt thereof, R ³ is H, -CH3, -CH2CH3, or -O-cyclopropyl; and the remaining variables are as described in the forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, or forty-eighth embodiment.

In a fiftieth embodiment, for the compunds of Formula (I) or (X), or a pharmaceutically acceptable salt thereof, R ⁴ is -CF2CH3 and the remaining variables are as described in the forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth, or forty-ninth embodiment.

In a fifty-first embodiment, the present disclosure provides a compound selected from the group consisting of:

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-ethoxyp yridin-2-yl)acetamide;

N-(4-((4-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-ethoxyp yridin-2-yl)acetamide;

N-(4-((4-(l,l-difluoroethyl)pyrimidin-2-yl)amino)-5-ethox ypyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypy ridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methoxypyrimidin-4-yl)amin o)-5-ethoxypyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(difl uoromethoxy)pyridin-2- yl)acetamide;

N-(5-cyclobutyloxy-4-((2-(l,l-difluoroethyl)pyrimidin-4-y l)amino)pyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-propa n-2-yloxypyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-ethoxypyridin-2- yl)propanamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-ethoxypyridin-2- yl)acetamide;

N-(5-(cyclopropylmethoxy)-4-((2-(l,l-difluoroethyl)-6-met hylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-ethoxypyridin-2- yl)acetamide;

N-(4-((6-cyclopropyl-2-(l,l-difluoroethyl)pyrimidin-4-yl) amino)-5-ethoxypyridin-2- yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)-4-(3-methoxycyclobutyl)oxypy ridin-2-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)-4-(3-methoxycyclobutyl)oxypy ridin-2-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(3-methoxycyclobutyl)oxypy rimidin-4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((6-cyclopropyl-2-(l, 1 -difluoroethyl )pyrimidin-4-yl)amino)-5-methoxypyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methoxypyrimidin-4-yl)amin o)-5-methoxypyri din-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(3-methoxycyclobutyl)oxypy rimidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(2- methoxyethoxy)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methoxypyrimidin-4-yl)amino)- 5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)acetamide;

N-(5-(2,2-difluoroethoxy)-4-((2-(l,l-difluoroethyl)-6-met hylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2- (dimethylamino)ethoxy)pyridin-2-yl)acetamide;formic acid;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-ethoxypyridin-2-yl)-2- methoxyacetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-ethoxypyridin-2-yl)-3- methoxypropanamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-ethoxypyridin-2- yl)cyclopropanecarboxamide;

N-(5-cyclopropyl-4-((2-(l,l-difluoroethyl)-6-methylpyrimi din-4-yl)amino)pyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5- phenylmethoxypyridin-2-yl)acetamide;

N-(5-ethoxy-4-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)ami no)pyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin -4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-ethox ypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-5-fluoropyrimidin-4-yl)amino )-5-ethoxypyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-5-fluoro-6-methylpyrimidin-4 -yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-methoxypyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin -4-yl)amino)-5- methoxypyridin-2-yl)acetamide; N-(5-cyclopropyloxy-4-((2-(l,l-difluoroethyl)pyrimidin-4-yl) amino)pyri din-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-propan-2- yloxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((3- methoxycyclobutyl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-methylpyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-ethylpyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-propylpyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-propan-2-ylpyridin-2- yl)acetamide;

N-(5-cyclopropyloxy-4-((2-(l,l-difluoroethyl)-6-methylpyr imidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-methoxypyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5- (methoxymethyl)pyridin-2-yl)acetamide;

N-(5-(methoxymethyl)-4-((6-methoxy-5-(l-methylpyrazol-3-y l)pyridin-2- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-( 1 , 1 -difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-( 1 , 1 ,2,2,2- pentadeuterioethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-methoxypyrimidin-4-yl)amino)-5-(l -methyl pyrazol-3- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-ethoxypyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-propan-2-ylpyrimidin-4-yl) amino)-5-methoxypyridin- 2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-(3 -hydroxy-3 -methyl cy cl obutyl)oxypyrimidin-4- yl)amino)-5-ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)-meth ylamino)-5-ethoxypyridin- 2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-vinylpyrimidin-4-yl)amino)-5- (2- methoxyethoxy)pyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(2-meth oxyethoxy)pyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((l- (trifluoromethyl)cyclopropyl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((l- methylcyclopropyl)methoxy)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((l- methoxypropan-2-yl)oxy)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(2- methoxypropoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(oxetan-3- ylmethoxy)pyridin-2-yl)acetamide;

N-(5-(cyclobutylmethoxy)-4-((2-(l,l-difluoroethyl)-6-meth ylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)- 5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

N-(4-((6-( 1 , 1 -difluoroethyl)pyridin-2-yl)amino)-5-(2-(pyrrolidin- 1 -yl)ethoxy)pyridin- 2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(2-(dim ethylamino)ethoxy)pyridin- 2-yl)acetamide;

N-(4-((6-cyclopropyl-2-(l,l-difluoroethyl)pyrimidin-4-yl) amino)-5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyrazin-2-yl)amino)-5-(2-meth oxyethoxy)pyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(2- (difluoromethoxy)ethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(3- methoxypropoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(2- morpholinoethoxy)pyridin-2-yl)acetamide;

N-(4-((2-( 1 , 1 -difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(4-methylp iperazin- 1 - yl)ethoxy)pyridin-2-yl)acetamide; (R)-N-(5-(2-methoxyethoxy)-4-((6-(tetrahydrofuran-3-yl)pyrid in-2-yl)amino)pyridin- 2-yl)acetamide;

(S)-N-(4-((6-(l,2-difluoroethyl)pyridin-2-yl)amino)-5-(2- methoxyethoxy)pyridin-2- yl)acetamide;

(R)-N-(5-((2,2-difluorocyclopropyl)methoxy)-4-((2-(l,l-di fluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((4-(l,l-difluoroethyl)pyrimidin-2-yl)amino)-5-(2-me thoxyethoxy)pyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-isopropoxypyrimidin-4-yl)a mino)-5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethoxypyrimidin-4-yl)amino )-5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

N-(4-((4-(l,l-difluoroethyl)-6-methylpyrimidin-2-yl)amino )-5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,2-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((4-(l,2-difluoroethyl)-6-methylpyrimidin-2-yl)a mino)-5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,2-difluoropropan-2-yl)-6-methylpyrimidin- 4-yl)amino)-5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l-fluoropropan-2-yl)-6-methylpyrimidin-4-yl )amino)-5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

(R)-N-(5-(l-cyclopropylethoxy)-4-((2-(l,l-difluoroethyl)- 6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(5-((l-cyanocyclopropyl)methoxy)-4-((2-(l,l-difluoroeth yl)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(oxetan-2- ylmethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(oxetan-3- yloxy)pyridin-2-yl)acetamide; methyl (4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2 - methoxyethoxy)pyridin-2-yl)carbamate;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(2- methoxyethoxy)pyridin-2-yl)propionamide; (S)-N-(4-((6-(l,2-difluoroethyl)pyrazin-2-yl)amino)-5-(2-met hoxyethoxy)pyridin-2- yl)acetamide;

N-(4-((6-(l-fluorovinyl)pyrazin-2-yl)amino)-5-(2-methoxye thoxy)pyridin-2- yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5- methoxypyridin-2-yl)acetamide; methyl (4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2 - (dimethylamino)ethoxy)pyridin-2-yl)carbamate;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5- (trifluoromethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-fluoropyrimidin-4-yl)amino )-5-ethoxypyridin-2- yl)acetamide;

N-(4-((6-(2-oxabicyclo[2.1. l]hexan-4-yl)-4-methylpyridin-2-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(pyridin-3-yl)pyrimidin-4- yl)amino)-5-ethoxypyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-ethyl-lH-pyrazol-4-yl)p yrimidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((6-methylpyrazin-2- yl)oxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((l- fluorocyclopropyl)methoxy)pyridin-2-yl)acetamide;

N-(5-(bicyclo[ 1.1.1 ]pentan- 1 -ylmethoxy)-4-((2-( 1 , 1 -difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(pyridin-2- ylmethoxy)pyridin-2-yl)acetamide;

2-((6-acetamido-4-((2-(l,l-difluoroethyl)-6-methylpyrimid in-4-yl)amino)pyridin-3- yl)oxy)-N-methylacetamide;

2-((6-acetamido-4-((2-(l,l-difluoroethyl)-6-methylpyrimid in-4-yl)amino)pyridin-3- yl)oxy)-N,N-dimethylacetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(3,3- difluoropropoxy)pyridin-2-yl)acetamide;

N-(5-butoxy-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4 -yl)amino)pyridin-2- yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(2-(4-methylpiperazin- l-yl)ethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(3- methoxypropoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(thiazol-2- ylmethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((3-ethyloxetan-3- yl)methoxy)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((2,2-dimethyl- l,3-dioxolan-4-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((3-methylisothiazol- 4-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((4-methylthiazol-2- yl)methoxy)pyridin-2-yl)acetamide;

N-(5-(2-(tert-butoxy)ethoxy)-4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((2-methoxypyri din-4- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((5-methylisothiazol- 3-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((6-methylpyridin-3- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((2-methylthiazol-4- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methyl- 1,3,4- thiadiazol-2-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-fluoro-2- methylpropoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((2-fluoropyridin-4- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((3-methylisoxazol-5- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(oxazol-5- ylmethoxy)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -((4,6-dimethylpyridin- 2-yl)methoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((2,2-dimethyl- l,3-dioxolan-4-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((5-fluoropyridin-2- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(pyrazin-2- ylmethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((5-methoxypyri din-2- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((4-methoxypyridin-2- yl)methoxy)pyridin-2-yl)acetamide;

N-(5-((4-cyanopyri din-2 -yl)methoxy)-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((5-methylpyridin-2- yl)methoxy)pyridin-2-yl)acetamide;

N-(5-((5-cyanopyri din-2 -yl)methoxy)-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((6-methoxypyridin-2- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((4-methylpyridin-2- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(pyrimidin-2- ylmethoxy)pyridin-2-yl)acetamide;

(R)-N-(5-((l,4-dioxan-2-yl)methoxy)-4-((2-(l,l-difluoroet hyl)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((tetrahydro-2H- pyran-3-yl)methoxy)pyri din-2 -yl)acetamide;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(3- methoxybutoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((l,5-dimethyl-lH- pyrazol-4-yl)methoxy)pyridin-2-yl)acetamide;

(R)-N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin- 4-yl)amino)-5-

((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)acetamide; N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(2-hydroxy ethoxy)pyridin-2- yl)acetamide;

N-(4-((2-(2-oxabicyclo[2.1.l]hexan-4-yl)-6-methylpyrimidi n-4-yl)amino)-5-(5- methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin -2-yl)acetamide;

N-(4'-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5- ((difluoromethoxy)methyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(5-cyclopropyl-4-((2-(l,l-difluoroethyl)-5-methoxypyrim idin-4-yl)amino)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2,2- dimethyl-2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide;

N-(5-cyano-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4 -yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide;

N-(5-cyano-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino )-[2,3'-bipyridin]-6'- yl)acetamide;

N-(4-((6-( 1 , 1 -difluoroethyl)pyridin-2-yl)amino)-5-( 1 -methyl- lH-pyrazol-3 - yl)pyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)-4-((lr,3r)-3-methoxy cyclobutoxy )pyridin-2-yl)amino)-5- (l-methyl-lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

(S)-N-(4-((6-(l,2-difluoroethyl)pyridin-2-yl)amino)-5-(l- methyl-lH-pyrazol-3- yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-6-(difluoromethoxy)-

[2,3'-bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(3- (dimethylamino)propyl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(3- methoxypropyl)pyridin-2-yl)acetamide;

N-(5-(cyclopropyldifluoromethyl)-4-((2-(l,l-difluoroethyl )-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l , 1 -difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(l , 1 - difluoropropyl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-methoxy-2- methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-methoxy-6- methylpyrimidin-4-yl)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(l-methyl-lH-l,2,4- triazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(l-meth yl-6-oxo-l,6- dihydropyridazin-3-yl)pyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(4-meth yl-5-oxo-4,5- dihydropyrazin-2-yl)pyri din-2 -yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(l-meth yl-2-oxo-l,2- dihydropyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(l-meth yl-6-oxo-l,6- dihydropyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(6-meth oxypyrimidin-4-yl)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-me thoxy-2-methylpyrimidin-

4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-me thoxy-6-methylpyrimidin-

4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)pyrimidin-4-yl)amino)-5-(l -methyl- 1H-1, 2, 4-triazol-3- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(l-methyl-lH - 1,2,4- triazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5-methyl-l,3,4- thiadiazol-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5-methyl-l,3,4- oxadiazol-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(3-methyl-l,2,4- thiadiazol-5-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5-methyl-l,2,4- oxadiazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((6-(difluoromethoxy)pyridin-2-yl)amino)-5-(pyrimidi n-4-yl)pyri din-2- yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(2-meth ylpyrimidin-4-yl)pyri din-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-me thylpyrimidin-4- yl)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(2-methylpyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-5-(2- methylpyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)ami no)-5-(2- methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(2-meth oxypyrimidin-4-yl)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-me thoxypyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-methoxypyrimidin- 4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-5-(2- methoxypyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)ami no)-5-(2- methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-fluoropyrimidin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5-fluoropyrimidin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-(5-fluoropyrimidin-

2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-fl uoropyrimidin-2-yl)pyridin- 2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(5-fluo ropyrimidin-2-yl)pyri din-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyridin-4-yl)amino)-5-(5-fluo ropyrimidin-2-yl)pyridin-2- yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyrazin-2-yl)amino)-5-(5-fluo ropyrimidin-2-yl)pyridin-2- yl)acetamide;

N-(4-((6-(2-fluoropropan-2-yl)pyrazin-2-yl)amino)-5-(5-fl uoropyrimidin-2- yl)pyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)- 5-(5-fluoropyrimidin-2- yl)pyridin-2-yl)acetamide; N-(4-((6-(l, l-difluoroethyl)-4-methoxypyri din-2 -yl)amino)-5-(5-fluoropyrimidin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methoxypyrimidin-4-yl)amin o)-5-(5-fluoropyrimidin-

2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-me thoxypyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-methoxypyrimidin-

4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-5-(6- methoxypyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)ami no)-5-(6- methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-methylpyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-5-(6- methylpyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyridin-4-yl)amino)-5-(6-meth ylpyrimidin-4-yl)pyridin-2- yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)ami no)-5-(6- methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-me thylpyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-( 1 , 1 -difluoroethyl)pyrimidin-4-yl)amino)-5-(l -methyl- 1 H-pyrazol-3 - yl)pyridin-2-yl)acetamide;

N-(4-((4-( 1 , 1 -difluoroethyl)pyrimidin-2-yl)amino)-5-(l -methyl- 1 H-pyrazol-3 - yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(l-methyl-lH-pyrazol-3- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(l -methyl- 1H- pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((6-cyclopropyl-2-( 1 , 1 -difluoroethyl )pyrimidin-4-yl)amino)-5-( 1 -methyl- 1H- pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin -4-yl)amino)-5-(l -methyl- lH-pyrazol-3-yl)pyridin-2-yl)acetamide; (R)-N-(5-(l-methyl-lH-pyrazol-3-yl)-4-((6-(tetrahydrofuran-3 -yl)pyridin-2- yl)amino)pyridin-2-yl)acetamide;

N-(4-((6-(l, l-difluoroethyl)-4-methoxypyri din-2 -yl)amino)-5-(l -methyl-lH-pyrazol- 3 -yl)pyridin-2-yl)acetami de;

N-(4-((6-(l -difluoroethyl)-4-(2 -methoxyethoxy)pyri din-2 -yl)amino)-5-(l -methyl- lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)-4-((ls, 3s)-3-methoxy cyclobutoxy )pyridin-2-yl)amino)-5- (l-methyl-lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyrazin-2-yl)amino)-5-(l-meth yl-lH-pyrazol-3- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-methoxypyridazin-

3 -yl)pyridin-2-yl)acetamide-2,2,2-d3 ;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-me thoxypyridazin-3- yl)pyridin-2-yl)acetamide;

N-(4-((6-(2-fluoropropan-2-yl)pyridin-2-yl)amino)-5-(5-fl uoropyrimidin-2-yl)pyridin- 2-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)pyridin-4-yl)amino)-5-(5-fl uoropyrimidin-2-yl)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyridin-4-yl)amino)-5-(6-meth oxypyrimidin-4-yl)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-methyl-lH-pyrazol- 3 -yl)pyridin-2-yl)acetami de;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-methylpyridazin-3- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(6-methoxypyridazin-3- yl)pyridin-2-yl)acetamide;

N-(4-((2-( 1 , 1 -difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(6-oxo- 1 ,6- dihydropyridazin-3-yl)pyridin-2-yl)acetamide;

N-(5-(5-acetyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2 -yl)-4-((2-(l,l- difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyri din-2 -yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-oxo-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide ;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(7-hydroxy-5- methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin -2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(5- (dimethylamino)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-methyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide ;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-methyl-2H-l,2,3- triazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-(2-hydroxy-2- methylpropyl)-lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-(2-ethoxyethyl)- lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-(2-methoxy-2- methylpropyl)-lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5- (methoxymethyl)thiazol-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2- (methoxymethyl)thiazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4- (methoxymethyl)thiazol-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-morpholinothiazol-

4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l,2,4-thiadiazol-5- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-(dimethylamino)- l,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-methyl-4,5,6,7- tetrahydrothiazolo[4,5-c]pyridin-2-yl)pyridin-2-yl)acetamide ;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-methyl-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyridin-2-yl)acetamide ;

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(7-methyl-5 , 6,7,8- tetrahydroimidazof 1 ,2-a]pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-methyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrimidin-2-yl)pyridin-2-yl)acetami de;

N-(5-(6-(2-cyanopropan-2-yl)pyrimidin-4-yl)-4-((2-(l,l-di fluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(6- isopropoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-ethoxypyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-ethylpyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-isopropylpyrimidin- 4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6- (difluoromethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6- (dimethylamino)pyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-(4-methylpiperazin-

1-yl)pyrimidin-4-yl)pyri din-2 -yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-(2- methoxyethoxy)pyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-(2-methoxyethyl)- 6-oxo-l,6-dihydropyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(pyridazin-3- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-methylpyridazin-3- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5- (dimethylamino)pyridazin-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5- (isopropylamino)pyridazin-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-mo rpholino-l,3,4-thiadiazol-

2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(d imethylamino)pyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-(2-methoxyethyl)- lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-(2-methoxyethyl)- lH-pyrazol-5-yl)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(l-(2-methoxyethyl)- lH-l,2,3-triazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-(2-methoxyethyl)- 2H-l,2,3-triazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(2-(2-methoxyethyl)- 2H-l,2,3-triazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(l-(2-methoxyethyl)- lH-l,2,3-triazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-(2-methoxyethyl)- lH-l,2,4-triazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-(2-methoxypropan-

2-yl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((di fluoromethoxy)methyl)-

[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-5-

((dimethylamino)methyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-5-morpholino-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-5-(morpholinomethyl)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(6-(2- methoxyethoxy)pyridazin-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(pyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2- (dimethylamino)thiazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-(2-hydroxypropan- 2-yl)-l-methyl-lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-me thoxypyrazin-2-yl)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(( 2- methoxyethyl)amino)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(( 2- methoxyethyl)(methyl)amino)pyrazin-2-yl)pyridin-2-yl)acetami de; N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(dimeth ylamino)-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-methyl-4,5,6,7- tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pyridin-2-yl)aceta mide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(tetrahydrofuran- 2-yl)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(tetrahydrofuran-

2-yl)pyridin-2-yl)acetamide;

N-(4'-((2-(2-oxabicyclo[2.1.1]hexan-l-yl)-6-methylpyrimid in-4-yl)amino)-5- (methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(3-methyl-l,2,4- oxadiazol-5-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide ;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-ethyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide ;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-me thyl-5,6-dihydro-4H- pyrrolo[3,4-d]thiazol-2-yl)pyridin-2-yl)acetamide;

N-(5-(5-(cyanomethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]py ridin-2-yl)-4-((2-(l,l- difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyri din-2 -yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-(pyrrolidin-l- ylmethyl)pyrimidin-2-yl)pyridin-2-yl)acetamide;

N-(5-(5-cyanopyridazin-3-yl)-4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5- ((dimethylamino)methyl)-l-methyl-lH-pyrazol-3-yl)pyridin-2-y l)acetamide; l-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(l-methyl-lH-pyrazol-

3 -yl)pyridin-2-yl)urea; l-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(l-methyl-lH-pyrazol- 3 -yl)pyridin-2-yl)-3 -methylurea; l-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)- 5-fluoro-[2,3'-bipyridin]- 6 ' -y 1 ) -3 -methylurea; l-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)- 5-fluoro-[2,3'-bipyridin]- 6'-yl)urea; 1-(5-cyano-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl )amino)-[2,3'-bipyridin]- 6'-yl)urea;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((tetrahydrofuran- 2-yl)methoxy)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((tetrahydrofuran- 2-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(3- fluoropropoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(5-methoxypyridin-3-yl)pyr imidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((6-((2-oxaspiro[3.3]heptan-6-yl)oxy)-2-(l,l-difluor oethyl)pyrimidin-4- yl)amino)-5-ethoxypyridin-2-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin- 4-yl)amino)-5-(2- methoxypropoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-((l-methyl-lH- pyrazol-4-yl)oxy)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-(l -methyl- lH-pyrazol-4-yl)pyrimidin-4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-(difluoromethyl)-lH-pyr azol-4-yl)pyrimidin-4- yl)amino)-5-ethoxypyridin-2-yl)acetamide;

N-(4-((6-( 1 -cyclopropyl- lH-pyrazol-4-yl)-2-( 1 , 1 -difluoroethyl )pyrimidin-4- yl)amino)-5-ethoxypyridin-2-yl)acetamide;

2-(4-(6-((2-acetamido-5-ethoxypyridin-4-yl)amino)-2-(l,l- difluoroethyl)pyrimidin-4- yl)-lH-pyrazol-l-yl)acetic acid;

N-(4-((2-(l,l-difluoroethyl)-6-(l-isopropyl-lH-pyrazol-4- yl)pyrimidin-4-yl)amino)- 5-ethoxypyridin-2-yl)acetamide; tert-butyl 4-(6-((2-acetamido-5-ethoxypyridin-4-yl)amino)-2-(l,l- difluoroethyl)pyrimidin-4-yl)-lH-pyrazole-l-carboxylate;

N-(4-((2-(l,l-difluoroethyl)-6-(l-(2-(dimethylamino)ethyl )-lH-pyrazol-4- yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-(l-(2,2,2-trifluoroethyl)-lH- pyrazol-4-yl)pyrimidin-4- yl)amino)-5-ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-(2-methoxyethyl)-lH-pyr azol-4-yl)pyrimidin-4- yl)amino)-5-ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-ethyl-lH-pyrazol-4-yl)p yrimidin-4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((6-( 1 -cyclobutyl- lH-pyrazol-4-yl)-2-(l -difluoroethyl)pyrimidin-4-yl)amino)- 5-ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-(2-morpholinoethyl)-lH- pyrazol-4-yl)pyrimidin-4- yl)amino)-5-ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-(methyl-d3)-lH-pyrazol- 4-yl)pyrimidin-4- yl)amino)-5-ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-(methoxy- d3)pyridin-2-yl)acetamide;

N-(5-(2-cyclopropoxyethoxy)-4-((2-(l,l-difluoroethyl)-6-m ethylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((4-methyltetrahydro- 2H-pyran-4-yl)methoxy)pyridin-2-yl)acetamide;

(S)-N-(5-(2-(tert-butoxy)propoxy)-4-((2-(l,l-difluoroethy l)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((3-ethylisoxazol-5- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2 -methyl oxazol-5- yl)methoxy)pyridin-2-yl)acetamide;

(R)-N-(5-(2-(tert-butoxy)propoxy)-4-((2-(l,l-difluoroethy l)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((3-methoxyisoxazol- 5-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(isothiazol-3- ylmethoxy)pyridin-2-yl)acetamide;

N-(5-((3 -oxabicyclo[3.1.1 ]heptan- 1 -yl)methoxy)-4-((2-(l , 1 -difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((4-methyloxazol-2- yl)methoxy)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -((l- (methoxymethyl)cyclopropyl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((5-ethyloxazol-2- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-(2-fluoropyri din-3 - yl)ethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((5-methylthiazol-4- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((4,6- dimethylpyrimidin-5-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-ethyl- 1,2,4- oxadiazol-5-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(((lr,3r)-3- fluorocyclobutyl)methoxy)pyridin-2-yl)acetamide;

N-(5-((5-cyanofuran-2-yl)methoxy)-4-((2-(l,l-difluoroethy l)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((4-methylthiazol-5- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((3-methylisoxazol-4- yl)methoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(3- fluorobutoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((4- methoxytetrahydro-2H-pyran-4-yl)methoxy)pyridin-2-yl)acetami de;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((4,5-dimethyloxazol- 2-yl)methoxy)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(3- fluorobutoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((4-

(fluoromethyl)tetrahydro-2H-pyran-4-yl)methoxy)pyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((5-methyloxazol-2- yl)methoxy)pyridin-2-yl)acetamide;

N-(5-((5-cyclopropyloxazol-2-yl)methoxy)-4-((2-(l,l-diflu oroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide; N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methyl- 1,2,4- thiadiazol-5-yl)methoxy)pyridin-2-yl)acetamide;

N-(5-((2-cyclopropyloxazol-5-yl)methoxy)-4-((2-(l,l-diflu oroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((4- methoxypyrimidin-2-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((6- methoxypyrimidin-4-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(((ls,4s)-4-methyl-2- oxabicyclo[2.2.2]octan-l-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-(pyridin-2- ylmethoxy)pyridin-2-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-((3,4- difluorobenzyl)oxy)pyridin-2-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-((lr,3r)-3- methoxycyclobutoxy)pyridin-2-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-((ls,3s)-3- methoxycyclobutoxy)pyridin-2-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-((lr,3r)-3- fluorocyclobutoxy)pyridin-2-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-((ls,3s)-3- fluorocyclobutoxy)pyridin-2-yl)acetamide;

N-(5-((l-cyclobutyl-lH-pyrazol-4-yl)methoxy)-4-((2-(l,l-d ifluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(pyridin-3- ylmethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((5-methoxypyrazin-2- yl)oxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((6-methoxypyrazin-2- yl)oxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((6-methoxypyridazin- 3-yl)oxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((2-

(trifluoromethyl)pyrimidin-4-yl)oxy)pyridin-2-yl)acetamid e; methyl (4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyri din-2 - yl)carbamate;

N-(4-((2-(l,l-difluoroethyl)-6-(l-isopropyl-lH-pyrazol-4- yl)pyrimidin-4-yl)amino)- 5-(ethoxy-d5)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-(ethoxy-d5)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-isopropyl-lH-pyrazol-4- yl)pyrimidin-4-yl)amino)- 5-methoxypyridin-2-yl)acetamide;

N-(4-((2-( 1 , 1 -difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(ethoxy- 1,1- d2)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-(pyridin-2- ylmethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-isopropyl-lH-pyrazol-4- yl)pyrimidin-4-yl)amino)- 5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-(5-methylpyri din-3 -yl)pyrimidin-4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-(6-ethylpyri din-3 -yl)pyrimidin-4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(6-methoxypyridin-3-yl)pyr imidin-4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(5-methoxypyridin-3-yl)pyr imidin-4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-isobutyl-lH-pyrazol-4-y l)pyrimidin-4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((6-chloro-2-(l,l -difluoroethyl )pyrimidin-4-yl)amino)-5-ethoxypyri din-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(3-fluoropyridin-4-yl)pyri midin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((6-(l -cyclobutyl- lH-pyrazol-4-yl)-2-( 1,1 -difluoroethyl)pyrimidin-4-yl)amino)- 5-methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-(difluoromethyl)-lH-pyr azol-4-yl)pyrimidin-4- yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((6-( 1 -cyclopropyl- lH-pyrazol-4-yl)-2-( 1 , 1 -difluoroethyl )pyrimidin-4- yl)amino)-5-methoxypyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-(l-(oxetan-3-yl)-lH-pyrazol-4 -yl)pyrimidin-4- yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((6-(l -(cyclopropylmethyl)- lH-pyrazol-4-yl)-2-( 1,1 -difluoroethyl)pyrimidin-4- yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((2-( 1,1 -difluoroethyl)-6-(l-(2-morpholinoethyl)-lH-pyrazol -4-yl )pyrimidin-4- yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-(2-(dimethylamino)ethyl )-lH-pyrazol-4- yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((2-( 1,1 -difluoroethyl)-6-(l -(2,2, 2-trifluoroethyl)-lH-pyrazol -4-yl )pyrimidin-4- yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(pyridin-4-yl)pyrimidin-4- yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(5-fluoro-l-isopropyl-lH-p yrazol-4-yl)pyrimidin-4- yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-(5-fluoropyri din-2 -yl)pyrimidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(5-fluoro-lH-pyrazol-4-yl) pyrimidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-(2-methoxyethyl)-lH-pyr azol-4-yl)pyrimidin-4- yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(2-methylthiazol-5-yl)pyri midin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(pyridin-3-yl)pyrimidin-4- yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-(5-methylpyri din-3 -yl)pyrimidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-2'-morpholino-[4,5'-bipyrimi din]-6-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(6-methoxypyridin-3-yl)pyr imidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-isobutyl-lH-pyrazol-4-y l)pyrimidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((6-(4-cyanophenyl)-2-( 1 , 1 -difluoroethyl)pyrimidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide; N-(4-((6-(3-cyano-4-fluorophenyl)-2-(l, 1 -difluoroethyl )pyrimidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-methyl-3-(trifluorometh yl)-lH-pyrazol-4- yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(7-fluoro-2-methyl-2H-inda zol-5-yl)pyrimidin-4- yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(2,8-dimethyl-[l,2,4]triaz olo[l,5-a]pyridin-6- yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((2-( 1 , 1 -difluoroethyl)-6-(8-fluoro-2-methylimidazo[ 1 ,2-a]pyridin-6- yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((2-( 1 , 1 -difluoroethyl)-6-(2-methylimidazo[ 1 ,2-b]pyridazin-6-yl)pyrimidin-4- yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(2,7-dimethyl-2H-indazol-5 -yl)pyrimidin-4-yl)amino)- 5-methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(8-methoxy-2-methylimidazo [l,2-a]pyridin-6- yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((6-(8-cyano-2-methylimidazo[ 1 ,2-a]pyridin-6-yl)-2-(l , 1 - difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)ac etamide;

N-(4-((2-( 1 , 1 -difluoroethyl)-6-(2,8-dimethylimidazo[ 1 ,2-a]pyridin-6-yl)pyrimidin-4- yl)amino)-5-methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2- fluoroethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(3- fluoropropoxy)pyridin-2-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)ami no)-5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(2-fluoroethoxy)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-((lr,3r)-3- methoxycyclobutoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-((ls,3s)-3- methoxycyclobutoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-((lr,3r)-3- fluorocyclobutoxy)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino )-5-((ls,3s)-3- fluorocyclobutoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((ls,3s)-3- fluorocyclobutoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-((ls,3s)-3- fluorocyclobutoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(l-isopropyl-lH-pyrazol-4- yl)pyrimidin-4-yl)amino)- 5-((ls,3s)-3 -fluorocyclobutoxy )pyri din-2 -yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-(m ethoxy- d3)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(lH-pyrazol-4-yl)pyrimidin -4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

(R)-N-(4-((2-(l , 1 -difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -((3 - fluorotetrahydro-2H-pyran-3-yl)methoxy)pyridin-2-yl)acetamid e;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(((2S,6S)-6- methyltetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-yl)acetamid e;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((6,6-dimethyl- l,4-dioxan-2-yl)methoxy)pyridin-2-yl)acetamide;

(S)-N-(5-(2-cyclobutyl-2-fluoroethoxy)-4-((2-(l,l-difluor oethyl)-6-methylpyrimidin- 4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(((lr,4s)-l- (fluoromethyl)-2-oxabicyclo[2.1. l]hexan-4-yl)methoxy)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(spiro[2.2]pentan- l-ylmethoxy)pyridin-2-yl)acetamide;

N-(5-(((lr,4r)-7-oxabicyclo[2.2.1]heptan-l-yl)methoxy)-4- ((2-(l,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(2- methoxybutoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(((lS,2S)-2- fluorocyclopropyl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(((lS,2R)-2- fluorocyclopropyl)methoxy)pyridin-2-yl)acetamide;

(S)-N-(5-(2-(tert-butoxy)propoxy)-4-((2-(l,l-difluoroethy l)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(((lR,2S)-2- (fluoromethyl)cyclopropyl)methoxy)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(2-fluoro-3- methylbutoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((5,5-dimethyl- l,4-dioxan-2-yl)methoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((3- methyltetrahydrofuran-3-yl)methoxy)pyridin-2-yl)acetamide;

N-(5-(((lR,3R)-5-oxaspiro[2.4]heptan-l-yl)methoxy)-4-((2- (l,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

(R)-N-(5-((6-oxaspiro[3.4]octan-7-yl)methoxy)-4-((2-(l,l- difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(3-

(tetrahydrofuran-2-yl)propoxy)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((2- methyltetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-yl)acetamid e;

N-(5-methoxy-4-((4-methyl-6-(trifluoromethyl)pyrimidin-2- yl)amino)pyridin-2- yl)acetamide;

N-(4-((6-cyclopropoxy-2-(trifluoromethyl)pyrimidin-4-yl)a mino)-5-methoxypyridin- 2-yl)acetamide;

N-(5-methoxy-4-((4-methoxy-6-(trifluoromethyl)pyrimidin-2 -yl)amino)pyridin-2- yl)acetamide;

N-(4-((6-(2-fluoropropan-2-yl)pyrazin-2-yl)amino)-5-(2-me thoxyethoxy)pyridin-2- yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(3-methoxy-2- methylpropoxy)pyridin-2-yl)acetamide;

N-(4-((4-(2-fluoropropan-2-yl)-6-methylpyrimidin-2-yl)ami no)-5-(2- methoxyethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(((2R,6R)-6- methyltetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-yl)acetamid e;

(S)-N-(5-((5,8-dioxaspiro[3.5]nonan-6-yl)methoxy)-4-((2-( l,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(3- fluorobutoxy)pyridin-2-yl)acetamide; (S)-N-(5-((l,4-dioxan-2-yl)methoxy)-4-((6-cyclopropoxy-2-(l, l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(2-fluoropropan-2-yl)pyrimidin-4- yl)amino)-5-(2- methoxyethoxy)pyridin-2-yl)acetamide; methyl (4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl)amin o)-5-(2- (dimethylamino)ethoxy)pyridin-2-yl)carbamate;

N-(4-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(5-methoxy-4-((6-methyl-2-(l -methyl -2-oxabicyclo[2.1. l]hexan-4-yl)pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(5-methoxy-4-((2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)a mino)pyridin-2- yl)acetamide;

N-(5-methoxy-4-((6-methyl-2-(tetrahydrofuran-3-yl)pyrimid in-4-yl)amino)pyri din-2- yl)acetamide;

N-(5-methoxy-4-((2-methoxy-6-methylpyrimidin-4-yl)amino)p yridin-2-yl)acetamide;

(S)-N-(5-((l,4-dioxan-2-yl)methoxy)-4-((6-cyclopropoxy-2- (l,l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

(R)-N-(5-((l,4-dioxan-2-yl)methoxy)-4-((6-cyclopropoxy-2- (l,l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((6-cyclobutoxy-2-(l, 1 -difluoroethyl )pyrimidin-4-yl)amino)-5-methoxypyridin- 2-yl)acetamide;

N-(4-((6-((ls,3s)-3-cyanocyclobutoxy)-2-(l,l-difluoroethy l)pyrimidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-((lr,3r)-3-fluorocyclobuto xy)pyrimidin-4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-((ls,3s)-3-fluorocyclobuto xy)pyrimidin-4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((6-(3,3-difluorocyclobutoxy)-2-(l,l-difluoroethyl)p yrimidin-4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(4-((6-(3,3-difluorocyclobutoxy)-2-(l,l-difluoroethyl)p yrimidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-((ls,3s)-3-fluorocyclobuto xy)pyrimidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide; N-(4-((6-cyclobutoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl)ami no)-5-ethoxypyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-((ls,3s)-3-methylcyclobuto xy)pyrimidin-4-yl)amino)- 5-ethoxypyridin-2-yl)acetamide;

N-(4-((6-((ls,3s)-3-cyanocyclobutoxy)-2-(l,l-difluoroethy l)pyrimidin-4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(5-((3,3-difluorocyclobutyl)methoxy)-4-((2-(l,l-difluor oethyl)-6-methylpyrimidin- 4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((3- fluorobenzyl)oxy)pyridin-2-yl)acetamide;

N-(5-((3,4-difluorobenzyl)oxy)-4-((2-(l,l-difluoroethyl)- 6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((2- methoxybenzyl)oxy)pyri din-2 -yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((2-methylpyridin-3- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((4-methylpyridin-3- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((3-methylpyridin-2- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((3-methoxypyridin-2- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(pyridin-4- ylmethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((5-fluoropyridin-3- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((l -methyl- 1H- pyrazol-3-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-(pyridin-2- yl)ethoxy)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((tetrahydrofuran- 3-yl)oxy)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((l- methylpyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide; (R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5-((l- methylpyrrolidin-2-yl)methoxy)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((l- methylpyrrolidin-3-yl)methoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((tetrahydrofuran- 2-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2- isopropoxyethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((3-fluorooxetan-3- yl)methoxy)pyridin-2-yl)acetamide;

N-(5-(benzo[d][l,3]dioxol-5-ylmethoxy)-4-((2-(l,l-difluor oethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(methylamino)pyrimidin-4-y l)amino)-5-ethoxypyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-hydroxypyridin-2- yl)acetamide;

N-(5-(benzyloxy)-4-((6-cyclopropoxy-2-(l,l-difluoroethyl) pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((6-(cyclobutylamino)-2-(l,l-difluoroethyl)pyrimidin -4-yl)amino)-5-(ethoxy- d5)pyridin-2-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-(ethoxy- d5)pyridin-2-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-ethoxypyridin- 2-yl)acetamide;

N-(5-ethoxy-4-((6-methoxy-5-(l -methyl- lH-pyrazol-3-yl)pyri din-2-yl)amino)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-methoxy-2- methylpropoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((l- methoxycyclobutyl)methoxy)pyridin-2-yl)acetamide;

(S)-N-(5-((l-cyclopropylpyrrolidin-3-yl)methoxy)-4-((2-(l ,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(isoxazol-3- ylmethoxy)pyridin-2-yl)acetamide; N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((l -methyl- 1H- imidazol-2-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((5-methylisoxazol-3- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methyl- 1,2,4- oxadiazol-3-yl)methoxy)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((5- oxotetrahydrofuran-2-yl)methoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((5-oxopyrrolidin- 2-yl)methoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(2-(l- methylpyrrolidin-2-yl)ethoxy)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((5-oxopyrrolidin-

2-yl)methoxy)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((4- isopropylmorpholin-2-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(isoxazol-4- ylmethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(oxazol-4- ylmethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((l-methylazeti din-3- yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2- ethoxyethoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((l -methyl- 1H- pyrazol-4-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((l -ethyl- IH-pyrazol- 4-yl)methoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((l-isopropyl-5- oxopyrrolidin-3-yl)methoxy)pyridin-2-yl)acetamide;

(S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-((l-methyl-5- oxopyrrolidin-3-yl)methoxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((3-methoxy-l- methyl-lH-pyrazol-4-yl)methoxy)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(((lR,3S)-3- methoxycyclopentyl)oxy)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(((ls,4s)-4-methyl-2- oxabicyclo[2.1. l]hexan-l -yl)methoxy)pyri din-2 -yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(ethoxy-d5)pyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoropropyl)-6-methylpyrimidin-4-yl)amin o)-5-ethoxypyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-5-methoxypyrimidin-4-yl)amin o)-5-ethoxypyridin-2- yl)acetamide;

(R)-N-(4-((2-(2,2-dimethylcyclopropyl)-6-methylpyrimidin- 4-yl)amino)-5- ethoxypyridin-2-yl)acetamide;

N-(5-ethoxy-4-((6-((lr,3r)-3-methoxycyclobutoxy)-2-methyl pyrimidin-4- yl)amino)pyridin-2-yl)acetamide; l-(5-cyano-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl )amino)-[2,3'-bipyridin]- 6 ' -y 1 ) -3 -methylurea;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(4-methyl-l,3,5-triazin- 2-yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5-(2-methoxy ethoxy)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2 -methoxy ethoxy)-[2, 3'- bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5-

((difluoromethoxy)methyl)-[2,3'-bipyridin]-6'-yl)acetamid e;

N-(5-cyano-4'-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)- [2,3'-bipyridin]-6'- yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(6-meth oxypyridazin-3-yl)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-me thoxypyridazin-3- yl)pyridin-2-yl)acetamide-2,2,2-d3;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6,7-dihydro-4H- pyrazolo[5,l-c][l,4]oxazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6,7- dihydro-4H-pyrazolo[5,l- c] [ 1 ,4]oxazin-2-yl)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazin-2-yl)-4-((2- (2-fluoropropan-2-yl)- 6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(5-(5,6-dihydro-8H-imidazo[2,l-c][l,4]oxazin-2-yl)-4-(( 2-(2-fluoropropan-2-yl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(5-([l,2,4]triazolo[4,3-a]pyrazin-6-yl)-4-((2-(2-fluoro propan-2-yl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)ami no)-5-(imidazo[l,2- a]pyrimidin-7-yl)pyridin-2-yl)acetamide;

N-(5-([l, 2, 4]tri azolof l,5-a]pyrimidin-5-yl)-4-((2-(2-fluoropropan-2-yl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6,7-dihydro-5H- pyrazolo[5,l-b][l,3]oxazin-3-yl)pyridin-2-yl)acetamide;

N-(5-([ 1 , 2, 4]tri azolof 1 ,5-a]pyrimidin-5-yl)-4-((2-( 1 , 1 -difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(5-([ 1 , 2, 4] tri azolof 1 ,5-a]pyrimidin-5-yl)-4-((2-( 1 , 1 -difluoroethyl)pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)ami no)-5-(pyrazolo[l,5- a]pyrimidin-5-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(pyra zolo[l,5-a]pyrimidin-5- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(pyrazolo[l,5- a]pyrimidin-5-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-methyl -4-oxo-

4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-y l)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(l -(ethyl sulfonyl)- 1H- pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5-(methylsulfonyl)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(4-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(5-ethyl-

4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-y l)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-(methyl-d3)-

4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-y l)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6- (difluoromethyl)pyridazin-3-yl)pyridin-2-yl)acetamide; (R)-N-(4-((6-methyl-2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)a mino)-5-(5-methyl- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)a cetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(5,6-dimethyl- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)a cetamide;

N-(4-((2-(2-methoxyethoxy)pyrimidin-4-yl)amino)-5-(l -methyl- lH-pyrazol-3- yl)pyridin-2-yl)acetamide;

N-(4-((4-(2-methoxyethoxy)pyrimidin-2-yl)amino)-5-(l -methyl- lH-pyrazol-3- yl)pyridin-2-yl)acetamide;

N-(4-((2-methoxy-6-methylpyrimidin-4-yl)amino)-5-(l-methy l-lH-pyrazol-3- yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(l- methyl-lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((4-methoxypyrimi din-2 -yl)amino)-5-(l -methyl- lH-pyrazol-3-yl)pyri din-2- yl)acetamide;

N-(5-(l -methyl-lH-pyrazol-3-yl)-4-((6-methyl -2-(l -methyl -2- oxabicyclo[2.1. l]hexan-4-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(5-(l-methyl-lH-pyrazol-3-yl)-4-((6-methyl-2-(tetrahydr ofuran-3-yl)pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(5-(l-methyl-lH-pyrazol-3-yl)-4-((2-(tetrahydrofuran-3- yl)pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(2-oxabicyclo[2.2.1]heptan-4-yl)-6-methylpyrimid in-4-yl)amino)-5-(l- methyl-lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l-fluorocyclopropyl)-6-methylpyrimidin-4-yl)ami no)-5-(l-methyl-lH- pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-methoxyethoxy)-6-methylpyrimidin-4-yl)amino)- 5-(l-methyl-lH- pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-((ls,4s)-l-(fluoromethyl)-2-oxabicyclo[2.1.1]hex an-4-yl)-6- methylpyrimidin-4-yl)amino)-5-(l -methyl- lH-pyrazol-3-yl)pyri din-2 -yl)acetamide;

N-(4-((2-(l-(methoxymethyl)-2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4- yl)amino)-5-(l-methyl-lH-pyrazol-3-yl)pyridin-2-yl)acetamide ;

N-(4-((2-(2-oxabicyclo[2.1.1]hexan-l-yl)-6-methylpyrimidi n-4-yl)amino)-5-(l- methyl-lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(2,2- dimethyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)pyridin -2-yl)acetamide; N-(4-((2-(2-oxabicyclo[2.1.l]hexan-4-yl)-6-methylpyrimidin-4 -yl)amino)-5-(5,5- difluoro-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-2-yl)pyridin-2 -yl)acetamide;

N-(4'-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5- (methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-ethylpyrimidin-4-yl)amino)-5- (methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(5-(methoxymethyl)-4'-((2-(tetrahydrofuran-3-yl)pyrimid in-4-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide;

N-(5-(methoxymethyl)-4'-((6-methyl-2-(tetrahydrofuran-3-y l)pyrimidin-4-yl)amino)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((6-ethyl-2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)am ino)-5-(methoxymethyl)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(5-(methoxymethyl)-4'-((6-(methoxymethyl)-2-(tetrahydro furan-3-yl)pyrimidin-4- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(5-(methoxymethyl)-4'-((6-methyl-2-(tetrahydro-2H-pyran -3-yl)pyrimidin-4- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5- (difluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6,7- dihydro-4H-pyrano[4,3- d]thiazol-2-yl)pyridin-2-yl)acetamide;

N-(4'-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5- morpholino-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(2-oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimid in-4-yl)amino)-5-(l- methoxyethyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-4- (difluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(2-oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimid in-4-yl)amino)-5-(l- fluoroethyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-methyloxazol-4- yl)pyridin-2-yl)acetamide;

N-(5-(l-cyclobutyl-lH-pyrazol-4-yl)-4-((2-(l,l-difluoroet hyl)pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-fluo ro-[2,3'-bipyridin]-6'- yl)acetamide; N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methy loxazol-4-yl)pyri din-2- yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-5-fluoro-[2,3'-bipyridin]- 6'-yl)acetamide;

N-(5-cyano-4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4- yl)amino)-[2,3'-bipyridin]- 6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(2-methyloxazol-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin -4-yl)amino)-5- (pyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(5-fluoro-4'-((6-methoxypyrazin-2-yl)amino)-[2,3'-bipyr idin]-6'-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-(2-(2- methoxyethyl)-2H- 1,2, 3 -tri azol -4-yl)pyri din-2 -yl)acetamide;

N-(4'-((6-(difluoromethoxy)pyrazin-2-yl)amino)-5-(methoxy methyl)-[2,3'-bipyridin]- 6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-5-methoxypyrimidin-4-yl)ami no)-5-(methoxymethyl)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-5-methoxypyrimidin-4-yl)amino)-5-(l -methyl- 1H- pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-[2,3'-bipyridin]-6'- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-methyloxazol-2- yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5-methyl-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5-fluoro-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-methylpyrimidin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(oxazol -4-yl )pyri din- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(3-methyl-lH-pyrazol- l-yl)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(5-fluoropyrazin-2- yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5-methoxy-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-methyloxazol-5- yl)pyridin-2-yl)acetamide;

N-(5-(2-cyano-l -methyl- IH-imidazol -4-yl)-4-((2-(l, 1 -difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(5-(l-cyclopropyl-lH-pyrazol-3-yl)-4-((2-(l,l-difluoroe thyl)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(l -isopropyl- 1H- pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(5-(l-cyclobutyl-lH-pyrazol-4-yl)-4-((2-(l,l-difluoroet hyl)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(thiazol-2-yl)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-methylthiazol-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-methyl-lH-l,2,3- triazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-(methoxymethyl)- 2H-l,2,3-triazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l -difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methoxy-l -methyl- lH-l,2,4-triazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-isopropyl-2H-l,2,3- triazol-4-yl)pyridin-2-yl)acetamide;

N-(5-(5-(tert-butyl)- 1 ,3 ,4-thiadiazol-2-yl)-4-((2-( 1 , 1 -difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-isopropylthiazol-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-ethyl-lH-pyrazol-3- yl)pyridin-2-yl)acetamide;

N-(5-(l-(cyclopropylmethyl)-lH-pyrazol-3-yl)-4-((2-(l,l-d ifluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide; N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(l -propyl- IH-pyrazol- 3 -yl)pyridin-2-yl)acetami de;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-fluoro-l -methyl- lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-methoxythiazol-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(3-methyl-l,2,4- thiadiazol-5-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l,5-dimethyl-lH- pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(pyrazin-2-yl)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-methoxy-6- methylpyrimidin-2-yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-6-fluoro-5-methoxy-

[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-6-fluoro-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-4-fluoro-[2,3'- bipyridin]-6'-yl)acetamide;

N-(6'-bromo-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4 -yl)amino)-[3,3'- bipyridin]-6-yl)acetamide;

N-(5-bromo-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4 -yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-4-(dimethylamino)-

[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-6-morpholino-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2- (dimethylamino)pyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(6-cyano-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4 -yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4-cyano-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4 -yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; N-(5-cyano-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl )amino)-3-fluoro-[2,3'- bipyridin]-6'-yl)acetamide;

N-(6-cyano-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4 -yl)amino)-5-fluoro-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5-(methoxymethyl)-

[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-6-methoxy-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-6-(methoxymethyl)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5,6-dimethoxy-[2,3'- bipyridin]-6'-yl)acetamide;

(S)-N-(4'-((2-(l -difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(l -hydroxyethyl)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-6-(tetrahydrofuran-2- yl)-[2,3'-bipyridin]-6'-yl)acetamide;

(S)-N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl) amino)-6-(4- methylmorpholin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide;

(S)-N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl) amino)-6-(4- methylmorpholin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide;

(R)-N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl) amino)-6-(4- methylmorpholin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide;

(R)-N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl) amino)-5-(4- methylmorpholin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide;

(S)-N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl) amino)-5-(4- methylmorpholin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide;

(R)-N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl) amino)-5-(4- methylmorpholin-3-yl)-[2,3'-bipyridin]-6'-yl)acetamide;

(S)-N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl) amino)-5-(4- methylmorpholin-3-yl)-[2,3'-bipyridin]-6'-yl)acetamide;

(S)-N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl) amino)-6-(tetrahydro-2H- pyran-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5- ((dimethylamino)methyl)-[2,3'-bipyridin]-6'-yl)acetamide; N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)- 5-(morpholinomethyl)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-6-(morpholinomethyl)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5-(4-methylpiperazin-l- yl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5-(dimethylamino)-

[2,3'-bipyridin]-6'-yl)acetamide;

N-(6-(2-cyanopropan-2-yl)-4'-((2-(l,l-difluoroethyl)pyrim idin-4-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide;

N-(6-(2-cyanopropan-2-yl)-4'-((2-(l,l-difluoroethyl)-6-me thylpyrimidin-4-yl)amino)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(5-(5-cyanopyrimidin-2-yl)-4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-methoxypyrimidin- 2-yl)pyridin-2-yl)acetamide;

N-(5-(4-cyano-6-methylpyrimidin-2-yl)-4-((2-(l,l-difluoro ethyl)-6-methylpyrimidin- 4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-methoxypyrimidin- 2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-fluoro-4- methoxypyrimidin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5- (difluoromethoxy)pyrimidin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2- (methoxymethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5- ((difluoromethoxy)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide ;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-methoxy-5- methylpyrimidin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-(2- methoxyethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6- (methoxymethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide; N-(5-(4-cyclopropylpyrimidin-2-yl)-4-((2-(l,l-difluoroethyl) -6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(5-(6-cyclopropylpyrazin-2-yl)-4-((2-(l,l-difluoroethyl )-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(pyrimidin-2- yl)pyridin-2-yl)acetamide;

N-(5-(5-chloropyrimidin-2-yl)-4-((2-(l,l-difluoroethyl)-6 -methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5- (difluoromethyl)pyrimidin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-methylpyrimidin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5- (methoxymethyl)pyrimidin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-fluoro-4- methylpyrimidin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4- morpholinopyrimidin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6- ((dimethylamino)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-methoxypyridazin- 3 -yl)pyridin-2-yl)acetami de;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-oxo-6,7-dihydro- 5H-cyclopenta[b]pyridin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5,7-dihydrofuro[3,4- d]pyrimidin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(7,8-dihydro-5H- pyrano[4,3-b]pyridin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-( 1 , 1 -difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(imidazo[ 1 ,2- b]pyridazin-6-yl)pyridin-2-yl)acetamide;

N-(4-((2-( 1 , 1 -difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(imidazo[ 1 ,2- a]pyrazin-6-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(7-oxo-5,7- dihydrofuro[3,4-d]pyrimidin-2-yl)pyridin-2-yl)acetamide; (R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5-(4,5-dimethyl- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)a cetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-methyl-5,6- dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)pyridin-2-yl)acetamide ;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(pyri midin-2-yl)pyri din-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5,6- dimethoxypyrazin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2,6- dimethoxypyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(5-(6-(cyanomethyl)pyrazin-2-yl)-4-((2-(l,l-difluoroeth yl)pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(d ifluoromethoxy)pyrazin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(o xetan-3-yloxy)pyrazin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(2 -methoxyethoxy)pyrazin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-

((difluoromethoxy)methyl)pyrazin-2-yl)pyridin-2-yl)acetam ide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-me thylpyrazin-2-yl)pyridin- 2-yl)acetamide;

N-(5-(5-cyclopropylpyrazin-2-yl)-4-((2-(l, 1 -difluoroethyl )pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(5-(5-(l,l -difluoroethyl )pyrazin-2-yl)-4-((2-(l,l -difluoroethyl )pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(m ethoxymethyl)pyrimidin-

4-yl)pyridin-2-yl)acetamide;

N-(5-(5-chloropyrimidin-2-yl)-4-((2-(l,l-difluoroethyl)py rimidin-4-yl)amino)pyridin- 2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-3-fluo ro-[2,3'-bipyridin]-6'- yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-fluo ro-4-methoxy-[2,3'- bipyridin]-6'-yl)acetamide; N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-4-methyl- [2,3'-bipyridin]-6'- yl)acetamide;

N-(5-cyano-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino )-4-methyl-[2,3'- bipyridin]-6'-yl)acetamide;

N-(5-((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)-4'-(( 2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)a cetamide;

N-(5-((2-oxa-6-azaspiro[3.4]octan-6-yl)methyl)-4'-((2-(l, l-difluoroethyl)pyrimidin-4- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(5-(l-(cyclopropylmethyl)-lH-pyrazol-3-yl)-4-((2-(l,l-d ifluoroethyl)pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(l-pr opyl-lH-pyrazol-3- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)pyrimidin-4-yl)amino)-5-(l -ethyl- lH-pyrazol-3- yl)pyridin-2-yl)acetamide;

N-(5-(2-cyano-l -methyl- lH-imidazol-4-yl)-4-((2-(l,l-difluoroethyl)pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2 -isopropyl -2H-1, 2, 3 -tri azol-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-et hyl-2H-l,2,3-triazol-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(2 -methoxyethyl)-2H-l,2,3- triazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(m ethoxymethyl)-2H-l,2,3- triazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-me thoxythiazol-4-yl)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(2 -fluoropropan-2-yl)thiazol-

4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-et hyl-l,3,4-thiadiazol-2- yl)pyridin-2-yl)acetamide;

N-(5-(5-(tert-butyl)- 1 ,3 ,4-thiadiazol-2-yl)-4-((2-( 1 , 1 -difluoroethyl )pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(3-me thyl-l,2,4-thiadiazol-5- yl)pyridin-2-yl)acetamide; N-(5-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)-4-((2-(l,l-difluor oethyl)pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-ox o-6,7-dihydro-5H- cyclopenta[b]pyridin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(pyrimidin-2-yl)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(2- (methoxymethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5-methyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide ;

N-(4'-((5-(2-fluoropropan-2-yl)pyridin-3-yl)amino)-5-(2-h ydroxypropan-2-yl)-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)ami no)-5-(5-fluoropyrimidin- 2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5- (dimethylamino)pyridin-2-yl)acetamide;

N-(4-((2-( 1 , 1 -difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrrolidin- 1 - yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-morpholinopyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-me thyl-lH-pyrazol-l- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-methyl-lH-pyrazol- l-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-me thoxy-lH-pyrazol-l- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-methoxy-lH- pyrazol-l-yl)pyridin-2-yl)acetamide;

N-(5-(4-cyano-lH-pyrazol-l-yl)-4-((2-(l,l-difluoroethyl)p yrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(5-(4-cyano-lH-pyrazol-l-yl)-4-((2-(l,l-difluoroethyl)- 6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide; N-(4-((2-( l, l -difluoroethyl )pyrimidin-4-yl )ami no)-5-(3-methyl- l H-l, 2, 4-triazol- l- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(3-methyl-lH-l,2,4- triazol-l-yl)pyridin-2-yl)acetamide;

N-(5-(5-(cyanomethyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]py razin-2-yl)-4-((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5- ((dimethylamino)methyl)thiazol-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-(pyrrolidin-l- ylmethyl)thiazol-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-methyl-5- (morpholinomethyl)-lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-4-

((dimethylamino)methyl)-[2,3'-bipyridin]-6'-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(5-(l- (dimethylamino)ethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(5-(l-(pyrrolidin- l-yl)ethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

(S)-N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl) amino)-4-(l- (dimethylamino)ethyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l,3,4-thiadiazol-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-(2- methoxyethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(6- methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(2- methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5- (pyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(6- methoxypyridazin-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(6- methoxypyrimidin-4-yl)pyridin-2-yl)acetamide; N-(4'-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-cyano- [2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-fluoro- [2,3'-bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-methoxypyridazin- 3 -yl)pyridin-2-yl)acetami de;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-(2-methoxyethyl)- l,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-(methoxymethyl)-

1.3.4-thiadiazol-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-(2- methoxyethyl)thiazol-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-(methoxymethyl)- 1 -methyl- lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-(2-methoxypropan- 2-yl)-l-methyl-lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(7-methyl-5,6,7,8- tetrahydro-[ 1 , 2, 4]tri azolof 1 ,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5,6-dihydro-8H- [ 1 ,2,4]triazolo[5, 1 -c] [ 1 ,4]oxazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(isothiazol-3- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(3-(methoxymethyl)-

1.2.4-thiadiazol-5-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-(dimethylamino)-

1.2.4-thiadiazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-(2-methoxyethyl)- IH-pyrazol- 1 -yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-(methoxymethyl)- IH-pyrazol- 1 -yl)pyridin-2-yl)acetamide;

N-(5-(6-cyanopyrazin-2-yl)-4-((2-(l,l-difluoroethyl)pyrim idin-4-yl)amino)pyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(d ifluoromethoxy)pyrimidin- 4-yl)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(5,6-dihydro-8H- imidazo[2, 1 -c] [ 1 ,4]oxazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6,7-dihydro-5H- pyrrolof 1 ,2-a]imidazol-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-( 1 , 1 -difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2,3 - dihydroimidazo[2,l-b]oxazol-6-yl)pyri din-2 -yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-(4-methylpiperazin- l-yl)thiazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-((2- methoxyethyl)(methyl)amino)thiazol-4-yl)pyridin-2-yl)acetami de;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(( 2- methoxyethyl)(methyl)amino)-l,3,4-thiadiazol-2-yl)pyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(4 -methylpiperazin-l-yl)- l,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(d ifluoromethyl)pyrimidin-4- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-(2- methoxyethoxy)pyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-(2- methoxyethoxy)pyrimidin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(2 -morpholinoethyl)-2H- l,2,3-triazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(2 -(4-methylpiperazin-l- yl)ethyl)-2H-l,2,3-triazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5,6, 7,8-tetrahydroimidazo[l,2- a]pyridin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(m ethoxymethyl)thiazol-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5- ((dimethylamino)methyl)thiazol-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-((4- methylpiperazin-l-yl)methyl)thiazol-2-yl)pyridin-2-yl)acetam ide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4-

((dimethylamino)methyl)thiazol-2-yl)pyridin-2-yl)acetamid e; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(4-((4- methylpiperazin-l-yl)methyl)thiazol-2-yl)pyridin-2-yl)acetam ide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2- ((dimethylamino)methyl)thiazol-4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-((4- methylpiperazin-l-yl)methyl)thiazol-4-yl)pyridin-2-yl)acetam ide;

N-(5-(2-(azetidin-l-yl)thiazol-4-yl)-4-((2-(l,l-difluoroe thyl)pyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(5-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazol-4-yl)-4 -((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(5-(2-cyanothiazol-4-yl)-4-((2-(l,l-difluoroethyl)pyrim idin-4-yl)amino)pyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-(pyrrolidin-l- ylmethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-((4- methylpiperazin-l-yl)methyl)pyrazin-2-yl)pyridin-2-yl)acetam ide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5- (morpholinomethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

1 -(4-((2-(l , 1 -difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methyl-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)-3-methyl urea;

1 -(4-((2-(l , 1 -difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methyl-4, 5,6,7- tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyridin-2-yl)-3-methyl urea;

N-(4-((2-(l, l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methyl-4, 5,6,7- tetrahydrothiazolo[4,5-c]pyridin-2-yl)pyridin-2-yl)formamide ;

N-(4-((2-(l, l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methyl-4, 5,6,7- tetrahydrothiazolo[4,5-c]pyridin-2-yl)pyridin-2-yl)acetamide ;

N-(4-((2-(l, l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methyl-4, 5,6,7- tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyridin-2-yl)acetamide ;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(pyrimidin-4-yl)pyridin- 2-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)ami no)-5-(pyrimi din-4- yl)pyridin-2-yl)acetamide;

N-(4-((6-ethyl-2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amin o)-5-(pyrimidin-4- yl)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(5-(2- (dimethylamino)propan-2-yl)-l-methyl-lH-pyrazol-3-yl)pyridin -2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-methyl-5-

(pyrrolidin-l-ylmethyl)-lH-pyrazol-3-yl)pyridin-2-yl)acet amide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-methyl-5-((4- methylpiperazin-l-yl)methyl)-lH-pyrazol-3-yl)pyridin-2-yl)ac etamide;

N-(4'-((2-( 1 , 1 -difluoroethyl)-6-methylpyrimidin-4-yl)amino)-4-(pyrrolidin- 1 - ylmethyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-4-(morpholinomethyl)-

[2,3'-bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-

((dimethylamino)methyl)pyrazin-2-yl)pyridin-2-yl)acetamid e;

N-(4-((2-(l,l-difluoroethyl)-6-methoxypyrimidin-4-yl)amin o)pyridin-2-yl)acetamide;

N-(4-((2-(l, l-difluoroethyl)-6-(2 -methoxy ethoxy)pyrimidin-4-yl)amino)pyridin-2- yl)acetamide;

N-(5-((lR,2S)-2-cyanocyclopropyl)-4-((2-(l,l-difluoroethy l)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-(difluoromethyl)- lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-methyl-lH-pyrazol-

4-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2,2-dimethyl-2,3- dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetami de;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-fluoro-l-methyl- lH-pyrazol-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-methoxypyrazin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-fluoropyridin-2- yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-fluoropyridin-2- yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-fluoropyridin-2- yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-(l-isopropyl-lH-pyrazol-4-yl) pyrimidin-4-yl)amino)- 5-fluoropyridin-2-yl)acetamide;

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(2,2-di methyl-2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(2,2-dimethyl-2,3- dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetami de;

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-(2,2-dimethyl-2,3- dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetami de;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(pyrazin-2-yl)pyri din-2- yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-(pyrazin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(d ifluoromethoxy)pyrimidin-

2-yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(dif luoromethoxy)-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5-(difluoromethyl)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-me thoxypyrazin-2-yl)pyridin- 2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5-methoxypyrazin-2- yl)pyridin-2-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-(5- methoxypyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(l-methyl-6-oxo-l,6- dihydropyridazin-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-(6- methoxypyridazin-3-yl)pyridin-2-yl)acetamide;

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-(6- methoxypyridazin-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5- (methoxymethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-5-(6- methoxypyridazin-3- yl)pyridin-2-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5- (5- (methoxymethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-(l,l- difluoroethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(5-(5-cyanopyrazin-2-yl)-4-((2-(l,l-difluoroethyl)-6-me thylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-5-(2-hydroxypropan-2- yl)-[2,3'-bipyridin]-6'-yl)acetamide;

(R)-N-(5-(5-(l,4-dioxan-2-yl)pyrimidin-2-yl)-4-((2-(l,l-d ifluoroethyl)-6- ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(d imethylamino)pyridazin-3- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(d imethylamino)pyrazin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(p yrrolidin-l-yl)pyrazin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-mo rpholinopyrazin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(p yrrolidin-l-yl)pyridazin-3- yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-5-(methoxymethyl)-[2,3'- bipyridin]-6'-yl)acetamide;

N-(5-(5-cyanopyrimidin-2-yl)-4-((2-(l,l-difluoroethyl)-6- ethylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5- (difluoromethoxy)pyrimidin-2-yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-5-(difluoromethoxy)-[2,3'- bipyridin]-6'-yl)acetamide;

N-(5-(5-cyanopyrazin-2-yl)-4-((2-(l,l-difluoroethyl)pyrim idin-4-yl)amino)pyridin-2- yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(met hoxymethyl)-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-h ydroxypropan-2-yl)-[2,3'- bipyridin]-6'-yl)acetamide; N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(2-hy droxypropan-2- yl)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(d ifluoromethoxy)pyrazin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5- (dimethylamino)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(met hylamino)-[2,3'-bipyridin]- 6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(d ifluoromethoxy)pyridazin- 3 -yl)pyridin-2-yl)acetami de;

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-5-(methylamino)-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5- (methylamino)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5-morpholinopyrazin-2- yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(6- (dimethylamino)pyridazin-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(6-morpholinopyridazin- 3 -yl)pyridin-2-yl)acetami de;

N-(5-(5-cyanopyrazin-2-yl)-4-((2-(l,l-difluoroethyl)-6-et hylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(l-methyl-6-oxo-l,6- dihydropyridazin-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(( 2- methoxyethyl)(methyl)amino)pyrazin-2-yl)pyridin-2-yl)acetami de;

(R)-N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-( 5-(3-methoxypyrrolidin-l- yl)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(3 -methoxy-3- methylazetidin-l-yl)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(5-(5-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrazin-2-yl)-4- ((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide; N-(5-(5-((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazi n-2-yl)-4-((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(5-(5-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyr azin-2-yl)-4-((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(5 -(5 -(6-oxa-2-azaspiro[3.4] octan-2-yl)pyrazin-2-yl)-4-((2-( 1 , 1 - difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

(R)-N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-( 6-(3-methoxypyrrolidin-l- yl)pyridazin-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(3 -methoxy-3- methylazetidin-l-yl)pyridazin-3-yl)pyridin-2-yl)acetamide;

N-(5-(6-(2-oxa-6-azaspiro[3.3 ]heptan-6-yl)pyridazin-3 -yl)-4-((2-( 1,1- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(5-(6-((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyr idazin-3-yl)-4-((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(5-(6-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3-yl)- 4-((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(pyr rolidin-l-ylmethyl)-[2,3'- bipyridin]-6'-yl)acetamide;

N-(4'-((2-( 1 , 1 -difluoroethyl)pyrimidin-4-yl)amino)-5-(((2- methoxyethyl)(methyl)amino)methyl)-[2,3'-bipyridin]-6'-yl)ac etamide;

(R)-N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5- ((3- methylmorpholino)methyl)-[2,3'-bipyridin]-6'-yl)acetamide;

(S)-N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5- ((3-methoxypyrrolidin-l- yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((3- methoxy-3-methylazetidin- l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(((t etrahydro-2H-pyran-4- yl)amino)methyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-4'-((2-(l ,l-difluoroethyl)pyrimidin- 4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(5-(((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methy l)-4'-((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)a cetamide;

N-(5-(((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methy l)-4'-((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)a cetamide; N-(5-(5-((lR,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyrazi n-2-yl)-4-((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(5-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazin-2-yl)-4 -((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(5-((6-oxa-2-azaspiro[3.4]octan-2-yl)methyl)-4'-((2-(l, l-difluoroethyl)pyrimidin-4- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(5-(6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyridazin-3-yl)- 4-((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(6- (difluoromethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

(S)-N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5- ((3- methylmorpholino)methyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5-(pyrrolidin-l- ylmethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(5-(5-(((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)me thyl)pyrazin-2-yl)-4-((2- (l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl )acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5- ((dimethylamino)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(2 -methoxypropan-2- yl)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(5-(6-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyr idazin-3-yl)-4-((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

(R)-N-(5-(5-(l,4-dioxan-2-yl)pyrazin-2-yl)-4-((2-(l,l-dif luoroethyl)-6- ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(5- (morpholinomethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

N-(5-(5-(((lR,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)me thyl)pyrazin-2-yl)-4-((2- (l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl )acetamide;

N-(4'-((2-( 1 , 1 -difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(pyrrolidin- 1 -ylmethyl)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(5-(((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methy l)-4'-((2-(l,l- difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-[2,3'-bipyridin] -6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(2-(pyrrolidin-l- ylmethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide; N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5 -fluoro-6-(pyrrolidin-l- ylmethyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(5-(6-(((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)me thyl)pyrimidin-4-yl)-4- ((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin- 2-yl)acetamide;

N-(6-(((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methy l)-4'-((2-(l,l- difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-b ipyridin]-6'-yl)acetamide;

N-(5-(2-(((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)me thyl)pyrimidin-4-yl)-4- ((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin- 2-yl)acetamide;

N-(6-(((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methy l)-4'-((2-(l,l- difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-b ipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(2- (morpholinomethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-5-fluoro-6-

(morpholinomethyl)-[2,3'-bipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-6- ((dimethylamino)methyl)-5-fluoro-[2,3'-bipyridin]-6'-yl)acet amide;

N-(5-(((lR,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methy l)-4'-((2-(l,l- difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-[2,3'-bipyridin] -6'-yl)acetamide;

N-(5-(2-(((lR,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)me thyl)pyrimidin-4-yl)-4- ((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin- 2-yl)acetamide;

N-(5-(6-(((lR,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)me thyl)pyrimidin-4-yl)-4- ((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin- 2-yl)acetamide;

N-(6-(((lR,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methy l)-4'-((2-(l,l- difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-b ipyridin]-6'-yl)acetamide;

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5-(dimethylphosphoryl)- [2,3'-bipyridin]-6'-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6- (dimethylphosphoryl)pyridazin-3-yl)pyridin-2-yl)acetamide;

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(2-methyl-2H-l,2,3- triazol-4-yl)pyridin-2-yl)acetamide; l-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5- (pyrazin-2-yl)pyri din-2- yl)-3 -methylurea; l-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5- (pyrazin-2-yl)pyri din-2- yl)urea; N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(5- (difluoromethyl)pyrazin-2-yl)pyridin-2-yl)acetamide; and

N-(5-(2-(cyanomethyl)thiazol-4-yl)-4-((2-(l,l -difluoroethyl )pyrimidin-4- yl)amino)pyridin-2-yl)acetamide; or a pharmaceutically acceptable salt thereof.

In a fifty-second embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g., according to the first aspect or any one of the preceding embodiments), or a pharmaceutically acceptable salt thereof.

The compounds and intermediates described herein may be isolated and used as the compound per se. Alternatively, when a moiety is present that is capable of forming a salt, the compound or intermediate may be isolated and used as its corresponding salt. As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound described herein. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds described herein and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids or organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandi sulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropyl amine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

The salts can be synthesized by conventional chemical methods from a compound containing a basic or acidic moiety. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Isotopically-labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagents in place of the non-labeled reagent previously employed. In one embodiment, the present disclosure provides deuterated compounds described herein or a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO.

It will be recognized by those skilled in the art that the compounds of the present invention may contain chiral centers and as such may exist in different stereoisomeric forms. As used herein, the term “an optical isomer” or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present disclosure. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the disclosure includes enantiomers, diastereomers or racemates of the compound.

“Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “racemic” or “rac” is used to designate a racemic mixture where appropriate. When designating the stereochemistry for the compounds of the present invention, a single stereoisomer with known relative and absolute configuration of the two chiral centers is designated using the conventional RS system (e.g., (1S,2S)). “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R- S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Alternatively, the resolved compounds can be defined by the respective retention times for the corresponding enantiomers/diastereomers via chiral HPLC.

Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

Unless specified otherwise, the compounds of the present disclosure are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns, such as CHIRALPAKRTM and CHIRALCELRTM available from DAICEL Corp, using the appropriate solvent or mixture of solvents to achieve good separation). If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

METHODS OF USE The compounds disclosed herein have TYK2 activity. As used herein, “TYK2 inhibitory activity” refers to the ability of a compound or composition to induce a detectable decrease in TYK2 activity in vivo or in vitro (e.g., at least 10% decrease in TYK2 activity as measured by a given assay such as the bioassay described in the examples and known in the art).

In certain embodiments, the present disclosure provides a method of treating a disease or disorder responsive to inhibition of TYK2 activity (referred herein as “TYK2 mediated disease or disorder” or “disease or disorder mediated by TYK2”) in a subject in need of the treatment. The method comprises administering to the subject a compound described herein (e.g., a compound of Formula (I) according to any one of embodiments ont to forty-two) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound of Formula (I) according to any one of embodiments ont to forty-two) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a TYK2 mediated disorder or disease in a subject in need of the treatment.

In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound of Formula (I) according to any one of embodiments ont to forty-two) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of a TYK2 mediated disorder or disease in a subject in need of the treatment.

In some embodiments, the disease or disorder responsive to inhibition of TYK2 activity is inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoisosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction , thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischaemia, reperfusion injury, brain edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration , glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infection, myalgia, endotoxic shock, toxic shock syndrome, autoimmune disease, osteoporosis, multiple sclerosis, endometriosis, menstrual cramps, vaginitis, candidiasis, cancer, fibrosis, systemic sclerosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis or sunburn.

In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a mammal. In certain embodiments, the subject is a primate. In certain embodiments, the subject is a human.

As used herein, an “effective amount” and a “therapeutically effective amount” can used interchangeably. It means an amount effective for treating or lessening the severity of one or more of the diseases, disorders or conditions as recited herein. In some embodiments, the effective dose can be between 10 pg and 500 mg.

The compounds and compositions, according to the methods of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases, disorders or conditions recited above.

In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered parenterally. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectally, intrathecally, topically or intranasally. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered systemically.

The compounds of the present invention can be used as a pharmaceutical composition (e.g., a compound of the present invention and at least one pharmaceutically acceptable carrier). As used herein, the term “pharmaceutically acceptable carrier” includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffering agents (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, and the like), and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. For purposes of this disclosure, solvates and hydrates are considered pharmaceutical compositions comprising a compound of the present invention and a solvent (i.e., solvate) or water (i.e., hydrate).

The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.

The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

The pharmaceutical composition comprising a compound of the present disclosure is generally formulated for use as a parenteral or oral administration or alternatively suppositories.

For example, the pharmaceutical oral compositions of the present disclosure can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methods known in the art.

Suitable compositions for oral administration include a compound of the disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

The parenteral compositions (e.g, intravenous (IV) formulation) are aqueous isotonic solutions or suspensions. The parenteral compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are generally prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1- 75%, or contain about 1-50%, of the active ingredient.

The compound of the present disclosure or pharmaceutical composition thereof for use in a subject (e.g., human) is typically administered orally or parenterally at a therapeutic dose. When administered intravenously via infusion, the dosage may depend upon the infusion rate at which an IV formulation is administered. In general, the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, pharmacist, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present invention can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10-3 molar and 10-9 molar concentrations.

DEFINITIONS

As used herein, a “patient,” “subject” or “individual” are used interchangeably and refer to either a human or non-human animal. The term includes mammals such as humans. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. Preferably, the subject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of any disease, condition or disorder, refers to the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of the present invention to obtaining desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, condition or disorder; ameliorating or improving a clinical symptom, complications or indicator associated with the disease, condition or disorder; or delaying, inhibiting or decreasing the likelihood of the progression of the disease, condition or disorder; or eliminating the disease, condition or disorder. In certain embodiments, the effect can be to prevent the onset of the symptoms or complications of the disease, condition or disorder. As used herein, the term “cancer” has the meaning normally accepted in the art. The term can broadly refer to abnormal cell growth.

As used herein, the term “autoimmune disease” has the meaning normally accepted the art. The term can broadly refer to a disease where the host’s immune system targets or attacks normal or healthy tissue of the host.

As used herein, the term “myelination” has the meaning normally accepted in the art. The term can broadly mean the process by which myelin is produced.

As used herein, the term “myelin-related disease or disorder”, “demyelinating disorder”, or “demyelation disorder” has the meaning normally accepted in the art. These terms can broadly refer to diseases or disorders which involve damage to myelin.

As used herein, a subject is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment (preferably, a human).

As used herein, the phrase “optionally substituted” is used interchangeably with the phrase “substituted or un substituted.” In general the term “optionally substituted” refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. In some embodiments, an optionally substituted group can be substituted with one or more substituents, each of which can the same or different. In some embodiments, the “one or more” substituents can be 1, 2, 3, 4, 5, 6, etc. substituents, each of which can the same or different. In some embodiment, the “one or more” substituents can be 1 to 6, 1 to 4, 1 to 3 or 1 to 2 substituents, each of which can the same or different. For the bicyclic heteroaryls and bicyclic, fused, spiro, or bridged heterocyclyls or carbocyclyls, the optional substituent can be on any or all of the rings. For example, when the bicyclic heteroaryl is depicted below, the substituent R ^3c can be on either the 6-membered ring or the 5-membered ring.

As used herein, the term “alkyl” refers to a fully saturated branched or unbranched hydrocarbon moiety. The term “Ci.4alkyl” refers to an alkyl having 1 to 4 carbon atoms. The terms “Ci-salkyl” and “Ci.2alkyl” are to be construed accordingly. Representative examples of “Ci-4alkyl” include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, secbutyl, iso-butyl, and tert-butyl. Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy have the same definition as above. When indicated as being “optionally substituted”, the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls).

As used herein, the term “alkoxy” refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e. a — O— Ci-4 alkyl group wherein Ci-4 alkyl is as defined herein). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy and the like. Preferably, alkoxy groups have about 1-4 carbons, more preferably about 1-2 carbons. The term “ Ci-2 alkoxy” is to be construed accordingly.

As used herein, the term “Ci-4 alkoxyCi-4 alkyl” refers to a Ci-4 allkyl group as defined herein, wherein at least of the hydrogen atoms is replaced by an Ci-4 alkoxy. The Ci- 4alkoxyCi-4 alkyl group is connected through the rest of the molecule described herein through the alkyl group.

The number of carbon atoms in a group is specified herein by the prefix “C _x -xx”, wherein x and xx are integers. For example, “C1.3 alkyl” is an alkyl group which has from 1 to 3 carbon atoms.

“Halogen” or “halo” may be fluorine, chlorine, bromine or iodine.

As used herein, the term “halo-substituted-Ci-4alkyl” or “ Ci.4haloalkyl” refers to a Ci-4alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom. The Ci.4haloalkyl group can be monohalo-Ci.4alkyl, dihalo-Ci.4alkyl or polyhalo- C1.4 alkyl including perhalo-Ci.4alkyl. A monohalo-Ci.4alkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihalo-Ci.4alkyl and polyhalo-Ci.4alkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically the polyhalo-Ci-4alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. Non-limiting examples of Ci.4haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and di chloropropyl. A perhalo-Ci.4alkyl group refers to a Ci.4alkyl group having all hydrogen atoms replaced with halo atoms. The term “aryl” refers to an aromatic carbocyclic single ring or two fused ring system containing 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

The term “heteroaryl” refers to a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. In some instances, nitrogen atoms in a heteroaryl may be quaternized. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, furanyl, oxadiazol yl, thiophenyl, and the like. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include pyrazolopyridinyl, pyrazolopyridinyl, benzotriazolyl, imidazopyridinyl, and indoyl.

The term “carbocyclic ring” or “carbocyclyl” refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring and may exist as a single ring, bicyclic ring (including fused, spiral or bridged carbocyclic rings) or a spiral ring. Bi-cyclic carbocyclyl groups include, e.g., unsaturated carbocyclic radicals fused to another unsaturated carbocyclic radical, cycloalkyl, or aryl, such as, for example, 2,3-dihydroindenyl, decahydronaphthal enyl, and 1,2,3,4-tetrahydronaphthalenyl. Unless specified otherwise, the carbocyclic ring generally contains 4- to 10- ring members.

The term “C3-6 cycloalkyl” refers to a carbocyclic ring which is fully saturated (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

The term “heterocycle” or “heterocyclyl” refers to a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. A heterocyclyl group may be mono- or bicyclic (e.g., a bridged, fused, or spiro bicyclic ring). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and piperdinyl. Bi-cyclic heterocyclyl groups include, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as, for example, tetrahydro-3H-[l,2,3]triazolo[4,5-c]pyridinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 5- oxabicyclo[2.1.1]hexanyl and 9-azabicyclo[3.3.1]nonanyl. In some embodiments, the heterocyclyl group is a 4 to 6 membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is a 4 to 6 membered monocyclic saturated heterocyclyl group. In some embodiments, the heterocyclyl group is a 8 to 10 membered bicyclic heterocyclyl group. In some embodiments, the heterocyclyl group is a 8 to 10 membered bicyclic saturated heterocyclyl group. As used herein the term “spiral” ring means a two-ring system wherein both rings share one common atom. Examples of spiral rings include, 2-oxa-6-azaspiro[3.3]heptanyl and the like.

The term “fused” ring refers to two ring systems share two adjacent ring atoms. Fused heterocycles have at least one the ring systems contain a ring atom that is a heteroatom selected from O, N and S (e.g., 3-oxabicyclo[3.1.0]hexane).

As used herein the term “bridged” refers to a 5 to 10 membered cyclic moiety connected at two non-adj acent ring atoms (e.g. 5-oxabicyclo[2.1.1]hexane).

The phrase “pharmaceutically acceptable” indicates that the substance, composition or dosage form must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

Unless specified otherwise, the term “compounds of the present disclosure” refers to compounds of Formula (I), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions). When a moiety is present that is capable of forming a salt, then salts are included as well, in particular pharmaceutically acceptable salts.

As used herein, the term “a,” “an,” “the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.

It is also possible that the intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

In one embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in free form. In another embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in salt form. In another embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in acid addition salt form. In a further embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in pharmaceutically acceptable salt form. In yet a further embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in pharmaceutically acceptable acid addition salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in free form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in acid addition salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in pharmaceutically acceptable salt form. In still another embodiment, the present disclosure relates to any one of the compounds of the Examples in pharmaceutically acceptable acid addition salt form.

Compounds of the present disclosure may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Sigma-Aldrich or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967- 1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.

According to a first process, compounds of Formula (I), may be prepared from compounds of Formulae (IF) and (III’), as shown in Scheme 1

Scheme 1

Hal ¹ is halogen, preferably Br or Cl.

The compound of Formula (I) may be prepared from the compounds of Formulae (IF) and (III’) according to process step (a) a Buchwald-Hartwig cross coupling reaction. Typical conditions comprise, reaction of the compound of Formula (IF) with the amine of Formula (IIF) in the presence of a suitable inorganic base, a suitable palladium catalyst in the presence of suitable phosphine ligands, in a suitable solvent at elevated temperature. Preferred conditions comprise, reaction of the compounds of Formulae (IF) and (III’) in the presence of Brettphos Pd G3, MolDalPhos Pd G3, Josiphos Pd G3, [XantPhos Pd(allyl)]Cl, or Xantphos or BINAP in combination with Pd(OAc)2 or Pd2(dba)3, or Xantphos in combination with Xantphos Pd G3, in the presence of a suitable base such as NaOtBu, CS2CO3, K2CO3 or K3PO4 in a suitable solvent such as dioxane, DMA, DMF or toluene at between 80°C and 120°C. According to a second process, compounds of Formula (I), may be prepared from compounds of Formulae (IV’) and (V’), as shown in Scheme 2

Scheme 2

Hal ² is halogen, preferably Br, Cl or I The compound of Formula (I) may be prepared from the compounds of Formulae (IV’) and (V’), according to process step (a), a Buchwald reaction, as previously described in Scheme 1.

According to a third process, the compound of Formula (I) may be prepared from the compounds of Formulae (IF), (VI’), (VIF), (VIII’), (IX’), and (XV’) as shown in Scheme 3.

Scheme 3

Hal ³ is a halogen, preferably Br or I

Hal ⁴ is a halogen, preferably Cl The compound of Formula (VIF) may be prepared from the compounds of Formulae

(VI’) and (IF) according to process step (b) an alkylation reaction, in the presence of a suitable inorganic base and a suitable aprotic polar solvent at between rt and elevated temperature. Preferred conditions, comprise reaction of the compound of Formula (VI’) with the compound of Formula (IF) in the presence of CS2CO3 or K2CO3 in DMF or THF at between rt and 35 °C. Alternatively, the compound of Formula (VIF) may be prepared from the compounds of Formulae (VI’) and Formula (IF), according to process step (a), a Buchwald reaction, as previously described in Scheme 1.

Wherein, R ² is a 4-to 11-membered monocyclic or bicyclic heterocyclic ring, Ci- ealkyl or C3-7cycloalkyl, the compound of Formula (VIII’) may be prepared from the compound of Formula (VIF) and R ² BPin or R ² B(OH)2 according to process step (c) a palladium catalysed, cross-coupling reaction, such as a Suzuki reaction. Typical crosscoupling reaction conditions comprise a palladium catalyst containing suitable phosphine ligands, in the presence of an inorganic base, in a suitable aqueous solvent at between rt and the reflux temperature of the reaction. Preferred conditions comprise, reaction of the compound of Formula (VIF) and R ² BPin, in the presence of SPhos-Pd-G3, Pd(PCy3)2,, Pd(PPh3)4, XPhos Pd(crotyl)Cl, Pd(dppf)C12, or Pd(OAc)2 and P(Cy)3 and a suitable base such as K3PO4, Na2CC>3, or K2CO3 in a suitable solvent such as aqueous dioxane, DME, EtOH, or 2-MeTHF at between 70°C and 100°C.

Wherein, R ² is -OR ^2A or -N(R ^2b )2,the compound of Formula (VIII’) may be prepared from the compound of Formula (VIF) and HOR ^2A or HN(R ^2b )2, according to process steps (a) or (b) as previously described in Schemes 1 and 2.

Wherein, R ² is a 4-to 11-membered monocyclic or bicyclic heterocyclic ring, Ci- ealkyl or C3-7cycloalkyl, the compound of Formula (XV’) may be prepared from the compound of Formula (VI’) and R ² BPin or R ² B(OH)2 according to process step (c) a palladium catalysed, cross-coupling reaction as described in Scheme 3. Wherein, R ² is -OR ^2A or -N(R ^2b )2,the compound of Formula (XV’) may be prepared from the compound of Formula (VI’) and HOR ^2A or HN(R ^2b )2, according to process steps (a) or (b) as previously described in Schemes 1 and 2.

The compound of Formula (VIII’) may be prepared from the compounds of Formulae (XV’) and (II’) according to process steps (a) or (b), as previously described above.

The compound of Formula (I) may be prepared from the compound of Formula (VIII’) and R ¹ C(O)NR ^N1 according to process step (a), a Buchwald reaction as previously described in Scheme 1. According to a fourth process, the compounds of Formula (III’) and (V’) may be prepared from the compounds of Formulae (IX’), (X’), (XI’), (XII’), (XIII’) and (XIV’) as shown in Scheme 4.

Scheme 4

PG is a suitable N protecting group, typically a carbamate or substituted benzyl and preferably Boc or PMB.

LG is a suitable leaving group, such as a Cl or -OC(O)R ¹ .

The compound of Formula (XI’) may be prepared from the compound of Formula (X’) and R ^N2 NHPG according to process step (a), a Buchwald reaction, as previously described in Scheme 1.

Alternatively, the compound of Formula (XI’) may be prepared from the carboxylic acid of Formula (XII’) according to process step (d) a modified Curtius rearrangement. Preferred conditions comprise reaction of the carboxylic acid of Formula (XII’) with DPPA in t-BuOH in the presence of a suitable organic base, such as TEA at about 90°C.

The compound of Formula (V’) may be prepared from the compounds of Formulae (X’) and (IX’) according to process step (a), a Buchwald reaction, as previously described in Scheme 1.

Alternatively, the compound of Formula (V’) may be prepared from the amine of Formula (XIV’) and R ¹ C(O)LG according to process step (f) an amide bond formation. Preferred conditions comprise reaction of the amine of Formula (XIV’) with R^C^LG in a suitable solvent such as pyridine, optionally in the presence of an organic base such as DIPEA at about rt.

The compound of Formula (XIII’) may be prepared from the compounds of Formula (XI’) and (IX’) according to process step (a), a Buchwald reaction, as previously described in Scheme 1.

Alternatively, the compound of Formula (XIII’) may be prepared from the compound of Formula (V’) and and R ^N2 NHPG according to process step (a), a Buchwald reaction, as previously described in Scheme 1.

The compound of Formula (III’) may be prepared from the compound of Formula (XIII’) according to process step (e) a de-protection reaction. Typical conditions comprise reaction of the compound of Formula (XIII’), wherein PG is Boc, with a suitable acid such as TFA or HC1 in DCM or HFIP at rt or 2,6-lutidine and TMSOTf in DCM. Alternatively, wherein PG is PMB, typical conditions comprise ceric ammonium nitrate in aqueous MeCN at rt.

According to a fifth process, the compounds of Formula (I), wherein R ² is a 4-11 membered monocyclic or bicyclic heterocycle, may be prepared from the compounds of Formulae (IF), (XX’), (XIX’), (XVIII’), (XVII’), (XVI’) and (XXVI’) as shown in Scheme 5.

Scheme 5

W is a boronic ester or boronic acid

The compound of Formula (XVII’) may be prepared from the compound of Formula (XVF), by process step (h), a halogenation reaction, typically a bromination (h). Preferred conditions comprise reaction of the compound of Formula (XVF) with NBS in acetonitrile at 70°C. Alternatively, the compound of Formula (XVII’) may be prepared from the compound of Formula (XXVI’), by process step (o), an amide formation. Preferred conditions comprise reaction of the amine of Formula (XXVI’) with RJCOCl in the presence of an organic base, such as DIPEA in THF or dioxan at about rt.

The compound of Formula (XVIII’) may be prepared from the compound of Formula (XVIF), using process step (e), as previously described in Scheme 3.

The compound of Formula (XIX’) may be prepared from the compounds of Formulae (XVIIF) and (IF) using process step (a), as previously described in Scheme 1.

The compound of Formula (XX’) may be prepared from the compound of Formula (XIX’), according to step (i), a boronate ester formation achieved by treatment with a suitable boronate such as (BPin)2, in the presence of a suitable inorganic base, such as K2CO3 or KO Ac and a suitable catalyst, such as, BINAP, Brettphos, Xantphos, XPhos-Pd-G3, Pd(dppf)C12 , Pd2(dba)3 with a suitable phosphine ligand such as bis( 1 - adamantyl)butylphosphine, Pd(PPh3)C12 or Pd(PPh3)4. in a suitable non-polar solvent at between rt and elevated temperature.

The compound of Formula (I) may be prepared from the compound of Formula (XX’) and R ² Hal ¹ according to process step (c), a Suzuki-type boronic acid cross coupling reaction described above in Scheme 3.

Alternatively, the compound of Formula (I) may be prepared from the compound of Formula (XX’) and R ² Hal ¹ according to process step (p), a copper catalysed Suzuki cross coupling reaction. Preferred conditions comprise reaction of the compounds of Formula (XX’) and R ² Hal ¹ in the presence of a copper catalyst such as Cu(OAc)2 and DMAP in MeCN at about 40°C

Alternatively, the compound of Formula (I) may be obtained from the compound of Formula (XIX’) via step (j), by an in situ process without isolation of the compound of Formula (XX’). Preferred conditions comprise reaction of the compounds of Formulae (XIX’) and R ² -Hal ¹ in the presence of bis(pinacolato)diboron (W2), Pd(OAc)2, in the presence of a suitable phosphane ligand such as bis(l-adamantyl)-butyl-phosphane, a suitable base such as CsF in a suitable solvent such as toluene, MeOH, water at between 80°C and 120°C. According to a sixth process, compounds of Formula (XIII’), may be obtained from the compounds of Formula (XVII’) and (XXF) as shown in Scheme 6.

Scheme 6 Wherein R ² is a 4-11 membered monocyclic or bicyclic heterocycle, the compound of

Formula (XIII’) may be prepared from the compound of Formula (XVII’) and R ² Hal' according to process step (j), as previously described in Scheme 5.

Alternatively, the compound of Formula (XXF) may be prepared according to process step (i) as previously described in Scheme 5. The compound of Formula (XIII’) may be prepared from the compound of Formula (XXF) and R ² Hal ¹ according to process step (c) as previously described in Scheme 3.

Alternatively, the compound of Formula (XIII’) may be prepared from the compound of Formula (XVII’) and R ² -SnBu3 according to process step (r), a Stille type cross-coupling reaction. Preferred conditions comprise, reaction of the compound of Formula (XVII’) with R ² SnBu3, in the presence of a suitable catalyst such as PdCh(PPh3)2 in DMF, at about 100°C Wherein R ² is alkyl or cycloalkyl, the compound of Formula (XIII’) may be obtained from the compound of Formula (XVII’) and KR ² BF,, according to process step (q), a palladium catalysed Suzuki coupling. Preferred conditions comprise reaction of the compound of Formula (XVII’) and KR ² BF3 in the presence of catalyst, cataCXium A and KO Ac, a suitable base such as CS2CO3 in aq toluene at about 90°C

According to a seventh process, compounds of Formula (XIII’), wherein R ² is C2-C6 alkyl, may be obtained from the compounds of Formula (XVII’), (XXII’) and (XXIII’) as shown in Scheme 7.

Scheme 7

R ³ -C=C is an unsaturated pre-cursor to R ²

The compound of Formula (XXIF) may be prepared from compounds of Formulae (XVII’) and (XXIII’) by process step (k), a Sonogashira type cross-coupling reaction. Typical conditions comprise reaction of the compound of Formula (XVII’) with an alkyne of Formula (XXIII’) in the presence of , a suitable palladium catalyst in the presence of suitable phosphine ligands, Cu salt and base, in a suitable solvent at elevated temperature. Preferred conditions comprise, reaction of the compounds of Formulae (XVII’) and (XXIII’) in the presence of Pd(PPh3)2C12.DCM, Cui and a suitable base such as TEA in a solvent such as DMF at between 80°C and 120°C.

The compound of Formula (XIII’) may be prepared from the compound of Formula (XXIF) by step (1), a hydrogenation reaction. Typical conditions comprise, reaction of the compound of Formula (XXIF) in the presence of a Pd catalyst and H2 in THF at rt.

According to an eighth process, compounds of Formula (I), wherein R ² is a 4-11 membered monocyclic or bicyclic heterocycle, may be obtained from the compounds of Formula (XXIV’), (XXV’) and (XIII’) as shown in Scheme 8.

(XIII')

(XXV)

Scheme 8

X is a carbonyl group, preferably a carboxylic ester, or a nitrile.

Compounds of Formula (I) may be prepared from compounds of Formulae (XXIV’) or (XXV’) using standard chemical transformations (m) known to those skilled in the art to convert carboxylic esters or other carboxyl derivatives into heterocycles. E.g methyl ester (XXIV’), X = CChMe, may be hydrolysed with LiOH to carboxylic acid (XXIV’), X = CO2H, and subsequently treated with N’-hydroxyacetimidamide (acetamide oxime) to obtain 3-methyl-l,2,4-oxadiazoles. Compounds of Formula (XIII’) may be obtained from compounds of Formula (XXV’) using standard chemical transformations (n) known to those skilled in the art to convert nitriles or other carboxyl derivatives into heterocycles. E.g. nitrile (XXV’), X = CN, may be reacted with hydroxylamine and subsequently with N’- l,l-dimethoxy-N,N-dimethylethan- 1 -amine to obtain 5-methyl-l,2,4-oxadiazoles. According to a ninth process, the compounds of Formula (I), wherein R ^N2 is H, may be obtained from the compounds of Formula (XXVII’) and (XXVIII’) as shown in Scheme 9.

Scheme 9

The compound of Formula (XXVIII’) may be obtained from the compounds of Formula (XXVIF) and (IF), by process step (b), an alkylation reaction, as previoulsy described in Scheme 3.

The compound of Formula (I), wherein R ^N2 is H, may be obtained by the deprotection of the compound of Formula (XXVIIF), according to process step (e), a deprotection reaction, as previously described in Scheme 4.

According to a tenth process, wherein R ² is a heteroalkyl or alkyl, the compounds of Formula (I) may be obtained from the compound of Formula (XIX’) as shown inScheme 10.

Scheme 10

The compound of Formula (I) may be obtained from the compound of Formula (XIX’) and R ² CO2H according to process step (s), a photo catalysed cross-coupling reaction. Preferred conditions comprise reaction of the compound of Formula (XIX’) with R ² CO2H, in the presence of Ir[dF(CF3)ppy]2(dtbpy)PFe, NiBr2(dtbbpy) and (2-tert-butyl-l,l,3,3- tetramethyl-guanidine in DMF at rt, under an LED light source.

The compounds of Formulae (IF), (IV’), (VI’), (IX’), (X’), (XII’), (XIV’), (XV’), (XVI’), (XVII’), (XXIII’), (XXIV’), (XXV’), (XXVI’), (XXVIF), R ^N2 NH-PG, R ² CO ₂ H, and Rj C^LG are either commercially available or may be prepared by analogy to methods known in the literature, or the methods described in the Experimental section below.

Compounds of Formulae (I), (III’), (IV’), (V’), (VII’), (VIII’), (XI’), (XIII’), (XIV’) (XV’), (XIX’) (XXIV’) (XXVI’) and (XXVII’) may be converted to alternative compounds of Formulae (I), (III’), (IV’), (V’), (VII’), (VIII’) (XI’), (XIII’), (XIV’) (XV’), (XIX’) (XXIV’) (XXVF) and (XXVII’) respectively, by standard chemical transformations, known to those skilled in the art. Examples of these transformations include, but are not limited to:

• alkyation of a heteroatom, such as N or O, using an alkyl or aryl halide, a suitable inorganic or organic base.

• reductive amination oa a N atom to provide a secondary or tertiary amine.

• reaction of an aryl or heteroaryl halide with an alcohol in the presence of an inorganic base to provide an aryl or heteroaryl ether.

• reaction of an alkyl halide with a primary or secondary amine or alcohol in the presence of a base to provide a secondary or tertiary amine or ether.

• reaction of a primary alcohol with an alternative alcohol under Mitsunobu conditions to provide an ether

• fluorination of aryl chloride with a fluorinating agent, such as TBAF, to provide an aryl fluoride

• demethylation of an alkyl methoxy group to provide an alkyl hydroxy group

• photocatalysed reaction of an aryl or heteroaryl halide with a (l,3-dioxoisoindolin-2- yl)alkyl, cycloalkyl or heterocycyl carboxylate to provide an alkyl, cycloalkyl or heterocyclyl substituted aryl or heterocycle

• transition metal catalysed cross-coupling of an aromatic or heteroaryl halide with an o appropriate boronic acid or boronate ester under Suzuki reaction conditions as described in step (c), (p) or (q), o appropriate alkyl or heteroaryl zinc compound under Negishi type reaction conditions, o appropriate alkyl or heteroaryl stannane under Stille type reaction conditions o amine or alcohol under Buchwald type conditions, as described in process step

(a) to provide the corresponding substitued aromatic or heteroaromatic group. It will be appreciated by those skilled in the art that it may be necessary to utilise a suitable protecting group strategy for the preparation of compounds of Formula (I). Typical protecting groups may comprise, a carbamate group, preferably Boc for the protection of amines, a benzyl group for the protection of a phenolic OH or a TBS group for the protection of an alkyl OH.

It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

EXEMPLIFICATION

Abbreviations:

AcOH = acetic acid;

AC2O = acetic anhydride;

Aq. = aqueous;

Bn = benzyl;

BnOH = benzyl alcohol;

Boc = /crt-butoxy carbonyl;

BOC2O = di-tert-butyl dicarbonate; br = broad;

Brettphos Pd G3 = [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl- 1 , 1 '-biphenyl)-2-(2'-amino- 1,1 ' -biphenyl)]palladium(II) methanesulfonate; t-BuOH = tert-butanol; t-BuONa = sodium tert-butoxide; n-BuLi = n-butyl lithium;

°C = degrees Celsius;

CDCh = deutero-chloroform;

CS2CO3 = cesium carbonate;

Cui = copper (I) iodide;

6 = chemical shift; d = doublet;

DAST = (diethylamino)sulfur trifluoride; dd = double doublet;

DCE = 1,2-di chloroethane; DCM = dichloromethane;

DIPEA = N-ethyldiisopropylamine or N,N-diisopropylethylamine;

DMAP = 4-(Dimethylamino)pyridine;

DME = 1,2-dimethoxy ethane;

DMF = N,N-dimethylformamide;

DMSO= Dimethylsulfoxide;

DMSO-de = hexadeuterodimethyl sulfoxide;

DPPA = diphenyl phosphoryl azide;

Et = ethyl;

EtOH = ethanol;

EtOAc = ethyl acetate;

Eq. = equivalent; g = gram;

HC1 = hydrochloric acid;

HCO2H = formic acid; = proton nuclear magnetic resonance;

H2O = water;

HPLC = high pressure liquid chromatography; h = hour;

IPA = 2-propanol;

Josiphos Pd G3 = {(R)-l-[(Sp)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-ter t- butylphosphine}[2-(2'-amino-l,r-biphenyl)]palladium(II) methanesulfonate;

K2CO3 = potassium carbonate;

KF = potassium fluoride;

KOH = potassium hydroxide;

KOtBu = potassium Zc/V-butoxide;

K3PO4 = potassium phosphate tribasic;

L = litre;

LCMS = liquid chromatography mass spectrometry;

Li AIH4 = lithium aluminium hydride; m = multiplet;

M = molar; m-CPBA = 3 -chloroperoxybenzoic acid;

Me = methyl; MeCN = acetonitrile;

Mel = iodomethane;

MeOH = methanol;

MeOH-d4 = deutero-methanol; mg = milligram;

MgSC = magnesium sulfate;

MHz = mega Hertz; mins = minutes; mL = millilitres; mmol = millimole;

MorDalPhos Pd G3 = mesyl(2-(di-l-adamantylphosphino)morpholinobenzene)[2-(2'- amino- 1 , 1 '-biphenyl)]palladium(II);

MS m/z = mass spectrum peak;

MTBE = tert-butyl methyl eher;

N2 = nitrogen;

NaBH4 = sodium borohydride;

NaBHsCN = sodium cycanoborohydride;

ISfeCCh = sodium carbonate;

NaH = sodium hydride;

NaHCCh = sodium bicarbonate;

NaOH = sodium hydroxide;

NaOMe = sodium methoxide;

Na2SOs = sodium thiosulfate;

Na2SO4 = sodium sulfate;

NBS = N-bromosuccinimide;

NH2B0C = tert-butyl carbamate;

NH3 = ammonia;

NH4CI = ammonium chloride;

NH4OH is ammonium hydroxide;

NMP = l-methyl-2-pyrrolidone;

PE = petroleum ether;

Pd(dppf)C12 = [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II);

Pd(OAc)2 = palladium (II) acetate;

Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium (0); Pd(PPh ₃ )2Cl ₂ = bis(triphenylphosphine)palladium(II) chloride;

POCh = phosphorus (V) oxychloride; q = quartet; rt = room temperature;

RT = retention time; s = singlet; sat. = saturated; soln. = solution; t = triplet;

TBSC1 = /c/V-butyldimethyl silyl chloride;

TEA = triethylamine;

TFA = tri fluoroacetic acid;

THF = tetrahydrofuran;

TLC = thin layer chromatography; pL = micro litres; pmol = micromole;

Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene;

Xantphos Pd G3 = [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-ami no- 1,1 '-biphenyl)]palladium(II) methanesulfonate.

GENERAL METHODS

Prep HPLC conditions:

Method A: Column: YMC -Tri art Prep C18 150*40mm*7um; Condition: water (NH4HCO3)-MeCN; Gradient Time (min): 15; 100%B Hold Time (min): 3; Flow Rate (mL/min): 50; Detection wavelength: 220 nm

Method B: Column: Welch Xtimate C18 150*25mm*5um; Condition: water (lOmM NH4HCO3)-MeCN; Gradient Time (min): 11; 100%B Hold Time (min): 2; Flow Rate (mL/min): 25; Detection wavelength: 220 nm)

Method C: Column: Boston Prime C18 150*30mm*5um; Condition: water (lOmM NH4HCO3)-MeCN; Gradient Time (min): 10; 100%B Hold Time (min): 2; Flow Rate (mL/min): 25; Detection wavelength: 220 nm)

Method D: Column: Boston Green ODS 150*30mm*5um, Condition: water (FA)- MeCN; Gradient Time (min): 10; 100% B Hold Time (min): 2; Flow Rate (mL/min): 25 Method E: Column: Boston Uni C18 40*150*5um; Condition: water (TFA)-MeCN;

Gradient Time (min): 10; 100%B Hold Time (min): 2; Flow Rate (mL/min): 60

Method F: Column: Shapsil-T C18 50*250mm 8um, Condition: water (0.1%FA)- MeCN, Gradient: Gradient time: 20 min, Flow rate 80 mL /min

Method G: Column: Boston Green ODS 150*30mm*5um; Condition: water (NH4HCO3)-MeCN; Gradient Time (min): 11; Flow Rate (mL/min): 25

Method H: Column: Boston Green ODS 150*30mm*5um; Condition: water (HC1)- MeCN; Gradient Time (min): 10; 100%B Hold Time (min): 2; Flow Rate (mL/min): 25

Method I: YMC-Actus Triart C18 150*30mm*5um, Condition: water (TFA)-MeCN; Gradient Time (min): 10.5; 100% B Hold Time (min): 1.5; Flow Rate (mL/min): 40

Method J: Waters Sunfire Prep Cl 8, 5 pm, 19 mm * 100 mm column with mobile phase H2O and MeCN (0.2% NH4HCO3 final v/v % modifier) with flow rate at 30 mL/min.

Method K: Column: Boston Prime C18 150*30mm*5um; Condition: water (NH ₃ H ₂ O+NH ₄ HCO3)-MeCN; Gradient Time (min): 10; 100%B Hold Time (min): 2; Flow Rate (ml/min): 25.

Method L: Column: Welch Xtimate C18 150*25mm*5um; Condition: water (ammonia hydroxide v/v)-MeCN; Gradient Time (min): 11; 100 % B Hold Time (min): 2; Flow Rate (ml/min): 25;

Method M: Column: Boston Prime C18 150*30mm*5um; Condition: water (FA)- MeCN; Gradient Time (min): 12; 100%B Hold Time (min): 2; Flow Rate (ml/min): 25.

Method N: Column: Phenomenex Cl 8 150*25mm*10um; mobile phase: water (NH4HCO3)-MeCN; Gradient Time (min): 10; 100%B Hold Time (min): 2; Flow Rate (ml/min): 25.

Method O: Column: Phenomenex C18 150*40mm*5um; Condition: water (NH ₃ H ₂ O+NH ₄ HCO3)-MeCN; Gradient Time (min): 10; 100 % B Hold Time (min): 2; Flow Rate (ml/min): 25.

Method P: ColummWaters Xbridge BEH C18 100*30mm*10um; Condition: water( NH4HCO3)-MeCN; Gradient Time (min): 11; 100%B Hold Time (min): 3; Flow Rate (ml/min): 25.

Method Q: Column: Phenomenex Gemini-NX 150*30mm*5um ; Condition: water (NH ₃ H ₂ O+NH ₄ HCO3)-MeCN; Gradient Time (min): 15; 100%B Hold Time (min): 3; Flow Rate (ml/min): 25.

Method R: Column: Phenomenex Gemini-NX 150*30mm*5um: water (NH4HCO3)- MECN; Gradient Time (min): 11; Flow Rate (ml/min): 25. Method S: Column: C18-1 150*30mm*5um; Condition: water (NH4HCO3)-MECN; Begin B: Gradient Time (min): 11; Flow Rate (ml/min): 25.

Method T: Column: Boston Green ODS 150 x 30 mm, 5 mm; MeCN/H ₂ O (TFA).

Method U: Column: Waters XSelect CSH C18, 5 gm, 30 mm x 100 mm column with mobile phase H ₂ O (A) and MeCN (B) (0.2% NFUOH final v/v % modifier) with flow rate at 60 mL/min).

Method V: Column: Waters Sunfire Prep Cl 8 OBD 5um 19x100mm, Gradient: MeCN in water, modifier 0.1% TFA, Gradient time, 12 min. Flow rate: 30 ml/min.

Method W: Column: Waters Xbridge BEH C18 100*30mm*10um, Condition: water (HCl)-MeCN; Gradient Time (min): 11; Flow Rate (ml/min): 50).

Method X: Column: Waters Xbridge BEH C18 100*30mm*10um; Condition: water (FA)-MeCN; Gradient Time (min): 11; 100 % B Hold Time (min): 3; Flow Rate (ml/min): 50.

Method Y: Column: Phenomenex luna C18 150*25mm* lOum; Condition: water (FA)-MeCN; gradient over 10 min, flow rate 25 mL/min.

Method Z: Waters Xbridge BEH C18 100 x 30 mm, 10 mm; MeCN/H ₂ O (TFA))

Method AA: Column: Agela DuraShell C18 150*25mm*5um; Condition: water (NH3.H2O)-MECN; B%: gradient over 10 min.

Preparation 1

2-bromo-5-ethoxypyridine 1 -oxide solution of 2-bromo-5-ethoxypyridine (27.0 g, 134 mmol) in DCE

(300 mL) was added m-CPBA (46.1 g, 267 mmol) and the reaction was stirred at 80 °C for 2 h. The mixture was adjusted to pH=10 with ethane- 1,2-diamine (16.1 g, 267 mmol), concentrated in vacuo, diluted with water (150 mL) and extracted with EtOAc (200 mL x 3). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na ₂ SO4, filtered and concentrated. The crude was purified by chromatography on silica gel (EtOAc) to give 2-bromo-5-ethoxypyridine 1 -oxide (23.0 g, 78.6 % yield) as a white solid. LCMS m/z = 218.0 [M+H] ⁺ .

Preparation 2 2-bromo-5-ethoxy-4-nitropyridine 1 -oxide solution of 2-bromo-5-ethoxypyridine 1-oxide (Preparation 1, 11.0 g,

50.5 mmol) in H2SO4 (12.0 mL) was added HNO3 (12.0 mL) dropwise and the reaction was stirred at 25 °C for 16 h. The mixture was poured into an ice/water mixture (200 mL). The solid was collected by filtration and washed with ice/water to give 2-bromo-5-ethoxy-4- nitropyridine 1-oxide (15.2 g, crude) as a light-yellow solid. 'H NMR: (400 MHz, CDCL) 8 ppm: 8.27 (s, 1H), 8.25 (s, 1H), 4.19 (q, J=6.8 Hz, 2H), 1.53 (t, J=6.8 Hz, 3H)

Preparation 3

2-bromo-5-ethoxypyridin-4-amine solution of 2-bromo-5-ethoxy-4-nitropyridine 1-oxide (Preparation 2,

15.0 g, 56.8 mmol) in AcOH (50.0 mL) was added iron (15.9 g, 284 mmol). The reaction was stirred at 25 °C for 30 min and the mixture was then diluted with water (500 mL) and extracted with EtOAc (400 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated to give 2-bromo-5- ethoxypyridin-4-amine (5.64 g, 45.7% yield) as a brown solid. LCMS m/z = 219.0 [M+H] ⁺ .

Preparation 4 tert-butyl (2-bromo-5-ethoxypyridin-4-yl)(tert-butoxycarbonyl)carbamate solution of 2-bromo-5-ethoxypyridin-4-amine (Preparation 3, 5.6 g,

25.9 mmol) and TEA (7.0 g, 69.2 mmol) in DCM (50 mL) was added DMAP (3.2 g, 25.9 mmol) and BOC2O (22.6 g, 104 mmol) and the reaction was stirred at 25 °C for 2 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (70 mL x 3). The combined organic phase was washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by chromatography on silica gel

(PEZEtOAc 1/0 to 3/1) to give tert-butyl (2-bromo-5-ethoxypyridin-4-yl)(tert- butoxycarbonyl)carbamate (1.7 g, 15.5% yield) as a yellow solid. LCMS m/z = 419.0 [M+H] ⁺ .

Preparation 5 tert-butyl (2-acetamido-5-ethoxypyridin-4-yl)(tert-butoxycarbonyl)carba mate solution of tert-butyl (2-bromo-5-ethoxypyridin-4-yl)(tert- butoxycarbonyl)carbamate (Preparation 4, 1.7 g, 4.00 mmol) in dioxane (20 mL) was added acetamide (260 mg, 4.40 mmol), CS2CO3 (2.6 g, 8.00 mmol) and BrettPhos Pd G3 (363 mg, 0.40 mmol) and the reaction was stirred at 100 °C for 1 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel (PE/EtOAc 1/0 to 2/1) to give tert-butyl (2-acetamido-5-ethoxypyridin-4-yl)(tert-butoxycarbonyl)carba mate (1.3 g, 82.1% yield) as a light-yellow solid. LCMS m/z = 396.2 [M+H] ⁺ .

Preparation 6

2-chloro-5-(difluoromethoxy)-4-iodopyridine

To a solution of 6-chl oro-4-iodopyri din-3 -ol (1 g, 3.91 mmol) in DMF (20 mL) was added sodium 2-chloro-2,2-difluoroacetate (1.2 g, 7.83 mmol) and CS2CO3 (2.6 g, 7.83 mmol) and the reaction was stirred at 100 °C for 4 h under N2. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mLx2). The combined organic phase was washed with brine (20 mLx2), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc = 3/1) to give 2-chloro-5- (difluoromethoxy)-4-iodopyridine (1.2 g, 97 % yield) as a yellow oil. NMR (400 MHz, CDCh) 8: ppm 8.17 (s, 1H), 7.84 (s, 1H), 6.76-6.40 (m, 1H).

Preparation 7

2-chloro-5-cyclobutoxy-4-iodopyridine

2-Chloro-5-cyclobutoxy-4-iodopyridine was obtained, 940 mg, 77.6% yield, from 6-chloro-4- iodopyri din-3 -ol and bromocyclobutane following the procedure described in Preparation 6. LCMS m/z = 309.8 [M+H] ⁺

Preparation 8

2-chloro-4-iodo-5-isopropoxypyridine

2-Chloro-4-iodo-5-isopropoxypyridine was obtained as a yellow liquid, 2.2 g, 94.4% yield, from 6-chloro-4-iodopyridin-3-ol and 2-iodopropane, following the procedure described in Preparation 6. 1H NMR (500 MHz, CDCh) 8 ppm: 7.82 (s, 1H), 7.73 (s, 1H), 4.66-4.59 (m, 1H), 1.45-1.38 (m, 6H).

Preparation 9 tert-butyl (2-chloro-5-(difluoromethoxy)pyridin-4-yl)carbamate

To a solution of 2-chloro-5-(difluoromethoxy)-4-iodopyridine (Preparation 6, 1.1 g, 3.44 mmol) in dioxane (20 mL) was added NH2B0C (382.6 mg, 3.27 mmol), CS2CO3 (2.24 g, 6.88 mmol), Xantphos (596.7 mg, 1.03 mmol) and Pd2(dba)3 (314.8 mg, 0.344 mmol) and the reaction was stirred at 100 °C for 16 h under N2. The cooled mixture was concentrated and the residue was purified by chromatography on silica gel (PE/EtOAc=3/l) to give tert-butyl (2-chloro-5-(difluoromethoxy)pyridin-4-yl)carbamate (940 mg, 93.0% yield) as a yellow oil. 'H NMR: (400 MHz, CDCh) 6: ppm 8.24 (s, 1H), 8.12 (s, 1H), 7.07 (s, 1H), 6.75-6.36 (m, 1H), 1.54 (s, 9H).

Preparation 10 tert-butyl (2-chloro-5-cyclobutoxypyridin-4-yl)carbamate

To a solution of 2-chloro-5-cyclobutoxy-4-iodopyridine (Preparation 7, 930 mg, 3.0 mmol) and NH2B0C (387.2 mg, 3.31 mmol) in dioxane (15 mL) was added CS2CO3 (2.94 g, 9.01 mmol), Pd2(dba)3 (275.13 mg, 0.3 mmol) and Xantphos (347.70 mg, 0.6 mmol) and the reaction was stirred at 100 °C for 1.5 h under N2. The cooled mixture was diluted with water (50 mL) and extracted with EtOAc (70 mL x 3). The combined organic phase was washed with brine (50 mL x 3), dried over anhydrous Na2SO4 and concentrated to give tert-butyl (2-chloro-5- cyclobutoxypyridin-4-yl)carbamate (1.4g, crude) as a white solid. LCMS m/z = 299.1 [M+H] ⁺

Preparation 11 tert-butyl (2-chloro-5-isopropoxypyridin-4-yl)carbamate

The title compound was obtained as a yellow solid, 1.03 g, 49% yield from 2-chloro-4-iodo-5- isopropoxypyridine (Preparation 8) and NH2B0C following the procedure described in Preparation 9. 'H NMR (400 MHz, CDCh) 8 ppm: 8.09 (s, 1H), 7.84 (s, 1H), 7.18 (s, 1H), 4.66-4.59 (m, 1H), 1.54 (s, 9H), 1.40 (d, J=6.4 Hz, 6H).

Preparation 12

2-bromo-5-(2-methoxyethoxy)isonicotinic acid t-BuONa (21.8 g, 227 mmol) was added to a solution of 2-bromo-5-fluoroisonicotinic acid (10.0 g, 45.5 mmol) and 2-methoxyethan-l-ol (100 mL) and the reaction was stirred at 70 °C for 1 h. The mixture was concentrated and the residue was dissolved in H2O (10 mL) and adjusted to pH ~4 with 2N HC1. The precipitate was isolated by filtration, dissolved in EtOAc (25 mL) and washed with brine (25 mL). The organic layer was dried over ISfeSCU, filtered and concentrated to give 2-bromo-5-(2-methoxyethoxy)isonicotinic acid (10.0 g, 79.7% yield) as a yellow solid. 'H NMR: (400 MHz, DMSO-de) 6 ppm: 13.63 (br s, 1H), 8.35 (s, 1H), 7.69 (s, 1H), 4.29-4.27 (m, 2H), 3.67-3.64 (m, 2H), 3.30 (s, 3H).

Preparation 13

2-bromo-5-ethoxyisonicotinic acid

To a solution of 2-bromo-5-fluoroisonicotinic acid (110 g, 500 mmol) in EtOH (1500 mL) was added Z-BuONa (120.13 g, 1.25 mol) and the reaction was stirred at 90 °C for 12 h under N2. The mixture was concentrated under reduced pressure and the residue was diluted with water (500 mL). The water phase was adjusted to pH 4 with 12M HC1, the resulting mixture was filtered and the filter cake was washed with water (200 mL x 2) and concentrated under reduced pressure to give 2-bromo-5-ethoxyisonicotinic acid (115 g, 93.5% yield) as yellow solid. ^X H NMR (400MHz, DMSO ) d ppm 8.32 (s, 1H), 7.68 (s, 1H), 4.21 (q, J= 6.8 Hz, 2H), 1.32 (t, J= 6.8 Hz, 3H).

Preparation 14

2-bromo-5-(2,2,2-trifluoroethoxy)isonicotinic acid

To a solution of 2-bromo-5-fluoroisonicotinic acid (2.0 g, 9.09 mmol) in THF (20.0 mL) was added 2,2,2-trifluoroethan-l-ol (2.7 g, 27.27 mmol) and Z-BuONa (4.4 g, 45.46 mmol) and the reaction was stirred at 70 °C for 12 h under N2. The mixture was concentrated under reduced pressure, the residue was diluted with water (20 mL) and the pH adjusted to 4 with 12 M HC1. The mixture was filtered, the filter cake was washed with water (10 mL x 2) and dried under reduced pressure to give 2-bromo-5-(2,2,2-trifluoroethoxy)isonicotinic acid (2.4 g, 88% yield) as a white solid. 'H NMR: (500 MHz, DMSO-d ₆ ) 8 ppm: 13.88 (br s, 1H), 8.44 (s, 1H), 7.80 (s, 1H), 4.97 (q, J=8.5 Hz, 2H).

Preparation 15

2-bromo-5-(2,2-difluoroethoxy)isonicotinic acid

2-Bromo-5-(2,2-difluoroethoxy)isonicotinic acid was obtained, 1.5 g, 58.5% yield as a brown solid, from 2-bromo-5-fluoroisonicotinic acid and 2,2-difluoroethan-l-ol following the procedure described in Preparation 14. 'H NMR: (400 MHz, MeOH-d4) 8 ppm: 8.32 (s, 1H), 7.78 (s, 1H), 6.38-6.10 (m, 1H), 4.47-4.39 (m, 2H).

Preparation 16

2-bromo-5-(2-(dimethylamino)ethoxy)isonicotinic acid

2-Bromo-5-(2-(dimethylamino)ethoxy)isonicotinic acid was obtained as a yellow solid, 2.03 g, 76.9%, from 2-bromo-5-fluoroisonicotinic acid and 2-(dimethylamino)ethan-l-ol, following the procedure described in Preparation 14. LCMS m/z = 291.0 [M+H] ⁺

Preparation 17

5-(benzyloxy)-2-bromoisonicotinic acid

5-(Benzyloxy)-2-bromoisonicotinic acid was obtained as a yellow solid, 25 g, 93.9% yield, from 2-bromo-5-fluoroisonicotinic acid and and benzyl alcohol following the procedure described in Preparation 14. LCMS m/z = 307.9 [M+H] ⁺ .

Preparation 18

2-bromo-5-((3-methoxycyclobutyl)methoxy)isonicotinic acid To a solution of 2-bromo-5-fluoroisonicotinic acid (1 g, 4.55 mmol) in THF (10 mL) was added (3 -methoxy cy cl obutyl)methanol (580.80 mg, 5.0 mmol), Z-BuONa (873.68 mg, 9.09 mmol) and the reaction was stirred at 70 °C for 2 h. The mixture was concentrated and purified by Prep-HPLC (Method E, gradient: 25 to 55%) to give 2-bromo-5-((3- methoxycyclobutyl)methoxy)isonicotinic acid (340 mg, 23.7% yield) as a white solid. ^T H NMR: (400 MHz, CDCh) 8 ppm 8.26 (s, 1H), 8.10 (s, 1H), 4.31 (d, .7=6,4 Hz, 2H), 3.92-3.85 (m, 1H), 3.26 (s, 3H), 2.56-2.46 (m, 3H), 1.89-1.79 (m, 2H).

Preparation 19

2-bromo-5-(cyclopropylmethoxy)isonicotinic acid

To a solution of 2-bromo-5-fluoroisonicotinic acid (19 g, 86.37 mmol) and cyclopropylmethanol (12.45 g, 172.73 mmol) in THF (250 mL) was added Z-BuONa (20.75 g, 215.9 mmol). The reaction mixture was stirred at 90 °C for 16 h. The reaction was concentrated to give the residue, which was adjusted with HC1 (2 N) until pH to 5. The mixture was filtered and the solid was dried in vacuo to give 2-bromo-5- (cyclopropylmethoxy)isonicotinic acid (20 g, 85.1% yield) as a white solid.1H NMR: (400 MHz, CDCh) 6 ppm: 13.66 (br s, 1H), 8.31 (s, 1H), 7.69 (s, 1H), 4.03 (d, J = 7.2 Hz, 2H), 1.30-1.13 (m, 1H), 0.62-0.51 (m, 2H), 0.40-0.30 (m, 2H)

Preparation 20

2-bromo-5-(ethoxy-d5)isonicotinic acid

To a solution of Z-BuONa (2.18 g, 22.73 mmol) and THF (20 mL) was added 1,1, 1,2,2- pentadeuterio-2-deuteriooxy-ethane (1.2 g, 23.03 mmol) while stirring at rt. After 5 mins, 2- bromo-5-fluoro-pyridine-4-carboxylic acid (2 g, 9.09 mmol) was added, then the reaction was warmed to 65 °C. The reaction was allowed to stir for 1 h, then diluted with water (40 mL water) and concentrated to remove THF. The resulting aqueous mixture was acidified by the addition of HC1 (2 M, 13.64 mL) while stirring at rt. The thick aqueous slurry was filtered to collect the resulting solids. These were then dissolved in MeOH (50 mL), diluted with MeCN (25 mL) and concentrated to give, 2-bromo-5-(ethoxy-d5)isonicotinic acid as a tan solid (2.2 g, 96.4% yield) . LCMS m/z = 250.9 (M+H) ⁺ . ^X H NMR (DMSO-d ₆ ) 6: 14.14-13.10 (m, 1H), 8.32 (s, 1H), 7.68 (s, 1H).

Preparation 21 tert-butyl (2-bromo-5-(cyclopropylmethoxy)pyridin-4-yl)carbamate

To a solution of 2-bromo-5-(cyclopropylmethoxy)isonicotinic acid (Preparation 19, 20 g, 73.50 mmol) and TEA (8.93 g, 88.20 mmol) in t-BuOH (200 mL) was added DPPA (19.01 mL, 88.20 mmol) and the reaction was stirred at 90 °C for 16 h. The mixture was partitioned between EtOAc (3 x 150 mL) and water (250 mL). The organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated to give the residue, which was purified by column chromatography on silica gel (PEZEtOAc = 20/1 - 10/1) to give tert-butyl (2-bromo-5-(cyclopropylmethoxy)pyridin-4-yl)carbamate (22 g, 87.2% yield) as a yellow solid. ¹ HNMR: (400 MHz, CDCh) 8 ppm: 8.23 (s, 1H), 7.81 (s, 1H), 3.90 (d, J= 6.8 Hz, 2H), 1.55 (s, 9H), 1.38-1.22 (m, 1H), 0.80-0.61 (m, 2H), 0.47-0.30 (m, 2H).

Preparation 22 tert-butyl (2-bromo-5-(2-methoxyethoxy)pyridin-4-yl)carbamate

To a solution of 2-bromo-5-(2-methoxyethoxy)isonicotinic acid (Preparation 12, 10.0 g, 36.2 mmol) in t-BuOH (100 mL) was added TEA (7.3 g, 72.4 mmol) and DPPA (9.9 g, 36.2 mmol) and the reaction was stirred at 90 °C for 16 h under N2. The mixture was concentrated under reduced pressure, the residue diluted with H2O (30 mL) and extracted with EtOAc (35 mL x 3). The combined organic layers were washed with brine (35 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (PE/EtOAc 1/0 to 5/1) to give tert-butyl (2-bromo-5-(2- methoxyethoxy )pyridin-4-yl)carbamate (9.03 g, 71.8% yield) as a white crystal. LCMS m/z = 349.1 [M+H] ⁺ .

Preparation 23 tert-butyl (2-bromo-5-ethoxypyridin-4-yl)carbamate tert-Butyl (2-bromo-5-ethoxypyridin-4-yl)carbamate was obtained as a yellow solid, 85 g, 73.3% yield, from 2-bromo-5-ethoxyisonicotinic acid (Preparation 13) and DPP A, following the procedure described in Preparation 22. 1H NMR: (400MHz, DMSO-de) 8 ppm 8.60 (s, 1H), 8.03 (s, 1H), 8.02 (s, 1H), 4.16 (q, J = 6.8 Hz, 2H), 1.49 (s, 9H), 1.38 (t, J = 6.8 Hz, 3H).

Preparation 24 to 29

The compounds in the following table were obtained from the appropriate 2- bromoisonicotinic acid and DPP A, following a similar reaction to that described in Preparation 22.

Preparation 30 tert-butyl (2-bromo-5-(2-(dimethylamino)ethoxy)pyridin-4-yl)carbamate

To a solution of 2-bromo-5-(2-(dimethylamino)ethoxy)isonicotinic acid (Preparation 16, 2 g, 6.92 mmol) in t-BuOH (20 mL) was added TEA (1.40 g, 13.83 mmol) and DPPA (1.90 g, 6.92 mmol) and the reaction was stirred at 90 °C for 16 h under N2. The reaction mixture was purified by prep-HPLC (Method D, Gradient 20% isocratic) to give tert-butyl (2-bromo-5-(2- (dimethylamino)ethoxy)pyridin-4-yl)carbamate (800 mg, 32.1% yield) as a white solid. LCMS m/z = 361.8 [M+H] ⁺

Preparation 31 tert-butyl (2-bromo-5-(ethoxy-d5)pyridin-4-yl)carbamate

To a mixture of 2-bromo-5-(ethoxy-d5)isonicotinic acid (Preparation 20, 2.2 g, 8.76 mmol) in tBuOH (25 mL) was added DIPEA (2.26 g, 17.52 mmol), the solution stirred at rt for 10 mins, then DPPA (2.89 g, 10.51 mmol) was added. After 5 mins, the reaction was warmed to 75 °C with the cap loose to allow for N2 evolution for 2 h. The cooled reaction was concentrated to remove tBuOH, then diluted with NaHCOs (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were concentrated to dryness and the crude material was purified by silica gel chromatography (40 g, heptane to EtOAc) to give tertbutyl (2-bromo-5-(ethoxy-d5)pyridin-4-yl)carbamate as a white crystalline solid, (1.42 g, 50.30% yield). LCMS m/z = 322.0 [M+H] ⁺ . 1H NMR (DMSO-d ₆ ) 8: 8.62 (br s, 1H), 8.03 (d, J=4.9 Hz, 2H), 1.49 (s, 9H). Preparation 32 tert-butyl (2-acetamido-5-(2-methoxyethoxy)pyridin-4-yl)carbamate

To a solution of tert-butyl (2-bromo-5-(2-methoxyethoxy)pyridin-4-yl)carbamate (Preparation 22, 8.9 g, 25.6 mmol) and acetamide (7.6 g, 128 mmol) in dioxane (80 mL) was added CS2CO3 (25.1 g, 76.9 mmol) and BrettPhos Pd G3 (2.3 g, 2.56 mmol) and the reaction was stirred at 100 °C for 1 h under N2. The mixture was concentrated, diluted with H2O (50 mL), extracted with EtOAc (60 mL x 2), and the combined organic extracts washed with brine (50 mL x 2). The organic phase was concentrated and the residue purified by chromatography on silica gel (PE/EtOAc 5/0 to 0/1) to give tert-butyl (2-acetamido-5-(2- methoxyethoxy)pyridin-4-yl)carbamate (8.0 g, 95.9% yield) as a brown solid. LCMS m/z = 326.2 [M+H] ⁺ . 'H NMR: (400 MHz, CDCh) 8 ppm: 8.88 (br s, 1H), 8.27 (br s, 1H), 7.83- 7.79 (m, 2H), 4.14-4.10 (m, 2H), 3.70-3.67 (m, 2H), 3.46 (s, 3H), 2.15 (s, 3H), 1.54 (s, 9H).

Preparation 33 tert-butyl (2-acetamido-5-(cyclopropylmethoxy)pyridin-4-yl)carbamate

To a solution of tert-butyl (2-bromo-5-(cyclopropylmethoxy)pyridin-4-yl)carbamate (Preparation 21, 150 mg, 0.437 mmol) in dioxane (5 mL) was added acetamide (77.4 mg, 1.31 mmol), BrettPhos Pd G3 (39.6 mg, 0.0437 mmol) and CS2CO3 (427 mg, 1.31 mmol). The reaction was stirred at 100 °C for 2 h under N2. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, then purified by chromatography on silica gel

(PE/EtOAc 15/1 to 0/1) to give tert-butyl (2-acetamido-5-(cyclopropylmethoxy)pyridin-4- yl)carbamate (130 mg, 92.6% yield) as a white solid. 'H NMR: (400 MHz, CDCh) 6 ppm: 8.85 (br s, 1H), 7.89 (br s, 1H), 7.71 (s, 1H), 3.87 (d, J=7.2 Hz, 2H), 2.16 (s, 3H), 1.56 (s, 9H), 1.30-1.25 (m, 1H), 0.70-0.66 (m, 2H), 0.38-0.35 (m, 2H). Preparations 34 to 39

The compounds in the following table were prepared from the appropriate 2-bromo or 2- chloropyridine and acetamide, following a similar procedure to that described in Preparation 33.

*-purified by prep TLC (DCM/MeOH = 10/1)

** DMF was used instead of dioxane

Preparation 40 tert-butyl (2-acetamido-5-(ethoxy-d5)pyridin-4-yl)carbamate

To tert-butyl (2-bromo-5-(ethoxy-d5)pyridin-4-yl)carbamate (Preparation 31, 1.42 g, 4.41 mmol) was added acetamide (1.30 g, 22.04 mmol), CS2CO3 (4.31 g, 13.22 mmol) and BrettPhos Pd G3 (300 mg, 330.9 pmol) followed by dioxane (15 mL), the mixture was degassed by bubbling N2 for 10 mins at rt, then heated to 100 °C for 1 h. The reaction mixture was diluted with EtOAc (25 mL), filtered through Celite®, rinsing with EtOAc (15 mL), then concentrated to dryness. The crude material was purified by silica gel chromatography (40 g, heptane to EtOAc) to give tert-butyl (2 -acetamido- 5 -(ethoxy- d5)pyridin-4-yl)carbamate (1.26 g, 94.9% yield) as a white solid. LCMS m/z = 301.1 [M+H]+. 1H NMR (DMSO-d ₆ ) 8: 10.19 (br s, 1H), 8.63 (br s, 1H), 8.11 (br s, 1H), 7.92 (s, 1H), 2.04 (s, 3H), 1.49 (s, 9H).

Preparation 41 tert-butyl (2-acetamido-5-isopropoxypyridin-4-yl)carbamate

To a solution of tert-butyl (2-chloro-5-isopropoxypyridin-4-yl)carbamate (Preparation 11, 1 g, 3.49 mmol) in dioxane (10 mL) was added acetamide (618 mg, 10.46 mmol), Pd2(dba)3 (638.68 mg, 0.7 mmol), CS2CO3 (2.27 g, 6.97 mmol) and Xantphos (807.13 mg, 1.39 mmol) and the reaction was stirred at 120 °C for 16 h under N2. The mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 1/1) to give tert-butyl (2-acetamido-5- isopropoxypyridin-4-yl)carbamate (830 mg, 76.9% yield) as a yellow solid. NMR (500 MHz, CDCh) 6 ppm: 8.83 (s, 1H), 7.95 (s, 1H), 7.76 (s, 1H), 7.15 (s, 1H), 4.60-4.52 (m, 1H), 2.16 (s, 3H), 1.56 (s, 9H), 1.38 (d, J=6.0 Hz, 6H)

Preparation 42 tert-butyl (2-acetamido-5-cyclopropoxypyridin-4-yl)carbamate tert-Butyl (2-acetamido-5-cyclopropoxypyridin-4-yl)carbamate was obtained as a yellow solid, 130 mg, 34.8% yield, from tert-butyl (2-bromo-5-cyclopropoxypyridin-4-yl)carbamate (Preparation 25) and acetamide following the procedure described in Preparation 41. LCMS m/z = 308.1 [M+H] ⁺

Preparation 43 tert-butyl (2-acetamido-5-(2,2,2-trifluoroethoxy)pyridin-4-yl)carbamate tert-Butyl (2-acetamido-5-(2,2,2-trifluoroethoxy)pyridin-4-yl)carbamate was obtained as a white solid, 733 mg, 74% yield, from tert-butyl (2-bromo-5-(2,2,2-trifluoroethoxy)pyridin-4- yl)carbamate (Preparation 27) and acetamide following the procedure described in Preparation 41. ^X H NMR (400 MHz, CDCh) 8 ppm: 8.93 (br s, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 7.06 (s, 1H), 4.42 (q, J=8.0 Hz, 2H), 2.18 (s, 3H), 1.55 (s, 9H).

Preparation 44 tert-butyl (2-acetamido-5 -((3 -methoxy cyclobutyl)methoxy)pyridin-4-yl)carbamate tert-Butyl (2-acetamido-5-((3-methoxycyclobutyl)methoxy)pyridin-4-yl)ca rbamate was obtained as a yellow oil, 98 mg, 43.3% yield, from tert-butyl (2-bromo-5-((3- methoxycyclobutyl)methoxy)pyridin-4-yl)carbamate (Preparation 26) and acetamide following the procedure described in Preparation 41. 'H NMR: (500 MHz, CDCh) 6 ppm 8.84 (s, 1H), 7.76 (s, 1H), 7.71 (s, 1H), 7.28 (s, 1H), 4.02 (d, J=5.5 Hz, 2H), 3.88-3.82 (m, 1H), 3.26 (s, 3H), 2.53-2.46 (m, 2H), 2.43-2.34 (m, 1H), 2.16 (s, 3H), 1.86-1.80 (m, 2H), 1.56 (s, 9H).

Preparation 45 tert-butyl (5-ethoxy-2-propionamidopyridin-4-yl)carbamate

To a solution of tert-butyl (2-bromo-5-ethoxypyridin-4-yl)carbamate (Preparation 23, 400.0 mg, 1.26 mmol) and propionamide (460.9 mg, 6.31 mmol) in dioxane (5.0 mL) was added CS2CO3 (1.2 g, 3.78 mmol) and BrettPhos Pd G3 (114.3 mg, 0.13 mmol) and the reaction was stirred at 100 °C under N2 for 1 h. The mixture was concentrated under reduced pressure to give the residue, which was purified by column chromatography (PEZEtOAc = 3/1 to 0/1) to give tert-butyl (5-ethoxy-2-propionamidopyridin-4-yl)carbamate (255 mg, 65.4% yield) as a white solid. LCMS m/z = 310.2 [M+H] ⁺

Preparation 46 tert-butyl (5-ethoxy-2-(2-methoxyacetamido)pyridin-4-yl)carbamate tert-Butyl (5-ethoxy-2-(2-methoxyacetamido)pyridin-4-yl)carbamate was obtained as a yellow solid, 600 mg, 82.2% yield from 2-methoxyacetamide and tert-butyl (2-bromo-5- ethoxypyridin-4-yl)carbamate (Preparation 23), following the procedure described in Preparation 45. ^X H NMR (400 MHz, CDCh) 8: ppm 8.90 (s, 1H), 8.68 (s, 1H), 7.77 (s, 1H), 7.18 (s, 1H), 4.13 (q, J=6.8 Hz, 2H), 4.01 (s, 2H), 3.48 (s, 3H), 1.55 (s, 9H), 1.47 (t, J=7.2 Hz, 3H).

Preparation 47 tert-butyl (5-ethoxy-2-(3-methoxypropanamido)pyridin-4-yl)carbamate tert-Butyl (5-ethoxy-2-(3-methoxypropanamido)pyridin-4-yl)carbamate was obtained as a white solid, 372 mg, 86.9% yield, from 3-methoxypropanamide and tert-butyl (2-bromo-5- ethoxypyridin-4-yl)carbamate (Preparation 23) following a similar procedure to that described in Preparation 45. 'H NMR (500 MHz, CDCh) 8 ppm: 8.90 (br s, 1H), 8.49 (br s, 1H), 7.75 (s, 1H), 7.16 (s, 1H), 4.11-4.13 (m, 2H), 3.72 (t, ./=6,0 Hz, 2H), 3.42 (s, 3H), 2.63 (t, ./=6,0 Hz, 2H), 1.55 (s, 9H), 1.46 (t, J=7.0 Hz, 3H)

Preparation 48 tert-butyl (2-(cyclopropanecarboxamido)-5-ethoxypyridin-4-yl)carbamate

To a solution of tert-butyl (2-bromo-5-ethoxypyridin-4-yl)carbamate (Preparation 23, 200 mg, 0.631 mmol), Pd2(dba)3 (57.8 mg, 0.063 mmol), Xantphos (36.5 mg, 0.063 mmol) and K3PO4 (267.7 mg, 1.26 mmol) in dioxane (8.0 mL) was added cyclopropanecarboxamide (64.4 mg, 0.757 mmol) and the reaction was stirred at 100 °C for 2 h under N2. The cooled reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 1/1) to give tert-butyl (2-(cyclopropanecarboxamido)-5-ethoxypyridin-4-yl)carbamate (210 mg) as a yellow solid. LCMS m/z = 322.1 [M+H] ⁺

Preparation 49

2,4-dichloro-5-(methoxymethyl)pyridine

To a stirring solution of (4,6-dichloro-3-pyridyl)methanol (300 mg, 1.69 mmol) in THF (9 mL) was added NaH (60.66 mg, 2.53 mmol) at 0 °C. The mixture was stirred at rt for 15 mins, then iodomethane (358.80 mg, 2.53 mmol) was added. The reaction mixture was stirred at rt for 4 h then quenched with aq. NH4CI and was extracted with EtOAc. The combined organic extracts were concentrated in vacuo and the crude product was purified (0-100% heptaneZEtOAc- ethanol (3: 1)) to obtain 2,4-dichloro-5-(methoxymethyl)pyridine (225 mg, 69.5% yield) as colorless liquid. LCMS m/z = 192.0 [M+H] ⁺ .

Preparation 50

N-(4-chloro-5-(methoxymethyl)pyridin-2-yl)acetamide

To a stirring solution of 2,4-dichloro-5-(methoxymethyl)pyridine (Preparation 49, 317 mg, 1.65 mmol) and acetamide (97.50 mg, 1.65 mmol) in toluene (2 mL, degassed for 20 mins using N2) were added Josiphos Pd G3 (76.28 mg, 0.083 mmol) and K2CO3 (456.27 mg, 3.30 mmol). The resulting mixture was degassed using N2 then heated at 90 °C for 16 h. The reaction mixture was filtered through Celite® and the crude product was purified by silica gel column chromatography using (0-100%) heptane/EtOAc ZEtOH (3: 1) to obtain N-(4-chloro- 5-(methoxymethyl)pyridin-2-yl)acetamide (211 mg, 59.6 % yield) as an orange colored solid. LCMS m/z = 214.0 [M+H] ⁺ .

Preparation 51

N-(4-chloro-5-methylpyridin-2-yl)acetamide

Cl i xY

H

To a solution of 4-chloro-5-methylpyridin-2-amine (100 mg, 0.70 mmol) in DCM (2 mL) was added AC2O (85.92 mg, 0.84 mmol) and pyridine (77.67 mg, 0.98 mmol) and the mixture was stirred at 25 °C for 16 h. The mixture was added to water (10 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried overlSfeSCU, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 3/1) to give N-(4-chloro-5-methylpyridin-2-yl)acetamide (98 mg, 75.7% yield) as a yellow solid. 'H NMR: (500 MHz, CDCh) 6 ppm : 9.69 (br s, 1H), 8.38 (s, 1H), 7.97 (s, 1H), 2.30 (s, 3H), 2.11 (s, 3H).

Preparation 52 tert-butyl (2-acetamido-5-methylpyridin-4-yl)carbamate

To a solution of N-(4-chloro-5-methylpyridin-2-yl)acetamide (Preparation 51, 90 mg, 0.49 mmol) in dioxane (1 mL) was added NH2B0C (85.66 mg, 0.73 mmol), CS2CO3 (317.66 mg, 0.97 mmol), Xantphos (112.83 mg, 0.19 mmol) and Pd2(dba)3 (89.28 mg, 0.10 mmol) and the mixture was stirred at 120 °C for 16 h under N2. The mixture was added to water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 0/1) to give tert-butyl (2-acetamido-5- methylpyridin-4-yl)carbamate (90 mg, 69.6% yield) as a yellow solid. 1H NMR: (500 MHz, CDCh) 6 ppm : 8.81 (br s, 1H), 7.92 (s, 1H), 7.26 (s, 1H), 6.43 (s, 1H), 2.18 (s, 3H), 2.15 (s, 3H), 1.55 (s, 9H).

Preparation 53 tert-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate

To a solution of tert-butyl (2-acetamidopyridin-4-yl)carbamate (8.4 g, 33.43 mmol) in MeCN (90.0 mL) was added NBS (6.5 g, 36.77 mmol) and the reaction stirred at 70 °C for 1 h. The mixture was concentrated under vacuum and the crude was purified by column chromatography (PE/EtOAc = 1/1 to 0/1) to give tert-butyl (2-acetamido-5-bromopyridin-4- yl)carbamate (9.1 g, 82.5% yield) as a white solid. 'H NMR (500 MHz, CDCh) 8 ppm: 9.07 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.14 (s, 1H), 2.21 (s, 3H), 1.55 (s, 9H).

Preparation 54 tert-butyl (2-acetamido-5-vinylpyridin-4-yl)carbamate

To a solution of tert-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (Preparation 53, 500 mg, 1.51 mmol) in dioxane (5.0 mL) and H2O (1.0 mL) was added 4,4,5,5-tetramethyl-2-vinyl- 1,3,2-dioxaborolane (466.5 mg, 3.03 mmol), Pd(dppf)C12 (110.8 mg, 0.151 mmol) and K2CO3 (418.6 mg, 3.03 mmol) and the reaction was stirred at 100 °C for 2 h under N2. The mixture was poured into H2O (50 mL), extracted with EtOAc (50 mL x 3), the combined organic layer was washed with brine (30 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (PE/EtOAc =20/1 to 1/1) to give tertbutyl (2-acetamido-5-vinylpyridin-4-yl)carbamate (381.6 mg, 90.9% yield) as a yellow solid. ¹ H NMR (500 MHz, CDCl ₃ ) 6 ppm: 8.84 (s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 6.71 (s, 1H), 6.62 (dd, J=17.5 Hz, 11.0 Hz, 1H), 5.64 (d, J=17.5 Hz, 1H), 5.47 (d, J=11.0 Hz, 1H), 2.19 (s, 3H), 1.54 (s, 9H).

Preparation 55 tert-butyl (2-acetamido-5-(prop-l-en-2-yl)pyridin-4-yl)carbamate tert-Butyl (2-acetamido-5-(prop-l-en-2-yl)pyridin-4-yl)carbamate was obtained as a yellow solid, 220 mg, 83.1 % yield, from tert-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (Preparation 53) and 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane, following the procedure described in Preparation 54. 1H NMR (400 MHz, DMSO-de) 8 ppm: 10.40 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.02 (s, 1H), 5.28 (s, 1H), 5.00 (s, 1H), 2.06 (s, 3H), 1.06 (s, 9H).

Preparation 56 tert-butyl (2-acetamido-5-(prop-l-yn-l-yl)pyridin-4-yl)carbamate

To a solution of tert-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (Preparation 53, 500 mg, 1.51 mmol) in DMF (6.0 mL) was added tributyl(prop-l-yn-l-yl)stannane (747.6 mg, 2.27 mmol), NaOAc (62.1 mg, 0.757 mmol) and Pd(PPh3)2C12 (53.2 mg, 0.076 mmol) and the reaction was stirred at 100 °C for 3 h under N2. The mixture was poured into H2O (30 mL), extracted with EtOAc (30 mL x 3), the combined organic layer was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc = 20/1 to 1/1) to give tert-butyl (2- acetamido-5-(prop-l-yn-l-yl)pyridin-4-yl)carbamate (260.8 mg, 59.5% yield) as a white solid. ^X H NMR (400 MHz, CDCh) 8 ppm: 8.90 (br s, 1H), 8.13 (s, 2H), 7.29 (s, 1H), 2.18 (s, 3H), 2.15 (s, 3H), 1.56 (s, 9H).

Preparation 57 tert-butyl (2-acetamido-5-ethylpyridin-4-yl)carbamate

To a solution of tert-butyl (2-acetamido-5-vinylpyridin-4-yl)carbamate (Preparation 54, 361.8 mg, 1.30 mmol) in MeOH (5.0 mL) was added Pd/C (1.4 g, 1.30 mmol, 10% purity) and the reaction was stirred at 20 °C for 2 h under H2 (15 psi). The reaction was filtered and concentrated in vacuo to give tert-butyl (2-acetamido-5-ethylpyridin-4-yl)carbamate (262.1 mg, 71.9% yield) as a white solid.

'H NMR: (400 MHz, CDCh) 6 ppm: 8.81 (s, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 6.50 (s, 1H), 2.52 (q, ./=7,6 Hz, 2H), 2.17 (s, 3H), 1.55 (s, 9H), 1.24 (t, ./=7,6 Hz, 3H).

Preparation 58 tert-butyl (2-acetamido-5-isopropylpyridin-4-yl)carbamate

To a solution of tert-butyl (2-acetamido-5-(prop-l-en-2-yl)pyridin-4-yl)carbamate (Preparation 55, 200 mg, 0.69 mmol) in MeOH (5 mL) was added Pd/C (730.5 mg, 0.69 mmol, 10% purity) and the mixture was stirred at 25 °C for 16 h under H2 (15 psi). The mixture was filtered and the filtrate was concentrated under pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 1/2) to give tert-butyl (2- acetamido-5-isopropylpyridin-4-yl)carbamate (120 mg, 59.6% yield) as a white solid. 1H NMR (500 MHz, CDCh) 8 ppm: 8.80 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 6.56 (s, 1H), 2.90- 2.82 (m, 1H), 2.18 (s, 3H), 1.54 (s, 9H), 1.30 (d, J=6.5 Hz, 6H)

Preparation 59 tert-butyl (2-acetamido-5-propylpyridin-4-yl)carbamate

To a solution of tert-butyl (2-acetamido-5-(prop-l-yn-l-yl)pyridin-4-yl)carbamate (Preparation 56, 260.8 mg, 0.901 mmol) in THF (5.0 mL) was added Pd/C (959.3 mg, 0.901 mmol, 10% purity) and the reaction was stirred at 20 °C for 2 h under H2 (15 psi). The reaction was filtered and the filtrate concentrated to give tert-butyl (2-acetamido-5-propylpyridin-4- yl)carbamate (223.6 mg, 84.6% yield) as a white solid. 'H NMR (400 MHz, CDCh) 6 ppm: 8.81 (br s, 1H), 8.10 (s, 1H), 7.91 (s, 1H), 6.49 (s, 1H), 2.46 (t, J=7.6 Hz, 2H), 2.17 (s, 3H), 1.64-1.59 (m, 2H), 1.55 (s, 9H), 0.98 (t, J=7.2 Hz, 3H).

Preparation 60 tert-butyl (2-acetamido-5-cyclopropylpyridin-4-yl)carbamate To a solution of tert-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (Preparation 53, 200.0 mg, 0.606 mmol) in dioxane (5.0 mL) and H2O (0.5 mL) was added cyclopropylboronic acid (78.1 mg, 0.909 mmol), K2CO3 (251.2 mg, 1.82 mmol) and Pd(dppf)C12 (44.3 mg, 0.061 mmol) and the reaction was stirred at 100 °C for 2 h. The mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel (PE/EtOAc = 5/1 to 0/1) to give tertbutyl (2-acetamido-5-cyclopropylpyridin-4-yl)carbamate (160 mg, 90.7% yield) as yellow oil. LCMS m/z = 292.1 [M+H] ⁺

Preparation 61

N-(4-amino-5-methoxypyridin-2-yl)acetamide hydrochloride

To a solution of tert-butyl (2-acetamido-5-methoxypyridin-4-yl)carbamate (Preparation 35, 15 g, 53.32 mmol) in dioxane (200 mL) was added 4M HCl/di oxane (200 mL) and the reaction was stirred at 20 °C for 1 h. The mixture was filtered and the filter cake was dried in vacuo followed by lyophilization to yield N-(4-amino-5-methoxypyridin-2-yl)acetamide hydrochloride (10.36 g, 84.21% yield) as yellow solid. LCMS m/z = 182 [M+H] ⁺

Preparation 62N-(4-amino-5-ethoxypyridin-2-yl)acetamide hydrochloride

To a solution of tert-butyl (2-acetamido-5-ethoxypyridin-4-yl)(tert- butoxycarbonyl)carbamate (Preparation 5, 500 mg, 1.26 mmol) in dioxane (1 mL) was added 4M HCl/dioxane (5.0 mL) and the reaction was stirred at 25 °C for 2 h. The mixture was evaporated under reduced pressure to give N-(4-amino-5-ethoxypyridin-2-yl)acetamide hydrochloride (440 mg, crude) as a light yellow solid. LCMS m/z = 196.0 [M+H] ⁺ .

Preparation 63

N-(4-amino-5-(2-methoxyethoxy)pyridin-2-yl)acetamide hydrochloride

To a solution of tert-butyl (2-acetamido-5-(2-methoxyethoxy)pyridin-4-yl)carbamate (Preparation 32, 1.0 g, 3.07 mmol) in DCM (10 mL) was added 4M HCl/dioxane (10 mL) and the reaction was stirred at 25 °C for 1 h. The mixture was evaporated under reduced pressure to give N-(4-amino-5-(2-methoxyethoxy)pyri din-2 -yl)acetamide hydrochloride (810 mg, crude) as a brown solid. LCMS m/z = 226.1 [M+H] ⁺ . 'H NMR: (500 MHz, DMSO-de) 8 ppm: 12.94 (br s, 1H), 11.68 (s, 1H), 7.57 (s, 1H), 6.60 (s, 1H), 4.15-4.13 (m, 2H), 3.70-3.68 (m, 2H), 3.31 (s, 3H), 2.17 (s, 3H).

Preparation 64

N-(4-amino-5-(cyclopropylmethoxy)pyridin-2-yl)acetamide hydrochloride

To a solution of tert-butyl (2-acetamido-5-(cyclopropylmethoxy)pyridin-4-yl)carbamate (Preparation 33, 110 mg, 0.342 mmol) in DCM (2 mL) was added 4M HCl/dioxane (5 mL) and the reaction was stirred at 25 °C for 3 h. The mixture was evaporated under reduced pressure to give N-(4-amino-5-(cyclopropylmethoxy)pyridin-2-yl)acetamide hydrochloride (70.0 mg, crude) as a white solid. LCMS m/z = 222.1 [M+H] ⁺ .

Preparations 65 to 81

The compounds in the following table were prepared from the appropriate Boc protected amine, following a similar procedure to that described in Preparation 64.

Preparation 82

N-(4-amino-5-(benzyloxy)pyridin-2-yl)acetamide hydrochloride

To a solution of tert-butyl (2-acetamido-5-(benzyloxy)pyridin-4-yl)carbamate (Preparation 38, 19 g, 53.16 mmol) in dioxane (200 mL) was added 4M HCl/Dioxane (200 mL) and the reaction was stirred at 20 °C for 1 h. The mixture was filtered and the filter cake was dried under reduced pressure followed by lyophilization to yield N-(4-amino-5-(benzyloxy)pyridin- 2-yl)acetamide hydrochloride (14.93 g, 95.4% yield) as a white solid. LCMS m/z = 258.0 [M+H] ⁺

Preparation 83N-(4-amino-5-(ethoxy-d5)pyridin-2-yl)acetamide hydrochloride

To a solution of tert-butyl (2-acetamido-5-(ethoxy-d5)pyridin-4-yl)carbamate (Preparation 40, 1.26 g, 4.19 mmol) in dioxane (10 mL) was added HC1 (4 M, 5.24 mL) and the reaction mixture was stirred at 40 °C for 3 h. The reaction was diluted with dioxane (10 mL), filtered through filter paper to collect the white solids, rinsing with an additional dioxane (10 mL). The solids were dissolved in MeOH (50 mL) and concentrated to dryness, then azeotroped with dioxane, to give N-(4-amino-5-(ethoxy-d5)pyridin-2-yl)acetamide hydrochloride as a white solid, (1.06 g, crude). LCMS m/z = 201.0 [M+H] ⁺ .

Preparation 84 2-(l,l-difluoroethyl)-4-((lr,3r)-3-methoxycyclobutoxy)pyridi ne

To a solution of 4-chloro-2-(l, 1 -difluoroethyl )pyri dine (5.84 g, 32.9 mmol) and (lr,3r)-3- methoxycyclobutan-l-ol (2.8 g, 27.42 mmol) in DMF (50 mL) was added NaH (1.32 g, 32.9 mmol, 60% purity). The reaction mixture was stirred at 60 °C for 16 h, quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (PE/EtOAc = 10/1 - 5/1) to give 2-(l,l-difluoroethyl)-4-((lr,3r)-3-methoxycyclobutoxy)pyridi ne (5 g, 75 % yield) as a colorless oil. 1H NMR (400 MHz, CDCh) 8 ppm: 8.43 (d, J=5.6 Hz, 1H), 7.04 (d, J=1.8 Hz, 6.4 Hz, 1H), 6.73 (dd, J=2.4, 5.6 Hz, 1H), 4.94-4.88 (m, 1H), 4.20-4.09 (m, 1H), 3.28 (s, 3H), 2.54-2.38 (m, 4H), 1.99 (t, J=18.8 Hz , 3H).

Preparation 85

2-( 1 , 1 -difluoroethyl)-4-(( 1 s, 3 s)-3 -m ethoxy cy cl obutoxy)pyri dine

2-(l,l-Difluoroethyl)-4-((ls,3s)-3-methoxycyclobutoxy)pyr idine was obtained as a colorless oil, 3.7 g, 91.4% yield, from 4-chloro-2-(l,l-difluoroethyl)pyridine and (ls,3s)-3- methoxycyclobutan-l-ol following the procedure described in Preparation 84. 1H NMR (400 MHz, CDCh) ppm: 8.43 (d, J = 5.6 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 2.4, 5.6 Hz, 1H), 4.44-4.37 (m, 1H), 3.73-3.66 (m, 1H), 3.28 (s, 3H), 2.96-2.59 (m, 2H), 2.17-2.14 (m, 2H), 1.99 (t, J = 22.4 Hz, 3H).

Preparation 86

2-(l , 1 -difluoroethyl)-4-((lr,3r)-3 -methoxycyclobutoxy)pyridine 1 -oxide

To a solution of 2-(l,l-difluoroethyl)-4-((lr,3r)-3-methoxycyclobutoxy)pyridi ne (Preparation 84, 7 g, 28.78 mmol) in DCM (100 mL) was added m-CPBA (7.31 g, 37.41 mmol, 80% purity) and the reaction was stirred at 25°C for 16 h. The reaction mixture was quenched with sat.Na2S2O3 (280 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EtOAc = 1/1, DCM/MeOH = 10/1) to give 2-(l,l-difluoroethyl)-4-((lr,3r)-3-methoxycyclobutoxy)pyridi ne 1-oxide (7 g, 93.8% yield) as a colorless oil. 1H NMR: (400 MHz, CDCh) 8 ppm 8.14 (d, J=7.2 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.65 (dd, J=2.4, 7.2 Hz, 1H), 4.94-4.79 (m, 1H), 4.16-4.08 (m, 1H), 3.28 (s, 3H), 2.53-2.38 (m, 4H), 2.25 (t, J=19.2 Hz, 3H).

Preparation 87

2-(l , 1 -difluoroethyl)-4-(( 1 s,3 s)-3 -m ethoxy cy cl obutoxy)pyri dine 1 -oxide

2-(l,l-Difluoroethyl)-4-((ls,3s)-3-methoxycyclobutoxy)pyr idine 1-oxide was obtained as a colorless oil, 3.5 g, 88.8% yield, from 2-(l,l-difhioroethyl)-4-((ls,3s)-3- methoxycyclobutoxy)pyridine (Preparation 85) and m-CPBA, following the procedure described in Preparation 86. 'H NMR (400 MHz, CDCh ) 6 ppm 8.19 (d, J= 7.2 Hz, 1H), 7.08 (d, J= 7.2 Hz, 1H), 6.80 (dd, J= 3.4, 7.2 Hz, 1H), 4.41-4.34 (m, 1H), 3.73-3.70 (m, 1H), 3.30 (s, 3H), 2.97-2.90 (m, 2H), 2.25 (t, J= 22.4 Hz, 3H), 2.20-2.16 (m, 2H).

Preparation 88

2-chloro-6-(l,l-difluoroethyl)-4-((lr, 3r)-3 -methoxycyclobutoxy )pyri dine To a solution of 2-(l,l-difluoroethyl)-4-((lr,3r)-3-methoxycyclobutoxy)pyridi ne 1-oxide (Preparation 86, 7 g, 27 mmol) was added POCL (63.6 mL, 682.72 mmol) and the reaction mixture was stirred at 100°C for 16 h. The mixture was concentrated and dissolved in DCM (20 mL). The solution was poured into water (50 mL) and quenched with sat.NaHCOs (40 mL) until pH>8. The aqueous layer was extracted with DCM (80 mL x 3), the combined organic layers were washed with brine (100 mL), dried over ISfeSCU and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE/EtOAc = 10/1) to give 2-chloro-6-(l,l-difluoroethyl)-4-((lr,3r)-3-methoxycyclobuto xy)pyridine (3.8 g, 50.7% yield) as a yellow oil. LCMS m/z = 278.1 [M+H] ⁺

Preparation 89

2-chloro-6-(l,l-difluoroethyl)-4-((ls,3s)-3-methoxycyclob utoxy)pyridine Chloro-6-(l , 1 -difluoroethyl)-4-((l s,3 s)-3 - methoxycyclobutoxy)pyridine was obtained as a yellow oil, from 2-(l,l-difluoroethyl)-4- ((ls,3s)-3-methoxycyclobutoxy)pyridine 1-oxide (Preparation 87), following the procedure described in Preparation 88. LCMS m/z = 278.1 [M+H] ⁺

Preparation 90

2-(l , 1 -difluoroethyl)pyrimidine-4,6-diol

To a solution of malonamide (15.0 g, 146.9 mmol) in EtOH (500 mL) was added t-BuONa (49.4 g, 514.24 mmol) and the solution was stirred at 25 °C for 30 mins. Ethyl 2,2- difluoropropanoate (50.7 g, 367.32 mmol) was added and the reaction stirred under reflux at 100°C for 16 h. The reaction was cooled, 4N HC1 (75 mL) was added and the mixture concentrated. The resulting solid was collected and concentrated to give 2-(l , 1 - difhioroethyl)pyrimidine-4,6-diol (20.0 g, 77.3% yield) as a yellow solid. LCMS m/z = 177.0 [M+H] ⁺ Preparation 91

4, 6-di chi oro-2-(l,l -difluoroethyl )pyrimidine

A solution of 2-(l,l-difluoroethyl)pyrimidine-4,6-diol (Preparation 90, 20.0 g, 113.56 mmol) in POCh (200 mL, 2.15 mol) was stirred at 100 °C for 8 h. The mixture was evaporated to dryness, the residue diluted with DCM (150 mL) and added slowly into water. The mixture was extracted with DCM (200 mL x 3), the combined organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (EtOAc in PE 0% to 10%) to give 4,6-dichloro-2-(l,l- difluoroethyl)pyrimidine (23.0 g, 95.1% yield) as a yellow liquid. LCMS m/z = 213.0 [M+H] ⁺

Preparation 92

4-chloro-2-(l,l-difluoroethyl)-6-methylpyrimidine

To a solution of 4,6-dichloro-2-(l,l-difluoroethyl)pyrimidine (Preparation 91, 75.0 g, 352.1 mmol) in THF (750 mL) and NMP (75 mL) at 23°C was added Fe(acac)3 (12.44 g, 35.21 mmol). The mixture was purged with N2, then cooled to -20°C. To the cooled solution, CEEMgBr (3 M, 117.4 mL) was added dropwise, maintaining the internal temperature at between -20 and -10°C during addition. The resulting mixture was stirred at -20°C for 2 h. The mixture was poured into sat. aq. NH4CI (1.5 L) and extracted with MTBE (1.0 L). The organic layer was washed with brine (100 mL), dried over anhydrous MgSCU, filtered and concentrated. The resulting reddish-brown liquid was purified by Prep-HPLC (Method F, Gradient: 40%-58%). The desired fractions were evaporated in vacuo to remove MeCN. The mixture was extracted with MTBE (500 mL), the organic phase was washed with brine (100 mL), dried over anhydrous MgSCfi, filtered and concentrated to afford 4-chloro-2-(l,l- difluoroethyl)-6-methyl pyrimidine as a yellow liquid. LCMS m/z = 193.1 [M+H] ⁺ .

Preparation 93 2-(l,l-difluoroethyl)-6-methylpyrimidin-4-amine

To a stirring solution of 4-chloro-2-(l,l-difluoroethyl)-6-m ethylpyrimidine (Preparation 92, 200 mg, 1.04 mmol) in anhydrous dioxane (2 mL) were added Pd2(dba)3 (47.55 mg, 0.0519 mmol), Xantphos (60.09 mg, 0.104 mmol) and CS2CO3 (676.70 mg, 2.08 mmol).

Benzophenone imine (225.84 mg, 1.25 mmol) was then added and the reaction mixture was heated to 90 °C for 1 h. The reaction was diluted with EtOAc, washed with water and dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in MeOH (15 mL), NaOAc (196.87 mg, 2.40 mmol) and hydroxylamine hydrochloride (254.33 mg, 3.66 mmol) were added and the reaction stirred for 30 min at rt. The solvent was evaporated and the residue was redissolved in THF. The THF solution was washed once with a solution of 1 N NaOH-brine (1 :3 v/v), dried over MgSO4 and evaporatated under reduced pressure. The residue was purified by silica gel chromatography using 0-100% heptane/EtOAc-EtOH (3: 1) to afford 2-(l,l-difluoroethyl)-6-methylpyrimidin-4-amine (80 mg, 44.5% yield).

1H NMR (500 MHz, MeOH-d ₄ ) 6 6.35 (s, 1H), 2.29 (s, 3H), 1.87 (t, J = 18.6 Hz, 3H).

Preparation 94

4-chloro-2-(l,l-difluoroethyl)-6-ethylpyrimidine

To a solution of 4,6-dichloro-2-(l,l-difluoroethyl)pyrimidine (Preparation 91, 1.5 g, 7.04 mmol) in water (3 mL) and dioxane (15 mL) was added ethylboronic acid (520 mg, 7.04 mmol), K2CO3 (1.46 g, 10.6 mmol) and Pd(dppf)C12 (515 mg, 0.70 mmol) and the mixture was stirred at 100 °C for 16 h under N2. The mixture was diluted with water (10 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (PE/EtOAc 1/0 to 10/1) to give 4-chloro-2-(l,l-difluoroethyl)- 6-ethylpyrimidine (410 mg, 28.2% yield) as a yellow solid. ^T H NMR: (400 MHz, CDCL) 8 ppm: 7.28 (s, 1H), 2.86 (q, J=7.5 Hz, 2H), 2.06 (t, J=18.5 Hz 3H), 1.34 (t, J=7.5 Hz, 3H). Preparation 95

4-chloro-2-( 1 , 1 -difluoroethyl)-6-(prop- 1 -en-2-yl)pyrimidine

To a mixture of 4,6-dichloro-2-(l,l-difluoroethyl)pyrimidine (Preparation 91, 320 mg, 1.50 mmol), 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (252 mg, 1.50 mmol) and K2CO3 (415 mg, 3.00 mmol) in dioxane (10 mL) and water (2 mL) was added Pd(dppf)C12 (110 mg, 0.150 mmol) and the reaction was stirred at 70 °C for 1 h. The reaction mixture was concentrated to dryness and the residue purified by chromatography on silica gel (PE/EtOAc 0/1 to 3/1) to give 4-chloro-2-(l,l-difluoroethyl)-6-(prop-l-en-2-yl)pyrimidine (220 mg, 67.0% yield) as yellow oil. LCMS m/z = 219.1 [M+H] ⁺ .

Preparation 96

4-chloro-6-cy cl opropyl-2-( 1,1 -difluoroethyl )pyrimidine

To a solution of 4,6-dichloro-2-(l,l-difhioroethyl)pyrimidine (Preparation 91, 1.0 g, 4.69 mmol) in dioxane (10.0 mL) and water (1.0 mL) was added cyclopropylboronic acid (483.9 mg, 5.63 mmol), K2CO3 (1.3 g, 9.39 mmol) and Pd (dppf)C12 (343.5 mg, 469.5 umol). The mixture was stirred at 70 °C for 2 h under N2. The mixture was diluted with water (15 mL), extracted with EtOAc (20 mL x 3), the combined organic phase was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (PE/EtOAc = 1/0 to 5/1) to give 4-chloro-6-cyclopropyl-2-(l,l- difhioroethyl)pyrimidine (805.6 mg, 78.5% yield) as colorless oil. LCMS m/z = 219.1 [M+H] ⁺

Preparation 97

4-chloro-2-(l,l-difluoroethyl)-6-methoxypyrimidine

To a solution of 4,6-dichloro-2-(l,l-difluoroethyl)pyrimidine (Preparation 91, 300 mg, 1.41 mmol) in MeOH (5.0 mL) was added NaOMe (76.1 mg, 1.41 mmol) at 0 °C and the reaction was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (PE/EtOAc 15/1 to 5/1) to give 4- chloro-2-(l,l-difluoroethyl)-6-m ethoxypyrimidine (260 mg, 88.5% yield) as colourless oil. 'H N R: (400 MHz, CDCh) 6 ppm: 6.81 (s, 1H), 4.08 (s, 3H), 2.02 (t, J=18.5 Hz, 3H).

Preparation 98

2,4-dichloro-5-fluoro-6-methylpyrimidine

To a solution of 2,4-dichloro-5-fhioropyrimidine (15.0 g, 89.84 mmol) in DME (150.0 mL) was slowly added MeMgBr (3 M, 44.9 mL) at 0 °C under N2 and the mixture was stirred at 15 °C for 1 h. TEA (9.1 g, 89.84 mmol) in THF (10.0 mL) was added, the solution stirred at 0 °C for 5 mins, then I2 (22.8 g, 89.84 mmol) in THF (16.0 mL) was slowly added and the reaction stirred at 15 °C for 2 h. The mixture was quenched with H2O (200 mL) and the pH adjusted to 1 with 5N HC1. The mixture was extracted with EtOAc (150.0 mL x 3), the combined organic phase was washed with brine (300 mL), dried over ISfeSCU, filtered and concentrated in vacuo. The crude was purified by column chromatography on silica gel (PE/EtOAc = 0/1 to 10/1) to give 2,4-dichloro-5-fluoro-6-methylpyrimidine (9.3 g, 57% yield) as yellow oil. 'H NMR (500 MHz, CDCh) 8 ppm: 2.56 (d, ./=2,5 Hz, 3H).

Preparation 99

4-(benzyloxy)-2-chloro-5-fluoropyrimidine A solution of BnOH (6.5 g, 59.89 mmol) and Z-BuONa (5.8 g, 59.9 mmol) in toluene (150.0 mL) was stirred at 0 °C for 10 mins. 2,4-Dichloro-5-fluoropyrimidine (10.0 g, 59.9 mmol) was added slowly and the resulting mixture was stirred at 20 °C for 1 h. The mixture was poured into H2O (100 mL), extracted with EtOAc (3 x 100 mL), the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc = 20/1 to 5/1) to give 4-(benzyloxy)-2- chloro-5-fluoropyrimidine (12.5 g, 87.5% yield) as a white solid. ^X H NMR: (500 MHz, CDCL) 8 ppm: 8.21 (s, 1H), 7.49-7.42 (m, 2H), 7.41-7.38 (m, 3H), 5.51 (s, 2H).

Preparation 100

4-(benzyloxy)-2-chloro-5-fluoro-6-methylpyrimidine

4-(Benzyloxy)-2-chloro-5-fluoro-6-methylpyrimidine was obtained as a colorless oil, 7.9 g, 58.2% yield from 2,4-dichloro-5-fluoro-6-methylpyrimidine (Preparation 98) and BnOH, following the procedure described in Preparation 99. 'H NMR: (500MHz, CDCL) 6 ppm: 7.48-7.46 (m, 2H), 7.42-7.36 (m, 3H), 5.48 (s, 2H), 2.44 (d, J=3.Q Hz, 3H).

Preparation 101 methyl 4-(benzyloxy)-5-fluoropyrimidine-2-carboxylate

To a solution of 4-(benzyloxy)-2-chloro-5-fluoropyrimidine (Preparation 99, 26.0 g, 109 mmol) in MeOH (300 mL) was added Pd(dppf)C12 (1.6 g, 2.18 mmol) and TEA (22.1 g, 217.9 mmol). The resulting mixture was stirred at 80 °C for 16 h under CO (50 psi). The mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (PE/EtOAc = 20/1 to 3/1) to give methyl 4-(benzyloxy)-5-fluoropyrimidine-2-carboxylate (12.0 g, 42% yield) as a white solid. 'H NMR: (400 MHz, CDCL) 6 ppm: 8.44 (d, J=2.0 Hz, 1H), 7.53-7.39 (m, 2H), 7.38-7.35 (m, 3H), 5.61 (s, 2H), 4.03 (s, 3H). Preparation 102 methyl 4-(benzyloxy)-5-fluoro-6-methylpyrimidine-2-carboxylate

Methyl 4-(benzyloxy)-5-fluoro-6-methylpyrimidine-2-carboxylate was obtained as a yellow oil, 3.1 g, 35.8% yield from 4-(benzyloxy)-2-chloro-5-fluoro-6-methylpyrimidine (Preparation 100) and MeOH, following the procedure described in Preparation 101. 'H NMR: (400 MHz, CDCh) 8 ppm: 7.53-7.51 (m, 2H), 7.40-7.35 (m, 3H), 5.58 (s, 2H), 4.03 (s, 3H), 2.55 (d, J=2.8 Hz, 3H).

Preparation 103

1 -(4-(benzyloxy)-5 -fluoropyrimidin-2-yl)ethan- 1 -one

To a solution of methyl 4-(benzyloxy)-5-fluoropyrimidine-2-carboxylate (Preparation 101, 12.0 g, 45.76 mmol) in THF (120 mL) was added dropwise MeMgBr (3 M, 18.30 mL) at -78 °C and the solution was stirred for 2 h under N2. The mixture was quenched with NH4CI (sat. 30 mL) at -78 °C, poured into H2O (60 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc = 20/1 to 3/1) to give l-(4-(benzyloxy)-5-fluoropyrimidin-2-yl)ethan-l-one (7.3 g, 64.8% yield) as a white solid. 'H NMR: (400 MHz, CDCh) 6 ppm: 8.45 (d, ./=2,0 Hz, 1H), 7.52-7.49 (m, 2H), 7.42- 7.37 (m, 3H), 5.60 (s, 2H), 2.73 (s, 3H).

Preparation 104 l-(4-(benzyloxy)-5-fluoro-6-methylpyrimidin-2-yl)ethan-l-one l-(4-(Benzyloxy)-5-fluoro-6-methylpyrimidin-2-yl)ethan-l-one was obtained as a yellow oil, 1.6 g, 54.8% yield, from methyl 4-(benzyloxy)-5-fluoro-6-methylpyrimidine-2-carboxylate (Preparation 102, and MeMgBr following the procedure described in Preparation 103. 'H NMR (400 MHz, CDCh) 6 ppm: 7.51-7.49 (m, 2H), 7.40-7.36 (m, 3H), 5.57 (s, 2H), 2.71 (s, 3H), 2.54 (d, J=3.2 Hz, 3H).

Preparation 105

4-(benzyloxy)-2-(l,l-difluoroethyl)-5-fluoropyrimidine

To a solution of l-(4-(benzyloxy)-5-fluoropyrimidin-2-yl)ethan-l-one (Preparation 103, 7.3 g, 29.65 mmol) in DCM (80.0 mL) was added DAST (23.9 g, 148.23 mmol). The resulting mixture was stirred at 20 °C for 12 h. The mixture was slowly poured into H2O (80 mL), extracted with DCM (3 x 80 mL), the combined organic extracts were washed with brine (2 x 80 mL), dried over TsfeSCU and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (PEZEtOAc = 20/1 to 5/1) to give 4-(benzyloxy)-2-(l,l-difluoroethyl)-5-fluoropyrimidine (6.7 g, 84 % yield) as colorless oil. 'H NMR: (400 MHz, CDCh) 8 ppm: 8.38 (d, ./=2,4 Hz, 1H), 7.51-7.40 (m, 2H), 7.39- 7.36 (m, 3H), 5.56 (s, 2H), 2.02 (t, J=18.4 Hz, 3H).

Preparation 106

4-(benzyloxy)-2-(l,l-difluoroethyl)-5-fluoro-6-methylpyri midine

4-(Benzyloxy)-2-(l,l-difluoroethyl)-5-fluoro-6-methylpyri midine was obtained, 1.6 g, 95.9% yield, as a yellow oil, from l-(4-(benzyloxy)-5-fluoro-6-methylpyrimidin-2-yl)ethan-l-one (Preparation 104) following the procedure described in Preparation 105. 'H NMR (500 MHz, CDCh) 6 ppm: 7.48-7.46 (m, 2H), 7.38-7.32 (m, 3H), 5.51 (s, 2H), 2.48 (d, J=3.0 Hz, 3H), 1.98 (t, ./= I 8,O Hz, 3H).

Preparation 107

2-( 1 , 1 -difluoroethyl)-5 -fluoropyrimidin-4-ol

A solution of 4-(benzyloxy)-2-(l,l-difluoroethyl)-5-fluoropyrimidine (Preparation 105, 6.7 g, 24.9 mmol) in TFA (40 mL) was stirred at 100 °C for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (PE/EtOAc = 20/1 to 3/1) to give 2-(l,l-difluoroethyl)-5-fluoropyrimidin-4-ol (3.2 g, 72.1% yield) as a white solid. 'H NMR: (400 MHz, CDCh) 8 ppm: 11.61 (br s, 1H), 7.93 (d, ./=2,4 Hz, 1H), 2.03 (t, J=18.8 Hz, 3H).

Preparation 108

2-( 1 , 1 -difluoroethyl)-5 -fluoro-6-methylpyrimidin-4-ol

2-(l,l-Difluoroethyl)-5-fluoro-6-methylpyrimidin-4-ol was obtained as a colorless oil, 780 mg, 73.5%, from from 4-(benzyloxy)-2-(l,l-difluoroethyl)-5-fluoro-6-methylpyrimid ine (Preparation 106) following the procedure described in Preparation 107. 'H NMR: (500 MHz, CDCh) 6 ppm: 2.40 (d, J=3.5 Hz, 3H), 2.02 (t, J=18.5 Hz, 3H).

Preparation 109

4-chloro-2-(l,l-difluoroethyl)-5-fluoropyrimidine A solution of 2-(l,l-difluoroethyl)-5-fluoropyrimidin-4-ol (Preparation 107, 3.2 g, 18 mmol) in POCh (20.0 mL) was stirred at 100 °C for 2 h. The mixture was slowly poured into ice/water (50 mL) and extracted with EtOAc (3 x 60 mL). The combined organic phase was washed with brine (2 x 50 mL), dried over ISfeSCU and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (PE/EtOAc = 20/1 to 5/1) to give 4-chloro-2-(l,l-difluoroethyl)-5-fluoropyrimidine (2.3 g, 65.1% yield) as colorless oil. LCMS m/z = 197.1 [M+H] ⁺

Preparation 110

4-chloro-2-(l,l-difluoroethyl)-5-fluoro-6-methylpyrimidin e

4-Chloro-2-(l,l-difluoroethyl)-5-fluoro-6-methylpyrimidin e was obtained as a colorless oil, 3.1 g, 90.7% yield from 2-(l,l-difluoroethyl)-5-fluoro-6-methylpyrimidin-4-ol (Preparation 108) following the procedure described in Preparation 109. LCMS m/z = 211 [M+H] ⁺

Preparation 111

4-chloro-2-(l,l-difluoroethyl)-6-((lr, 3r)-3 -methoxycyclobutoxy )pyrimidine solution of 4,6-dichloro-2-(l,l-difluoroethyl)pyrimidine

(Preparation 91, 400 mg, 1.88 mmol) and CS2CO3 (1.9 g, 5.63 mmol) in DMF (6.0 mL) was added (lr,3r)-3-methoxycyclobutan-l-ol (211 mg, 2.07 mmol) and the reaction was stirred at 25 °C for 1 h. The mixture was diluted with water (80 mL) and extracted with EtOAc (40 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give 4-chloro-2-(l,l-difluoroethyl)-6-((lr,3r)-3- methoxycyclobutoxy)pyrimidine (450 mg, 86.0% yield) as a yellow oil. LCMS m/z = 278.9 [M+H] ⁺ . 'H NMR: (400 MHz, CDCh) 8 ppm: 6.77 (s, 1H), 5.47-5.41 (m, 1H), 4.15-4.08 (m, 1H), 3.27 (s, 3H), 2.57-2.49 (m, 2H), 2.43-2.40 (m, 2H), 1.99 (t, J=18.4 Hz, 3H).

Preparation 112 4-chloro-2-(l,l-difluoroethyl)-6-(2-m ethoxy ethoxy)pyrimidine

To a solution of 4,6-dichloro-2-(l,l-difluoroethyl)pyrimidine (Preparation 91, 200 mg, 0.939 mmol) and 2-methoxyethan-l-ol (78.6 mg, 1.03 mmol) in DMF (2 mL) was added CS2CO3 (918 mg, 2.82 mmol) and the reaction was stirred at 25 °C for 1 h. The mixture was concentrated and then water (10 mL) was added. The aquesous mixture was extracted with EtOAc (10 mL x 3), the combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (PEZEtOAc 3/1) to afford 4-chloro-2-(l,l-difluoroethyl)-6-(2-methoxy ethoxy )pyrimidine (150 mg, 63.2% yield) as a yellow oil. 'H NMR: (500 MHz, CDCh) 6 ppm: 6.86 (s, 1H), 4.62-4.60 (m, 2H), 3.75-3.74 (m, 2H), 3.43 (s, 3H), 2.05-1.97 (m, 3H).

Preparation 113

3 -(benzyl oxy)- 1 -m ethyl cy cl obutan- 1 -ol

To a solution of 3-(benzyloxy)cyclobutan-l-one (5.0 g, 28.4 mmol) in THF (50 mL) was added CH MgCl (3 M, 10.4 mL) at -78 °C under N2 and the reaction was stirred at 25 °C for 2 h. The mixture was diluted with water (60 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (60 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by chromatography on silica gel (PEZEtOAc 1/0 to 1/1) to give 3 -(benzyl oxy)- 1 -methyl cyclobutan-l-ol (4.9 g, 89.5% yield) as colorless oil. 'H NMR: (400 MHz, CDCh) 8 ppm: 7.35-7.28 (m, 5H), 4.42 (s, 2H), 3.76-3.69 (m, 1H), 2.47-2.42 (m, 2H), 2.12-2.09 (m, 2H), 1.31 (s, 3H).

Preparation 114

(3-(benzyloxy)-l-methylcyclobutoxy)(tert-butyl)dimethylsi lane To a solution of 3 -(benzyloxy)- 1 -methyl cy cl obutan-l-ol (Preparation 113, 2.0 g, 10.4 mmol) and imidazole (3.5 g, 52.0 mmol) in DCM (50 mL) was added TBSC1 (2.8 g, 18.7 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 h then diluted with water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous ISfeSCU, filtered and concentrated. The crude was purified by chromatography on silica gel (PE/EtOAc 3/1) to give (3-(benzyloxy)-l- methylcyclobutoxy)(tert-butyl)dimethylsilane (2.5 g, 78.4% yield) as colorless oil. 'H NMR: (500 MHz, CDCh) 8 ppm: 7.34-7.28 (m, 5H), 4.40 (s, 2H), 3.69-3.63 (m, 1H), 2.40-2.36 (m, 2H), 2.16-2.14 (m, 2H), 1.28 (s, 3H), 0.87 (s, 9H), 0.07 (s, 6H).

Preparation 115

3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutan-l-ol

To a solution of (3-(benzyloxy)-l-methylcyclobutoxy)(tert-butyl)dimethylsilan e (Preparation 114, 2.5 g, 8.16 mmol) in MeOH (200 mL) was added Pd/C (868 mg, 0.816 mmol, 10% purity) under H2 (40 psi) and the reaction was stirred at 25 °C for 32 h. The mixture was filtered and concentrated to give 3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutan-l-ol (1.8 g, crude) as colorless oil. 'H NMR: (500 MHz, CDCh) 6 ppm: 3.94-3.90 (m, 1H), 2.48- 2.44 (m, 2H), 2.08-2.05 (m, 2H), 1.28 (s, 3H), 0.88 (s, 9H), 0.07 (s, 6H).

Preparation 116

4-(3 -((tert-butyl dimethyl silyl)oxy)-3-methylcyclobutoxy)-6-chloro-2-( 1,1- difluoroethyl)pyrimidine

To a solution of 3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutan-l-ol (Preparation 115, 300 mg, 1.39 mmol) in THF (10 mL) was added NaH (83.2 mg, 2.08 mmol, 60% purity) at 0 °C. The mixture was stirred at 25 °C for 30 mins followed by addition of 4,6-dichloro-2-(l,l- difluoroethyl)pyrimidine (Preparation 91, 354 mg, 1.66 mmol). The mixture was stirred at 25 °C for 1 h, then diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by chromatography on silica gel (PE /EtOAc 1/0 to 10/1) to give 4-(3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutoxy)-6- chloro-2-(l,l-difluoroethyl)pyrimidine (400 mg, 73.4% yield) as colorless oil. 'H NMR: (400 MHz, CDCh) 8 ppm: 6.77 (s, 1H), 4.94-4.86 (m, 1H), 2.67-2.62 (m, 2H), 2.31-2.28 (m, 2H), 2.00 (t, J=18.4 Hz, 1H), 1.40 (s, 3H), 0.88 (s, 9H), 0.08 (s, 6H).

Preparation 117

N-(5-bromo-2-chloropyridin-4-yl)-6-chloro-2-(l,l-difluoro ethyl)pyrimidin-4-amine

A mixture of 5-bromo-2-chloropyridin-4-amine (250 mg, 1.21 mmol), CS2CO3 (1 g, 3.07 mmol) and DMF (5 mL) was stirred for 5 mins, then 4,6-dichloro-2-(l,l- difhioroethyl)pyrimidine (Preparation 91, 300 mg, 1.41 mmol) was added and the reaction stirred at 35 °C for 2 h. The reaction was concentrated to remove solvent, then diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated to dryness and the crude product purified by silica gel chromatography (heptane to 50% EtOAc) to give N-(5-bromo-2-chloropyridin-4-yl)-6-chloro-2-(l,l- difhjoroethyl)pyrimidin-4-amine (415 mg, 89.7% yield). LCMS m/z = 385.1 [M+H] ⁺ . 1H NMR (DMSO-d ₆ ) 6: 9.91 (s, 1H), 8.60 (s, 1H), 8.33 (s, 1H), 7.55-7.44 (m, 1H), 1.98 (t, J=18.9 Hz, 3H).

Preparation 118

N-(5-bromo-2-chloropyridin-4-yl)-2-(l,l-difluoroethyl)-6- methoxypyrimidin-4-amine To a solution of N-(5-bromo-2-chloropyridin-4-yl)-6-chloro-2-(l,l-difluoroeth yl)pyrimidin- 4-amine (Preparation 117, 415 mg, 1.08 mmol) in MeOH (10 mL) was added K2CO3 (400 mg) and the reaction stirred at 70 °C for 20 h. The cooled reaction was concentrated to dryness, diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated to dryness and purified by silica gel chromatography (heptane to 50% EtOAc) to give N-(5-bromo-2-chloropyridin-4-yl)-2-(l,l-difluoroethyl)-6- methoxypyrimidin-4-amine (390 mg, 95.4% yield). LCMS m/z = 381.1 [M+H] ⁺

Preparation 119

N-(2-chloro-5-(l -methyl- lH-pyrazol-3-yl)pyri din-4-yl)-2-(l, 1 -difluoroethyl)-6- methoxypyrimidin-4-amine

To a vial was added N-(5-bromo-2-chloropyridin-4-yl)-2-(l,l-difluoroethyl)-6- methoxypyrimidin-4-amine (Preparation 118, 150 mg, 0.395 mmol), l-methyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (100 mg, 0.481 mmol), K2CO3 (150 mg, 1.09 mmol) and Pd(dppf)C12 (15 mg, 0.0205 mmol) in dioxane (3 mL) and water (1 mL), the vial sealed and the reaction stirred at 80 °C for 20 h. The reaction was removed from heating, cooled to rt, diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated to dryness, then purified by silica gel chromatography (100% heptane to 100% EtOAc) to give a white solid, N-(2-chloro-5-(l- methyl-lH-pyrazol-3-yl)pyridin-4-yl)-2-(l,l-difluoroethyl)-6 -methoxypyrimidin-4-amine (30 mg, 19.9% yield). LCMS m/z = 381.3 [M+H] ⁺ . 1H NMR (DMSO-d ₆ ) 8: 11.60 (s, 1H), 8.84 (s, 1H), 8.77 (s, 1H), 8.01-7.89 (m, 1H), 7.09-6.94 (m, 1H), 6.67 (s, 1H), 4.05 (s, 3H), 3.98 (s, 3H), 2.08 (s, 6H), 1.07 (s, 2H).

Preparation 120

N-(4-((6-(3-((tert-butyldimethylsilyl)oxy)-3-methylcyclob utoxy)-2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)ace tamide

To a solution of 4-(3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutoxy)-6-c hloro-2-(l,l- difhioroethyl)pyrimidine (Preparation 116, 100 mg, 0.512 mmol) in dioxane (5 mL) was added N-(4-amino-5-ethoxypyridin-2-yl)acetamide hydrochloride (Preparation 62, 221 mg, 0.563 mmol), Brettphos Pd G3 (46.4 mg, 0.0512 mmol) and CS2CO3 (334 mg, 1.02 mmol). The mixture was stirred at 100 °C for 2 h under N2 then diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by chromatography on silica gel (DCM/MeOH 1/0 to 10/1) to give N-(4-((6-(3 -((tertbutyl dimethylsilyl)oxy)-3-methylcy cl obutoxy)-2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5- ethoxypyridin-2-yl)acetamide (225 mg, crude) as a yellow solid. LCMS m/z = 552.3 [M+H] ⁺ . 'H NMR: (400 MHz, CDCh) 8 ppm: 8.73 (s, 1H), 7.95 (s, 1H), 7.80 (s, 1H), 7.51 (s, 1H), 6.43 (s, 1H), 4.89-4.82 (m, 1H), 4.17 (q, J=6.8 Hz, 2H), 2.66-2.61 (m, 2H), 2.35-2.29 (m, 2H), 2.19 (s, 3H), 2.06 (t, J=18.4 Hz, 3H), 1.49 (t, J=7.2 Hz, 1H), 1.41 (s, 3H), 0.88 (s, 9H), 0.08 (s, 6H).

Preparation 121

N-(4-((2-(l,l-difluoroethyl)-6-(prop-l-en-2-yl)pyrimidin- 4-yl)amino)-5-methoxypyri din-2- yl)acetamide

To a mixture of 4-chloro-2-(l,l-difluoroethyl)-6-(prop-l-en-2-yl)pyrimidine (Preparation 95, 180 mg, 0.823 mmol), N-(4-amino-5-methoxypyridin-2-yl)acetamide hydrochloride (Preparation 61, 179 mg, 0.988 mmol) and CS2CO3 (536 mg, 1.65 mmol) in DMF (4 mL) was added BrettPhos Pd G3 (74.6 mg, 0.823 mmol) at 20 °C. The reaction mixture was stirred at 70 °C for 2 h. The mixture was concentrated and the residue was purified by prep-HPLC (Method C, Gradient: 42 to 72%) to give N-(4-((2-(l,l-difluoroethyl)-6-(prop-l-en-2- yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide (60 mg, 20.1% yield) as a white solid. LCMS m/z = 364.2 [M+H] ⁺ .

Preparation 122

N-(4-((2-(l,l-difluoroethyl)-6-(prop-l-en-2-yl)pyrimidin- 4-yl)amino)-5-ethoxypyri din-2- yl)acetamide

N-(4-((2-(l,l-Difluoroethyl)-6-(prop-l-en-2-yl)pyrimidin- 4-yl)amino)-5-ethoxypyri din-2- yl)acetamide was obtained as a white solid, 60 mg, 17.4% yield, from 4-chloro-2-(l,l- difhioroethyl)-6-(prop-l-en-2-yl)pyrimidine (Preparation 95) and N-(4-amino-5- ethoxypyridin-2-yl)acetamide hydrochloride (Preparation 62), following a similar procedure to that described in Preparation 121, except HPLC (Method B, Gradient 37 to 66%) was used. LCMS m/z = 378.3 [M+H] ⁺

Preparation 123

6-methoxy-5-(l -methyl- lH-pyrazol-3-yl)pyridin-2-amine

To a mixture of 5-bromo-6-methoxy-pyridin-2-amine (55 mg, 0.271 mmol), Pd(dppf)C12 (15.28 mg, 0.0209 mmol), K2CO3 (122.22 mg, 0.884 mmol) and l-methyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (76.39 mg, 0.367 mmol) was added dioxane (2 mL) and water (1 mL) and the reaction stirred at rt for 10 mins while degassing by bubbling N2. The vial was sealed and heated to 90 °C for 1 h. The reaction was diluted with water (10 mL), extracted with EtOAc (4 x 10 mL) and the combined organic layers concentrated in vacuo. The crude product was purified by silica gel chromatography (heptane to EtOAc) to give a clear colorless thick oil, 6-methoxy-5-(l-methyl-lH-pyrazol-3-yl)pyridin-2-amine (45 mg, 81.3% yield). LCMS m/z = 205.2 [M+H] ⁺ .

Preparation 124

6-chloro-2-methoxy-3-(l-methyl-lH-pyrazol-3-yl)pyridine

A mixture of 3-bromo-6-chloro-2-methoxy-pyridine (100 mg, 0.45 mmol), Pd(dppf)C12 (25 mg, 34.2 umol), K2CO3 (200 mg, 1.45 mmol) and l-methyl-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazole (125 mg, 0.601 mmol) in dioxane (2 mL) and water (1 mL) was stirred at rt for 10 mins while degassing by bubbling N2. The vial was sealed and heated to 90 °C for 1 h. The reaction was diluted with water (10 mL), extracted with EtOAc (4 x 10 mL) and the combined organic layers concentrated in vacuo. The residue was purified by silica gel chromatography (heptane to EtOAc) to give 6-chloro-2-methoxy-3-(l- methylpyrazol-3-yl)pyridine (73 mg, 72.6% yield) as a thick oil. LCMS m/z = 404.2 [M+ H] ⁺ . 'H NMR (DMSO-de) 8: 8.25 (d, J=7.6 Hz, 1H), 7.73-7.82 (m, 1H), 7.11-7.19 (m, 1H), 6.70-6.78 (m, 1H), 3.97 (s, 3H), 3.90 (s, 3H).

Preparation 125

4-chloro-2-(l,l-difluoroethyl)-6-vinylpyrimidine

A suspension of potassium vinyltrifluoroborate (1.38 g, 10.33 mmol) and 4,6-dichloro-2-(l,l- difluoroethyl)pyrimidine (Preparation 91, 2 g, 9.39 mmol) in MeCN (40 mL) and water (10 mL) was sparged with N2 for 10 min. K2CO3 (2.60 g, 18.8 mmol) and Pd(PPh3)4 (185 mg, 0.160 mmol) were added and the resulting mixture was heated to reflux for 18h. The reaction was concentrated under reduced pressure and the residue was partitioned between DCM and water. The layers were separated and the aqueous was extracted with DCM (2x). The combined organic extracts were dried (MgSCU), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% EtOAc in heptanes) to give 4- chloro-2-(l,l-difluoroethyl)-6-vinylpyrimidine (778 mg, 40% yield) as a colorless liquid. LCMS m/z = 205.0 [M+H] ⁺ .

Preparation 126

6-chloro-N-methoxy-N,4-dimethylpicolinamide

To a solution of 6-chloro-4-methylpicolinic acid (1.0 g, 5.83 mmol) in DCM (10 mL) was added DMF (42.6 mg, 0.583 mmol), followed by dropwise addition of oxalyl chloride (791.5 mg, 6.24 mmol). After 1.2 h, N,O-dimethylhydroxylamine (886.8 mg, 9.09 mmol) was added and the reaction mixture was cooled to 0 °C. Pyridine (2.1 g, 26.81 mmol) was added and the reaction mixture was allowed to warm to rt and stirred for 72 h. The reaction mixture was quenched by the addition of water and the layers were separated. The aqueous phase was extracted with DCM (10 mL x 3) and the combined organic layer was washed with brine (20 mL), dried with Na2SO4, filtered and concentrated. The crude was purified by column chromatography (PE/EtOAc = 3/1 to 0/1) on silica gel to give 6-chloro-N-methoxy-N,4- dimethylpicolinamide (600 mg, 48.0% yield) as yellow oil. LCMS m/z = 215.1 [M+H] ⁺

Preparation 127

1 -(6-chloro-4-methylpyri din-2 -yl)ethan- 1 -one

Under N2, to a solution of 6-chloro-N-methoxy-N,4-dimethylpicolinamide (Preparation 126, 600 mg, 2.80 mmol) in THF (10.0 mL) was added MeMgBr (3 M, 3.7 mL, 11.1 mmol) slowly at -60 °C and the mixture was stirred at 0 °C for 5 h under N2. The reaction mixture was quenched by the addition of saturated aqueous NH4CI solution and extracted with EtOAc (80.0 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified on silica gel column chromatography (PEZEtOAc= 10/1 to 3/1) to give l-(6-chloro-4-methylpyri din-2 -yl)ethan-l- one (460 mg, 97.0% yield) as a white solid. LCMS m/z = 170.1 [M+H] ⁺ Preparation 128

2-chloro-6-(l,l-difluoroethyl)-4-methylpyridine

To a solution of l-(6-chloro-4-methylpyridin-2-yl)ethan-l-one (Preparation 127, 460.0 mg, 2.71 mmol) in DCM (10 mL) was added DAST (5.0 mL, 37.84 mmol) and the solution stirred at 60 °C for 12 h. The reaction was concentrated and diluted with H2O (10 mL). The mixture was extracted with DCM (10 mL x 2) and washed with brine (10 mL x 2). The combined organic phase was concentrated and purified by column chromatography (PE/EtOAc = 15/1 to 5/1) on silica gel to give 2-chloro-6-(l,l-difluoroethyl)-4- methylpyridine (379.0 mg, 72.9% yield) as yellow oil. LCMS m/z = 191.9 [M+H] ⁺

Preparation 129

2-(6-bromopyridin-2-yl)propan-2-ol

To a solution of l-(6-bromopyridin-2-yl)ethan-l-one (1 g, 5.0 mmol) in THF (10 mL) was added MeMgBr (3 M, 2.50 mL, 7.5 mmol) slowly at 0 °C and the reaction stirred for 12 h at rt under N2. The reaction was concentrated, diluted with H2O (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over Na2SO4 and filtered. The mixture was concentrated and the residue was purified by chromatography on silica gel (PE/EtOAc = 3/1) to give 2-(6-bromopyridin-2-yl)propan-2-ol (910 mg, 84% yield) as a white oil. 'H NMR: (400 MHz, CDCh) 8 ppm: 7.57-7.53 (m, 1H), 7.39-7.26 (m, 2H), 4.06 (br s, 1H), 1.54 (s, 6H).

Preparation 130

2-bromo-6-(2-fluoropropan-2-yl)pyridine j

To a solution of 2-(6-bromopyridin-2-yl)propan-2-ol (Preparation 129, 200 mg, 0.926 mmol) in DCM (3.0 mL) was added DAST (298.4 mg, 1.85 mmol) and the reaction was stirred at 20 °C for 12 h. The mixture was quenched with aq. Na2COs (20 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (PE /EtOAc = 3/1) to give 2-bromo-6- (2-fhioropropan-2-yl)pyridine (190 mg, 94.1% yield) as a yellow oil. 1H NMR: (400 MHz, CDCh) 8 ppm: 7.58-7.49 (m, 2H), 7.38 (d, J=7.6 Hz, 1H), 1.73 (s, 3H), 1.67 (s, 3H).

Preparation 131

2 -bromo-6-(l,l-difluoroethyl)-4-m ethoxypyridine

2-Bromo-6-(l,l-difluoroethyl)-4-methoxypyridine was obtained as a yellow oil, 420 mg, crude, from l-(6-bromo-4-methoxypyridin-2-yl)ethan-l-one , following a similar procedure to that described in Preparation 130. LCMS m/z = 252.0 [M+H] ⁺

Preparation 132

1 -(2-chloro-6-methylpyrimidin-4-yl)ethan- 1 -one

To a solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (985 mg, 5.28 mmol) in THF (10 mL) was added MeMgBr (3 M, 1.76 mL) at 0°C under N2. The reaction mixture was stirred for 5 h, then hydrolysed with H2O (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE/EtOAc 5/1) to give l-(2-chloro-6- methylpyrimidin-4-yl)ethan-l-one (147 mg, 16.3% yield) as white solid. 'H NMR: (400 MHz, CDCh) 6 ppm: 7.69 (s, 1H), 2.70 (s, 3H), 2.63 (s, 3H).

Preparation 133

2-chloro-4-(l,l-difluoroethyl)-6-methylpyrimidine

2-Chloro-4-(l,l-difluoroethyl)-6-methyl pyrimidine was obtained as a yellow oil, 114 mg, 84.1% yield, from l-(2-chloro-6-methylpyrimidin-4-yl)ethan-l-one (Preparation 132) and DAST following the procedure described in Preparation 128. ^X H NMR: (500 MHz, CDCL) 8 ppm: 7.42 (s, 1H), 2.62 (s, 3H), 1.98 (t, J=19.0 Hz, 3H).

Preparation 134

4-(benzyloxy)-2-chloro-6-methylpyrimidine

Under N2, to a solution of 2,4-dichloro-6-methylpyrimidine (10 g, 61.35 mmol) in THF (60 mL) and DMF (20 mL) was added t-BuOK (1 M, 61.35 mL) and benzyl alcohol (13.27 g, 122.7 mmol) dropwise at -70 °C and the mixture was stirred at -70 °C for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH4CI solution (10 mL). The mixture was concentrated under reduced pressure and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (50 mL), dried over ISfeSCU, filtered and concentrated to give a residue, which was purified on silica gel column chromatography (PE/EtOAc = 9/1) to give 4-(benzyloxy)-2-chloro-6-methylpyrimidine (4.9 g, 34.0% yield) as a colorless oil. 1H NMR (500 MHz, MeOH-d ₄ ) ppm: 7.34-7.45 (m, 5H), 6.72 (s, 1H), 5.41 (s, 2H), 2.40 (s, 3H).

Preparation 135

Methyl 4-(benzyloxy)-6-methylpyrimidine-2-carboxylate

To a solution of 4-(benzyloxy)-2-chloro-6-methylpyrimidine (Preparation 134, 4.5 g, 19.17 mmol) and TEA (9.7 g, 95.87 mmol) in MeOH (50 mL) was added Pd(dppf)C12 (1.40 g, 1.92 mmol) and the reaction was stirred at 80 °C for 16 h under CO (50 psi). The mixture was concentrated under reduced pressure to give a residue which was purified on silica gel column chromatography (PE/EtOAc = 9/1 to 5/1) to give methyl 4-(benzyloxy)-6- methylpyrimidine-2-carboxylate (2.8 g, 56%) as a green oil. 'H NMR (500 MHz, MeOH-ch) 8: 7.28-7.53 (m, 5H), 6.94 (s, 1H), 5.50 (s, 2H), 4.00 (s, 3H), 2.50 (s, 3H).

Preparation 136 l-(4-(benzyloxy)-6-methylpyrimidin-2-yl)ethan-l-one l-(4-(Benzyloxy)-6-methylpyrimidin-2-yl)ethan- 1-one was obtained as a yellow oil, 312 mg, 13%, from methyl 4-(benzyloxy)-6-methylpyrimidine-2-carboxylate (Preparation 135), and CHsMgBr, following a similar procedure to that described in Preparation 129. LCMS m/z = 243.0 [M+H] ⁺ .

Preparation 137

4-(benzyloxy)-2-(l,l-difluoroethyl)-6-m ethylpyrimidine

4-(Benzyloxy)-2-(l,l-difluoroethyl)-6-m ethylpyrimidine was obtained as a yelow oil, 208 mg, 61% from l-(4-(benzyloxy)-6-methylpyrimidin-2-yl)ethan-l-one (Preparation 136), following the procedure described in Preparation 128. LCMS m/z = 265.1 [M+H] ⁺ .

Preparation 138

2-(l,l-difluoroethyl)-6-methylpyrimidin-4-ol

A mixture of 4-(benzyloxy)-2-(l,l-difluoroethyl)-6-methylpyrimidine (Preparation 137, 208 mg, 0.8 mmol) and TFA (1 mL) was stirred at 100 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue, which was purified on silica gel column chromatography (DCM/MeOH = 19/1) to give 2-(l,l-difhioroethyl)-6-methylpyrimidin-4-ol (124 mg, 90%) as a yellow solid. 'H NMR (500 MHz, MeOH-d ₄ ) 6: 6.37 (s, 1H), 2.34 (s, 3H), 1.98 (t, 3H).

Preparation 139

4-chloro-2-(l,l-difluoroethyl)-6-methylpyrimidine

A mixture of 2-(l,l-difluoroethyl)-6-methylpyrimidin-4-ol (Preparation 138, 124 mg, 0.7 mmol) and POCL(1 mL) was stirred at 100 °C for 1 h. The reaction mixture was added to ice water (5 mL) dropwise and extracted with EtOAc (10 mL x 3). The combined organics were washed with brine (15 mL), dried (Na2SO ₄ ) and evaporated to dryness in vacuo to give 4- chloro-2-(l,l-difluoroethyl)-6-m ethylpyrimidine (86 mg, 63%) as a brown oil. LCMS m/z = 193.1 [M+H]+.

Preparation 140

4-(benzyloxy)-2-(l,l-difluoroethyl)-6-(prop-l-en-2-yl)pyr imidine

Step 1 : To a solution of 4,6-dichloro-2-(l,l-difluoroethyl)pyrimidine (Preparation 91, 5.0 g, 23.47 mmol) in THF (40 mL) was added NaH (1.9 g, 46.95 mmol, 60 % purity) and BnOH (2.7 g, 24.55 mmol) and the reaction stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to give crude 4-(benzyloxy)-6-chloro-2-(l,l-difluoroethyl)pyrimidine. Step 2: To 4-(benzyloxy)-6-chloro-2-(l,l-difluoroethyl)pyrimidine (6.7 g, 23.5 mmol) was added THF and water (10 mL), then 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2- dioxaborolane (7.9 g, 46.9 mmol), K2CO3 (10.0 g, 72.4 mmol) and Pd(dppf)C12 (1.7 g, 2.35 mmol) and the reaction stirred at 70 °C for 2 h under N2. The mixture was quenched with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO ₄ , filtered and concentrated under vacuum to give the crude, which was purified on silica gel column chromatography (PEZEtOAc = 1/0 to 10/1) to give 4-(benzyloxy)-2-(l,l-difluoroethyl)-6-(prop-l-en-2-yl)pyrimi dine (6.0 g, yield: 88%, two steps) as a white solid. 'H NMR: (400MHz, DMSO-de) 8 ppm: 7.52-7.49 (m, 2H), 7.40-7.35 (m, 3H), 7.17 (s, 1H), 6.26 (s, 1H), 5.52-5.51 (m, 1H), 5.47 (s, 2H), 5.47-5.41 (s, 1H), 2.11-1.99 (m, 3H), 1.73-1.72 (m, 3H).

Preparation 141

2-( 1 , 1 -difluoroethyl)-6-i sopropylpyrimidin-4-ol

To a solution of 4-(benzyloxy)-2-(l,l-difluoroethyl)-6-(prop-l-en-2-yl)pyrimi dine (Preparation 140, 6.0 g, 20.67 mmol) in EtOH (60 mL) was added Pd/C (4.4 g, 4.13 mmol, 10% purity) and the reaction mixture was stirred at 65 °C under EE at 15 Psi for 4 h. The mixture was quenched with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified on silica gel column chromatography (PEZEtOAc = 1/0 to 1/1) to give 2-(l,l-difluoroethyl)-6-isopropylpyrimidin- 4-ol (3.0 g, 72.5% yield) as a white solid. ^T H NMR: (400MHz, DMSO-de) 8 ppm 12.71 (br s, 1H), 6.46 (br s, 1H), 2.87-2.79 (m, 1H), 2.03-1.91 (m, 3H), 1.17 (d, J=6.8 Hz, 6H).

Preparation 142

4-chloro-2-(l,l-difluoroethyl)-6-isopropylpyrimidine

To a solution of 2-(l,l-difhioroethyl)-6-isopropylpyrimidin-4-ol (Preparation 141, 3.0 g, 15.0 mmol) was added POCL (8.3 g, 54.2 mmol) and the reaction was stirred at 100 °C for 1 h. The mixture was concentrated, diluted with DCM (100 mL) and aq.NaHCOs (200 mL) slowly added. The mixture was stirred at 25 °C for 1 h, the layers separated and the aqueous extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give 4-chloro-2-(l,l-difluoroethyl)-6- isopropylpyrimidine (3.1 g, 93.7% yield) as a yellow oil. 'H NMR (400 MHz, CDCL) 6 ppm: 7.20 (d, ./=2,4 Hz, 1H), 3.07-2.98 (m, 1H), 2.03-1.94 (m, 3H), 1.27-1.25 (m, 6H).

Preparation 143 4-(benzyloxy)-2-chloropyrimidine

4-(Benzyloxy)-2-chloropyrimidine was obtained as a white solid, 4.8 g, 64.8%, from 2,4- di chloropyrimidine, following a similar procedure to that described in Preparation 134. 1H NMR (400 MHz, CDCh) 8 ppm: 8.31 (d, J=5.6 Hz, 1H), 7.37-7.46 (m, 5H), 6.70 (d, J=5.6 Hz, 1H), 5.43 (s, 2H).

Preparation 144 methyl 4-(benzyloxy)pyrimidine-2-carboxylate

To a solution of 4-(benzyloxy)-2-chloropyrimidine (Preparation 143, 9.5 g, 21.53 mmol) in MeOH (100 mL) was added Pd(dppf)C12 (315.0 mg, 0.43 mmol) and TEA (4.4 g, 43.1 mmol). The resulting mixture was stirred at 80 °C for 16 h under CO (50 psi). The mixture was concentrated and was purified by chromatography (PEZEtOAc = 3/1) on silica gel to give methyl 4-(benzyloxy)pyrimidine-2-carboxylate (3.6 g, 68.5% yield) as a yellow solid. 'H NMR: (400 MHz, CDCh) 6 ppm: 8.59 (d, J=5.6 Hz, 1H), 7.42-7.50 (m, 2H), 7.35-7.41 (m, 3H), 6.91 (d, J=6.Q Hz, 1H), 5.53 (s, 2H), 4.05 (s, 3H).

Preparation 145

1 -(4-(benzyloxy)pyrimidin-2-yl)ethan- 1 -one l-(4-(Benzyloxy)pyrimidin-2-yl)ethan-l-one was obtained as a colorless oil, 288 mg, 21%, from methyl 4-(benzyloxy)pyrimidine-2-carboxylate (Preparation 144), following a similar procedure to that described in Preparation 129. ^X H NMR (400 MHz, CDCh) 6: 8.61 (d, 1H), 7.49-7.35 (m, 5H), 6.90 (d, 1H), 5.52 (s, 2H), 2.75 (s, 3H).

Preparation 146

4-(benzyloxy)-2-(l,l -difluoroethyl )pyrimidine

4-(Benzyloxy)-2-(l,l-difluoroethyl)pyrimidine was obtained as a yellow oil, 537 mg, 76%, from l-(4-(benzyloxy)pyrimidin-2-yl)ethan-l-one (Preparation 145) following a similar procedure to that described in Preparation 130. ^X H NMR (500 MHz, CDCh) 6: 8.52 (d, 1H), 7.48-7.35 (m, 5H), 6.81 (d, 1H), 5.48 (s, 2H), 2.03 (t, 3H).

Preparation 147

2-(l , 1 -difluoroethyl )pyrimidin-4-ol

A solution of 4-(benzyloxy)-2-(l,l-difluoroethyl)pyrimidine (Preparation 146, 537.1 mg, 2.15 mmol) in TFA (4.47 g, 39.2 mmol) was stirred at 100 °C for 12 h. The mixture was purified by prep-HPLC-D (0-20% MeCN) to give 2-(l, 1 -difluoroethyl )pyrimidin-4-ol as a white solid (230 mg, 67%). 'H NMR (400 MHz, CDCh) 8: 7.99 (d, 1H), 6.55 (d, 1H), 2.03 (t, 3H).

Preparation 148

4-chloro-2-( 1 , 1 -difluoroethyl)pyrimidine

A solution of 2-(l,l-difhioroethyl)pyrimidin-4-ol (Preparation 147, 100 mg, 0.625 mmol) in POCh (2 mL) was stirred at 100 °C for 2 h. The reaction mixture was concentrated, the residue diluted with H2O (10 mL) and extracted with EtOAc (3x 10 mL). The combined organics were dried (ISfeSCh) and concentrated to give 4-chloro-2-(l,l- difhioroethyl)pyrimidine as a yellow oil (85 mg, 76%). 'H NMR (400 MHz, CDCh) 6: 8.74 (d, 1H), 7.44 (d, 1H), 2.07 (t, 3H).

Preparation 149

2-(4-chloropyrimidin-2-yl)propan-2-ol

To a solution of 4-chloro-2-iodopyrimidine (4.2 g, 17.64 mmol) in toluene (10 mL) was added n-BuLi (2.5 M, 10.6 mL) slowly at -70 °C over 30 mins under N2. Acetone (1.2 g, 21.16 mmol) was added slowly at -70 °C and the reaction then stirred for 3 h under N2. The mixture was poured into a .NBLCl (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine (30 mL), dried with ISfeSCU, filtered and the filtrate was concentrated. The residue was purified by chromatography (PE/EtOAc = 20/1 to 3/1) on silica gel to give 2-(4-chloropyrimidin-2-yl)propan-2-ol (1.5 g, 49.3% yield) as yellow oil. LCMS m/z = 173.1 [M+H] ⁺

Preparation 150

2-(4,6-dichloropyrimidin-2-yl)propan-2-ol

2-(4,6-Dichloropyrimidin-2-yl)propan-2-ol was obtained as a yellow oil, 500 mg, 66% from

4,6-dichloro-2-iodopyrimidine, following the procedure described in Preparation 149. ^T H NMR (500 MHz, CDCh) 8: 7.30 (s, 1H), 3.92 (br s, 1H), 1.59 (s, 6H).

Preparation 151

4,6-dichloro-2-(2-fluoropropan-2-yl)pyrimidine

4,6-Dichloro-2-(2-fluoropropan-2-yl)pyrimidine was obtained as a yellow oil, 350 mg, 69% from 2-(4,6-dichloropyrimidin-2-yl)propan-2-ol (Preparation 150) and DAST following a similar procedure to that described in Preparation 130. 1H NMR (500 MHz, CDCh) 6: ppm 7.34 (s, 1H), 1.80 (s, 3H), 1.75 (s, 3H).

Preparation 152

4-chloro-2-(l-ethoxyvinyl)-5-methoxypyrimidine

To a stirring solution of 2,4-dichloro-5-methoxypyrimidine (28.2 g, 157.7 mmol) and tributyl(l- ethoxyvinyl)stannane (66.5 g, 184.1 mmol) in DMF (980 mL, degassed with N2 for 10 min) were added Pd(PPh3)2Ch (3.3 g, 4.7 mmol) and TEA (19.3 g, 190.8 mmol). The resulting mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to 25 °C, diluted with EtOAc and filtered through silica. The filtrate was washed with saturated solution of KF (300 mL), H2O (300 mL) and brine (300 mL) and dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 4-chloro-2-(l-ethoxyvinyl)-5-methoxypyrimidine (28 g, 83.7% yield). LCMS m/z = 214.9 [M+H]+

Preparation 153

1 -(4-chloro-5-methoxypyrimidin-2-yl)ethan- 1 -one

IT

O

To a solution of 4-chloro-2-(l-ethoxyvinyl)-5-methoxypyrimidine (Preparation 152, 28 g, 130.5 mmol) in dioxane (450 mL) cooled to 0 °C was added HC1 (2.0 M, 65.22 mL) and the solution stirred for 2 h. The reaction was diluted with water (IL) and extracted with EtOAc (200 mL x 3), the combined organic phases washed with brine (400 mL), dried with anhydrous Na2SO4 and concentrated. The residue was purified with silica chromatography (EtOAc: PE from 0 to 15 %) to give l-(4-chloro-5-methoxypyrimidin-2-yl)ethan-l-one (23 g, 94.5% yield) as a yellow solid. LCMS m/z = 186.9 [M+H]+

Preparation 154

4-chloro-2-(l,l-difluoroethyl)-5-methoxypyrimidine

To a solution of l-(4-chloro-5-methoxypyrimidin-2-yl)ethan-l-one (Preparation 153, 23.0 g, 123.3 mmol) in DCM (200 mL) cooled to 0 °C was added DAST (49.7 g, 308.2 mmol) and the reaction stirred for 16 h at 45 °C. Saturated aq. NaHCOs (200 mL) was added dropwise to quench the reaction and it was extracted with DCM (200 mL), washed with brine (200 mL), dried over Na2SO4 and concentrate. The crude product was purified by silica gel chromatography (0~7% = EtOAc: PE) to give 4-chloro-2-(l,l-difluoroethyl)-5- methoxypyrimidine (19 g, 73.9% yield) as a yellow solid. LCMS m/z = 209.0 [M+H]+

Preparation 155

4-chloro-6-cy cl opropyl-2-( 1,1 -difluoroethyl )pyrimidine

4-Chloro-6-cyclopropyl-2-(l,l-difluoroethyl)pyrimidine was obtained as a colorless oil, 310 mg, crude, from 4, 6-dichloro-2-( 1,1 -difluoroethyl )pyrimidine (Preparation 91) and cyclopropylboronic acid following the procedure described in Preparation 94. LCMS m/z = 219.1 [M+H] ⁺ .

Preparation 156

4-chloro-6-ethyl-2-(2-fluoropropan-2-yl)pyrimidine

4-Chloro-6-ethyl-2-(2-fluoropropan-2-yl)pyrimidine was obtained as a colorless oil, 300 mg, crude, from 4,6-dichloro-2-(2-fluoropropan-2-yl)pyrimidine (Preparation 151) and ethyl boronic acid, following the procedure described in Preparation 94. LCMS m/z = 203.0 [M+H] ⁺ .

Preparation 157

4-chloro-2-(2-fluoropropan-2-yl)-6-methylpyrimidine

4-Chloro-2-(2-fluoropropan-2-yl)-6-methylpyrimidine was obtained as a yellow oil, 720 mg, 79.8% from 4,6-dichloro-2-(2-fluoropropan-2-yl)pyrimidine (Preparation 151) and methyl boronic acid, following a similar procedure to that described in Preparation 94. ¹ H NMR: (500 MHz, CDCh) 8 ppm: 7.13 (s, 1H), 2.56 (s, 3H), 1.79 (s, 3H), 1.75 (s, 3H).

Preparation 158

4-chloro-2-(l,l-difluoroethyl)-6-(2-m ethoxy ethoxy)pyrimidine

To a solution of 4,6-dichloro-2-(l,l-difluoroethyl)pyrimidine (Preparation 91, 200 mg, 0.939 mmol) and CS2CO3 (917.8 mg, 2.82 mmol) in DMF (5 mL) was added 2-methoxyethan-l-ol (78.59 mg, 1.03 mmol) and the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by the addition of water and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with H2O and brine (40 mL), dried over ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (PE/EtOAc = 10/1) to give 4-chloro-2-(l,l-difluoroethyl)-6-(2- methoxyethoxy)pyrimidine (180 mg, 75.9% yield) as a yellow oil. LCMS m/z = 253 [M+H] ⁺ Preparation 159

2-(l , 1 -difluoroethyl)-4-(2-methoxyethoxy)pyridine

To a solution of 4-chloro-2-(l, 1 -difluoroethyl )pyri dine (144.6 mg, 1.90 mmol) in DMF (1 mL) was added NaH (101.4 mg, 2.53 mmol, 60% purity) at 20 °C. 2-Methoxyethanol (250 mg, 1.27 mmol) was added and the resulting mixture was stirred at 75 °C for 5 h. The reaction mixture was quenched by addition H2O (20 mL) at 0 °C and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc = 100/1 to 5/1) to give 2-(l,l-difluoroethyl)-4-(2- methoxyethoxy)pyridine (210 mg, 68.7% yield) as a colorless oil. LCMS m/z = 218.2 [M+H] ⁺

Preparation 160

(2-(l , 1 -difluoroethyl)-4-(2-methoxyethoxy)pyridin- 1 -ium- 1 -yl)methanide

To a solution of 2-(l,l-difluoroethyl)-4-(2-methoxyethoxy)pyridine (Preparation 159, 210 mg, 0.87 mmol) in DCM (4 mL) was added m-CPBA (265 mg, 1.31 mmol) and the reaction mixture was stirred at 25 °C for 5 h under N2. The reaction mixture was quenched with sat.NaHCCh (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH = 100/1 to 10/1) to give (2-(l,l-difluoroethyl)-4-(2-m ethoxy ethoxy)pyri din- l-ium-l-yl)methanide (160 mg, 71.0 % yield) as a colorless oil. LCMS m/z = 234.2 [M+H] ⁺

Preparation 161

2-chloro-6-(l,l-difluoroethyl)-4-(2-m ethoxy ethoxy)pyri dine

A solution of (2-(l,l-difluoroethyl)-4-(2-methoxyethoxy)pyridin-l-ium-l-yl )methanide (Preparation 160, 160 mg, 0.618 mmol) in POCL (2 mL) was stirred at 95 °C for 3 h under N2. The reaction mixture was quenched with sat.NaHCOs (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (from PE/EtOAc = 100/1 to 25/2) to give 2-chloro-6-(l,l-difluoroethyl)- 4-(2-methoxyethoxy)pyridine (110 mg, 63.7% yield) as a colorless oil. LCMS m/z = 252.1 [M+H] ⁺

Preparation 162

4-chloro-2-(l,l-difluoroethyl)-6-isopropoxypyrimidine

To a solution of propan-2-ol (282 mg, 4.69 mmol) in THF (5.0 mL) was added NaH (103 mg, 2.58 mmol, 60% purity) at 0°C. The reaction mixture was stirred at 25°C for 30 min before addition of 4,6-dichloro-2-(l,l-difluoroethyl)pyrimidine (Preparation 91, 500 mg, 2.35 mmol). The reaction mixture was stirred at 25°C for 16 h, then quenched with H2O (10 mL) and extracted with EtOAc (3 x 8 mL). The organic phase was washed with brine (15 mL), dried with Na2SO4, filtered, concentrated, then purified by chromatography on silica gel (PEZEtOAc 15/1 to 5/1) to give 4-chloro-2-(l,l-difluoroethyl)-6-isopropoxypyrimidine (150 mg, 27.0% yield) as colorless oil. LCMS m/z = 237.1 [M+H] ⁺ .

Preparation 163

4-chloro-6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidine

A mixture of cyclopropanol (300 mg, 5.17 mmol) in THF (10 mL) was cooled on a dry ice/IPA bath, then NaH (240 mg, 6.00 mmol, 60% purity) was added and stirred for 5 mins, then allowed to warm to rt and stirred for 30 mins. The slurry was cooled on a dry ice/IPA bath, then 4,6-dichloro-2-(l,l-difhioroethyl)pyrimidine (Preparation 91, 1.1 g, 5.16 mmol) in THF (5 mL) was added and the reaction was stirred for 2 h. The reaction was quenched by addition of NH4CI (10 mL), then diluted with hexane (5 mL) and the phases separated. The aqueous phase was extracted with EtOAc:heptane (15 mL 1 : 1) and the combined organic layers were concentrated to dryness. The crude was purified via silica gel chromatography (40 g, heptane to 15% EtOAc in heptane) to give chloro-6-(cyclopropoxy)-2-(l,l- difhioroethyl)pyrimidine as a clear colorless oil, 4- (785 mg, 49.2% yield). LCMS m/z = 235.1 [M+ H] ⁺ .

Preparation 164

4-chloro-2-(l,l-difluoroethyl)-6-ethoxypyrimidine

To a solution of 4,6-dichloro-2-(l,l-difluoroethyl)pyrimidine (Preparation 91, 200 mg, 0.939 mmol) in DMF (4.0 mL) was added EtONa (95.9 mg, 1.41 mmol). The reaction mixture was stirred at 25°C for 1 h, then concentrated, treated with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (PE/EtOAc 1/0 to 10/1) to give 4-chloro-2-(l,l- difhioroethyl)-6-ethoxypyrimidine (200 mg, 95.7% yield) as a white solid. LCMS m/z = 223.0 [M+H] ⁺ . Preparation 165

4-chloro-6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidine

To a solution of 4,6-dichloro-2-(l,l-difluoroethyl)pyrimidine (Preparation 91, 20 g, 564 mmol) and cyclopropanol (45.8 g, 789 mmol) in THF (12 mL) was added t-BuONa (70.4 g, 732 mmol), dissolved in THF (20 mL). The reaction mixture was stirred at 25°C for 3 h. The resulting product was taken up in THF and filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc 1/0 to 10/1) to give 4- chloro-6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidine as colorless oil. LCMS m/z = 234.9 [M+H] ⁺ .

Preparation 166

4-chloro-6-cyclopropoxy-2-(trifluoromethyl)pyrimidine

4-Chloro-6-cyclopropoxy-2-(trifluoromethyl)pyrimidine was obtained as a colorless liquid, from 4,6-dichloro-2-(trifluoromethyl)pyrimidine and cyclopropanol, following a similar procedure to that described in Preparation 165. LCMS m/z = 238.8 [M+H] ⁺

Preparation 167

2-(l , 1 -difluoropropyl )pyrimidine-4,6-diol

To a solution of malonamide (0.210 g, 2.06 mmol) in EtOH (5 mL) was added t-BuONa (692 mg, 7.20 mmol) and the mixture was stirred at 25 °C for 30 min. Ethyl 2,2-difluorobutanoate (642 mg, 4.22 mmol) was added and the reaction was heated to 100°C for 1 d. The mixture was cooled to rt and 4M HC1 (2.57 mL, 10.3 mmol, 4 M in dioxane) was added carefully. The precipitate formed was removed by filtration and the filtrate was evaporated to dryness. The residue was partitioned between EtOAc and water (minimum) and separated. The organics were dried over MgSCU, filtered and evaporated. The residue was purified by silica gel chromatography (0-100% 3: 1 EtOAc/EtOH in heptanes) to give 2-(l, 1- difluoropropyl)pyrimidine-4,6-diol (0.104 g, 27% yield) as a white solid. LCMS m/z = 191.0 [M+H] ⁺ .

Preparation 168

4,6-dichloro-2-(l,l-difluoropropyl)pyrimidine

4,6-Dichloro-2-(l,l-difluoropropyl)pyrimidine was obtained as a colorless oil, 64 mg, 52%, from 2-(l,l-difluoropropyl)pyrimidine-4,6-diol (Preparation 167) and POCL, following a similar procedure to that described in Preparation 91. ^X H NMR (400 MHz, CDCh) 8 ppm 7.49 (s, 1 H), 2.27 - 2.45 (m, 2 H), 1.08 (t, J=7.51 Hz, 3 H).

Preparation 169

4-chloro-2-(l,l-difluoropropyl)-6-m ethylpyrimidine

4-Chloro-2-(l,l-difluoropropyl)-6-methylpyrimidine was obtained as a colorless oil, from

4,6-dichloro-2-(l,l-difluoropropyl)pyrimidine (Preparation 168) and methylboronic acid, following a similar procedure to that described in Preparation 94. LCMS m/z = 207.0 [M+H] ⁺ .

Preparation 170

4-chloro-6-(3-methoxycyclobutoxy)-2-methylpyrimidine

KOtBu (1.00 mL, 1.00 mmol, 1 M in THF) was added dropwise to a solution of 4,6-dichloro- 2-methylpyrimidine (163 mg, 1.0 mmol) in THF (4 mL). A solution of 3- methoxycyclobutan-l-ol (102 mg, 1.0 mmol) in THF (2 mL) was added dropwise and the reaction was stirred at rt overnight. The reaction was quenched by addition of saturated NH4CI solution and the mixture extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel chromatography (0- 100% EtOAc in heptanes) to give 4-chloro-6-(3 -m ethoxy cy cl obutoxy)-2-m ethylpyrimidine (14 mg, 6% yield). LCMS m/z = 229.0 [M+H] ⁺ . Preparation 171

2-oxabicyclo[2.1. l]hexane-4-carboxamide

To a solution of 2-oxabicyclo[2.1.1]hexane-4-carboxylic acid (2 g, 15.61 mmol) in DCM (30 mL) under N2 was added DMF (120 uL), followed by oxalyl chloride (2 M, 9.4 mL) and the reaction stirred at rt for Ih. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (20 mL), cooled to 0°C and ammonia (7 M in MeOH, 33.45 mL) was slowly added. The mixture was stirred at rt for 2h. The solid formed (inorganics) were filtered off, rinsed with DCM and the filtrate was concentrated. The residue was diluted with

MeCN, the solid formed was collected by filtration, rinsed with MeCN and dried to give 2- oxabicyclo[2.1. l]hexane-4-carboxamide as a white solid (1.86 g, 93% yield). ^T H NMR (MeOH-d ₄ , 400 MHz) 8 4.50 (t, IH, J=l.l Hz), 3.81 (s, 2H), 2.12 (td, 2H, J=1.3, 4.9 Hz), 1.7-1.9 (m, 2H).

Preparation 172

2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4(3H)-one

A mixture of NaOMe (3.92 mL, 19.11 mmol) (25wt% in MeOH) in n-BuOH (4 mL) was heated to 105°C in flask (poked with a needle open to air) while the solvent was removed. To this was slowly added a solution of methyl (E)-3-aminobut-2-enoate (550 mg, 4.78 mmol) and 2-oxabicyclo[2.1.1]hexane-4-carboxamide (Preparation 171, 1.53 g, 12.02 mmol) in MeOH (18 mL) and the reaction mixture was heated at 110°C for 2 h. The cooled mixture was neutralized with cone. HC1, the resulting solid was filtered off and rinsed with small volume of MeOH. The filtrate was concentrated under reduced pressure and the residue was diluted with MeCN. The solid formed was collected by filtration and dried to give 4-methyl-2-(2-oxabicyclo[2.1.1]hexan-4-yl)-lH-pyrimidin-6-on e (565mg, 61% yield). LCMS m/z = 193 [M+H] ⁺

Preparation 173

2-(2-oxabicyclo[2.1. l]hexan-4-yl)-4-chloro-6-methylpyrimidine

A mixture of 4-methyl-2-(2-oxabicyclo[2.1.1]hexan-4-yl)-lH-pyrimidin-6-on e (Preparation 172, 560 mg, 2.91 mmol), DMF (112 pL) and POCh (1.79 g, 11.65 mmol) in DCM (7 mL) was stirred at rt for 2h. The reaction mixture was concentrated under reduced pressure, the residue diluted with EtOAc and ice and the mixture neutralized with NaHCO3(aq). The layers were separated, the aqueous phase extracted with EtOAc and the combined organic layer was dried and concentrated to give 2-(2-oxabicyclo[2.1. l]hexan-4-yl)-4-chloro-6- methylpyrimidine (715 mg, crude) as a yellowish oil. LCMS m/z = 211 [M+H] ⁺

Preparation 174

2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-ethylpyrimidin-4(3H)-one

2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-ethylpyrimidin-4(3H)- one was obtained as a white solid, from methyl (E)-3-aminopent-2-enoate (400 mg, 3.10 mmol) and 2- oxabicyclo[2.1.1]hexane-4-carboxamide (Preparation 171), following a similar procedure to that described in Preparation 172. LCMS m/z = 207 [M+H] ⁺

Preparation 175

2-(2-oxabicyclo[2.1. l]hexan-4-yl)-4-chloro-6-ethylpyrimidine

2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-4-chloro-6-ethylpyrimid ine was obtained as a yellow oil,

253 mg, 43%, from 2-(2-oxabicyclo[2.1.1]hexan-4-yl)-6-ethylpyrimidin-4(3H)-one

(Preparation 174), following a similar procedure to that described in Preparation 173. LCMS m/z = 225 [M+H] ⁺

Preparations 176 to 180

The following compounds were prepared from the appropriate carboxylic acid, following a similar 3 step synthesis to that described for the synthesis of Preparation 173.

Preparation 181 l,3-dioxoisoindolin-2-yl 2-oxabicyclo[2.1. l]hexane-4-carboxylate

To a mixture of 2-oxabicyclo[2.1.1]hexane-4-carboxylic acid (1 g, 7.80 mmol), DMAP (19 mg, 0.156 mmol) and 2-hydroxyisoindoline-l, 3-dione (1.27 g, 7.80 mmol) in DCM (50 mL) was added a solution of DCC (1.93 g, 9.37 mmol) in DCM (25 mL) and the mixture was stirred at rt overnight. The reaction mixture was filtered through Celite®, rinsed with ether, the filtrate was then passed through a short silica gel plug. The filtrate was concentrated in vacuo to give l,3-dioxoisoindolin-2-yl 2-oxabicyclo[2.1.1]hexane-4-carboxylate (2.13 g, crude) as a white powder. 'H NMR (CDCh, 400 MHz) 8 7.9-8.0 (m, 2H), 7.8-7.9 (m, 2H), 4.6-4.7 (m, 1H), 4.08 (s, 2H), 2.4-2.5 (m, 2H), 2.0-2.1 (m, 2H).

Preparation 182

2-chloro-5-((difluoromethoxy)methyl)pyridine

A mixture of (6-chl oro-3 -pyridyl)m ethanol (1 g, 6.97 mmol), Cui (265.3 mg, 1.39 mmol) and molecular sieves (0.5g) in MeCN (8 mL) in a sealed tube was heated at 65°C. To this was added dropwise a solution of 2,2-difluoro-2-fluorosulfonyl-acetic acid (1.86 g, 10.45 mmol) in MeCN (2 mL) and the reaction stirred at 65°C for Ih. The cooled mixture was diluted with EtOAc, washed with NaHCCh, the organic layer was dried and concentrated. The crude was purified by chromatography on silica gel (0-100% EtOAc/heptane) to give 2-chl oro-5 - ((difluorom ethoxy )methyl)pyri dine (405 mg, 18% yield) as a yellow oil. LCMS m/z = 194 [M+H] ⁺

Preparation 183

2-bromo-5-(l-fluoroethyl)pyridine A mixture of l-(6-bromo-3-pyridyl)ethanol (500 mg, 2.47 mmol) in DCM (10 mL) was cooled to -78°C. DAST (1.60 g, 9.90 mmol, 1.31 mL) was dropwise added, the solution stirred for 1 h at -78°C then slowly warmed up to rt overnight. The reaction was quenched with water, the mixture stirred at rt for 15 min., washed with NaHCCh and the organic layer was dried and concentrated. The crude was purified by chromatography on silica gel (0- 50%EtOAc/heptane) to give 2-bromo-5-(l-fluoroethyl)pyridine (228 mg, 45% yield). LCMS m/z =204, 206 [M+H] ⁺

Preparation 184

2-bromo-5-(l-methoxyethyl)pyridine

To a mixture of NaH (89 mg, 3.7 mmol) in THF ( 8 mL) at 0°C was added dropwise, a solution of l-(6-bromo-3-pyridyl)ethanol (500 mg, 2.47 mmol) in THF (2 mL) and the solution stirred at rt for 20 min. The solution was cooled to 0°C, iodomethane (154 pL, 2.47 mmol) was added dropwise and the reaction then stirred at rt for Ih. The reaction was diluted with EtOAc, washed with brine, the organic layer was dried and concentrated. The crude was purified by chromatography on silica gel (0-80% EtOAc/heptane) to give 2-bromo-5-(l- methoxyethyl)pyridine (443 mg, 82% yield). LCMS m/z = 216, 218 [M+H]+

Preparation 185

2-bromo-6-(l,2-difluoroethyl)pyridine

To a solution of l-(6-bromopyridin-2-yl)ethane-l,2-diol (476.0 mg, 2.64 mmol) in DCM (6 mL) was added DAST (1.5 mL, 11.35 mmol) and the reaction was stirred at 25 °C for 2 h. The mixture was quenched with H2O (10 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over ISfeSCU and filtered. The filtrate was concentrated under reduced pressure and the residue purified by chromatography on silica gel (PE ZEtOAc =1/1) to give 2-bromo-6-(l,2- difluoroethyl)pyridine (440.0 mg, 75.0% yield) as a yellow oil. ^X H NMR (400 MHz, CDCL) 8 ppm: 7.57-7.61 (m, 1H), 7.41-7.47 (m, 2H), 5.71-5.77 (m, 1H), 4.64-4.95 (m, 2H)

Preparation 186

2-bromo-6-vinylpyrazine

To a solution of 2,6-dibromopyrazine (3.8 g, 16.0 mmol), 4, 4,5, 5-tetramethyl-2 -vinyl-1, 3,2- dioxaborolane (2.5 g, 16.0 mmol) and K2CO3 (4.5 g, 31.9 mmol) in dioxane (30.0 mL) and H2O (3.0 mL) was added Pd(dppf)C12 (1.17 g, 1.60 mmol). The mixture was stirred at 70°C for 3 h under N2, then concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (PE/EtOAc 1/0 to 10/1) to give 2-bromo-6- vinylpyrazine (2.0 g, 47.4% yield) as an oil. LCMS m/z = 187.0 [M+H] ⁺ .

Preparation 187

1 -(6-bromopyrazin-2-yl)ethane- 1 ,2-diol

To a solution of 2-bromo-6-vinylpyrazine (Preparation 186, 1.5 g, 5.68 mmol) in acetone (12 mL) and H2O (4 mL) was added OsCL (250 mg, 0.984 mmol). NMO (997 mg, 8.51 mmol) was added and the reaction mixture was stirred at 25°C for 2 h. The mixture was quenched with sat. Na2SOs (100 mL) and filtered through Celite®, then extracted with EtOAc (3 x 50 mL) and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (PE/EtOAc 1/0 to 1/1) to give l-(6-bromopyrazin-2-yl)ethane- 1,2-diol (220 mg, 17.7% yield) as a yellow oil. LCMS m/z = 221.1 [M+H] ⁺ .

Preparation 188

2-bromo-6-(l,2-difluoroethyl)pyrazine

2-Bromo-6-(l,2-difluoroethyl)pyrazine was obtained as a white oil, 150 mg, 67% from l-(6- bromopyrazin-2-yl)ethane-l,2-diol (Preparation 187) and DAST following the procedure described in Preparation 185. LCMS m/z = 223.0 [M+H] ⁺ .

Preparation 189

2-chloro-4-methyl-6-vinylpyrimidine To a solution of 2,4-dichloro-6-methylpyrimidine (2.0 g, 12.3 mmol) in dioxane (20 mL) and H2O (2 mL) was added 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (2.3 g, 14.7 mmol), Pd(dppf)C12 (898 mg, 1.23 mmol) and K3PO4 (5.2 g, 24.5 mmol). The reaction mixture was stirred at 80°C for 2 h under N2, then concentrated and purified by prep-HPLC (Method N, Gradient 10-40%) to give 2-chloro-4-methyl-6-vinylpyrimidine (1.5 g, 79.1% yield) as a brown solid. LCMS m/z = 155.1 [M+H] ⁺ .

Preparation 190

1 -(2-chloro-6-methylpyrimidin-4-yl)ethane- 1 ,2-diol

1-(2-Chloro-6-methylpyrimidin-4-yl)ethane-l,2-diol was obtained as a white solid, 200 mg, crude, from l-(2-chloro-6-methylpyrimidin-4-yl)ethan-l-one (Preparation 189) and OsCU following the procedure described in Preparation 187. ^T H NMR: (500 MHz, CDCh) 8 ppm: 7.32 (s, 1H), 3.96-4.00 (m, 1H), 3.80-3.83 (m, 1H), 3.68-3.70 (m, 1H), 2.54 (s, 3H).

Preparation 191

2-chloro-4-(l,2-difluoroethyl)-6-methylpyrimidine

2-Chloro-4-(l,2-difluoroethyl)-6-methyl pyrimidine was obtained as a yellow oil, 150 mg, 67.0% yield, from l-(2-chloro-6-methylpyrimidin-4-yl)ethane-l,2-diol (Preparation 190) and DAST following the procedure described in Preparation 185. 'H NMR: (500 MHz, CDCh) 6 ppm: 7.40 (s, 1H), 5.64-5.70 (m, 1H), 4.81-5.00 (m, 2H), 2.61 (s, 3H).

Preparation 192

4-chloro-2-iodo-6-methylpyrimidine t-BuONO (7.2 g, 69.6 mmol) was added to a solution of 4-chloro-6-methylpyrimidin-2-amine (5.0 g, 34.8 mmol) and CH2I2 (10.3 g, 38.3 mmol) in MeCN (50.0 mL). The reaction mixture was stirred at 80°C for 3.5 h, then concentrated under reduced pressure, treated with H2O (30 mL) and extracted with EtOAc (3 x 35 mL). The organic phase was washed with brine (30 mL), dried with Na2SO4, filtered, concentrated, then purified by column chromatography on silica gel (PE/EtOAc 15/1 to 1/1) to give 4-chloro-2-iodo-6-methylpyrimidine (4.2 g, 47.4% yield) as a white solid. LCMS m/z = 254.9 [M+H] ⁺ .

Preparation 193

2-((tert-butyldimethylsilyl)oxy)-l-(4-chloro-6-methylpyri midin-2-yl)ethan-l-ol

A solution of 4-chloro-2-iodo-6-methylpyrimidine (Preparation 192, 2.0 g, 7.86 mmol) in toluene (30 mL) was cooled to -70°C under N2. n-BuLi (2.5 M, 3.8 mL) was added dropwise over 30 min. After stirring at -70 °C for 20 min, 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (1.6 g, 9.43 mmol) was added slowly and the reaction mixture stirred at -70°C for 1 h. The mixture was quenched with MeOH (25 mL) and AcOH (1.6 mL), concentrated and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude was purified by column chromatography on silica gel (PE/EtOAc 1/0 to 3/1) to give 2-((tert- butyldimethylsilyl)oxy)-l-(4-chloro-6-methylpyrimidin-2-yl)e than-l-ol (890 mg, 37.4% yield) as yellow oil. LCMS m/z = 303.2 [M+H] ⁺ .

Preparation 194

1 -(4-chloro-6-methylpyrimidin-2-yl)ethane- 1 ,2-diol

To a solution of 2-((tert-butyldimethylsilyl)oxy)-l-(4-chloro-6-methylpyrimid in-2-yl)ethan- l-ol (Preparation 193, 880 mg, 2.91 mmol) in THF (5.0 mL) was added TBAF (1 M, 8.8 mL) at 25°C. The reaction mixture was stirred for 2 h, then quenched with H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with H2O (3 x 30 mL) and brine (3 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (PE/EtOAc 10/1 to 1/1) to give l-(4-chloro-6-methylpyrimidin-2-yl)ethane-l,2-diol (210 mg, 38.3% yield) as yellow oil. 'H NMR: (400 MHz, CDCh) 8 ppm: 7.15 (s, 1H), 4.80-4.86 (m, 1H), 3.97-4.04 (m, 2H), 2.53 (s, 3H).

Preparation 195 4-chloro-2-(l,2-difluoroethyl)-6-methylpyrimidine

4-Chloro-2-(l,2-difluoroethyl)-6-methyl pyrimidine was obtained as a yellow oil, 150 mg, 67.0% yield, from l-(4-chloro-6-methylpyrimidin-2-yl)ethane-l,2-diol (Preparation 194) and DAST following the procedure described in Preparation 185. LCMS m/z = 193.1 [M+H] ⁺ . Preparation 196

4-(benzyloxy)-6-methyl-2-(prop-l-en-2-yl)pyrimidine

4-(Benzyloxy)-6-methyl-2-(prop-l-en-2-yl)pyrimidine was obtained as a colorless oil, 7.5 g, 65.4%, from 4-(benzyloxy)-2-chloro-6-methylpyrimidine (Preparation 134) and 4, 4,5,5- tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane, following a similar procedure to that described in Preparation 140, step 2). 'H N R: (400 MHz, CDCh) 8 ppm: 7.44-7.46 (m, 2H), 7.32-7.39 (m, 3H), 6.46 (s, 1H), 6.39 (s, 1H), 5.48 (s, 1H), 5.45 (s, 2H), 2.44 (s, 3H), 2.22 (s, 3H).

Preparation 197

2-(4-(benzyloxy)-6-methylpyrimidin-2-yl)propan- 1 -ol

To a solution of 4-(benzyloxy)-6-methyl-2-(prop-l-en-2-yl)pyrimidine (Preparation 196, 5.0 g, 20.8 mmol) in THF (100 mL) at 0 °C was added BH3 THF (1 M, 41.6 mL). The reaction mixture was stirred at 25 °C for 3 h. After cooling to 0°C, the reaction mixture was quenched with water, then NaOH (4 M, 20.8 mL) and H2O2 (9.4 g, 83.2 mmol, 30% purity) were added. The solution was stirred at 60°C for 16 h, quenched with aq. Na2SCh, treated with H2O (150 mL) and extracted with DCM (3 x 100 mL). The combined organic phase was washed with brine (2 x 100 mL), dried over ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE/EtOAc 20/1 to 1/1) to give 2-(4-(benzyloxy)-6-methylpyrimidin-2-yl)propan-l-ol (2.3 g, 42.8% yield) as colourless oil. 'H NMR: (500 MHz, CDCh) 6 ppm: 7.33-7.43 (m, 5H), 6.49 (s, 1H), 5.41 (s, 2H), 4.21 (brs, 1H), 3.91-3.94 (m, 1H), 3.80-3.82 (m, 1H), 3.11-3.15 (m, 1H), 2.42 (s, 3H), 1.33 (d, =7.0 Hz, 3H).

Preparation 198

4-(benzyloxy)-2-(l-fluoropropan-2-yl)-6-methyl pyrimidine

4-(Benzyloxy)-2-(l-fluoropropan-2-yl)-6-methylpyrimidine was obtained as a colourless oil, 327 mg, 32.4% yield, from 2-(4-(benzyloxy)-6-methylpyrimidin-2-yl)propan-l-ol (Preparation 197) and DAST following the procedure described in Preparation 185. 'H NMR (500 MHz, CDCh) 8 ppm: 7.33-7.44 (m, 5H), 6.47 (s, 1H), 5.42 (s, 2H), 4.77-4.90 (m, 1H), 4.57-4.67 (m, 1H), 3.37-3.41 (m, 1H), 2.43 (s, 3H), 1.33 (d, J=7.0 Hz, 3H).

Preparation 199

2-(l-fluoropropan-2-yl)-6-methylpyrimidin-4-ol

To a solution of 4-(benzyloxy)-2-(l-fluoropropan-2-yl)-6-methylpyrimidine (Preparation 198, 327 mg, 1.26 mmol) in THF (3.0 mL) was added Pd/C (134 mg, 0.126 mmol, 10% purity). The reaction mixture was stirred at 25°C for 2 h, then filtered and concentrated under reduced pressure to give 2-(l-fluoropropan-2-yl)-6-methylpyrimidin-4-ol (197 mg, 92.0% yield) as a white solid. 'H NMR: (400 MHz, CDCh) 6 ppm: 12.87 (br s, 1H), 6.20 (s, 1H), 4.53-4.80 (m, 2H), 3.18-3.24 (m, 1H), 2.31 (s, 3H), 1.34 (d, J=7.2 Hz, 3H).

Preparation 200

4-chloro-2-(l-fluoropropan-2-yl)-6-methylpyrimidine

A solution of 2-(l-fluoropropan-2-yl)-6-methylpyrimidin-4-ol (Preparation 199, 197 mg, 1.15 mmol) in POCh (1.7 g, 10.73 mmol, 1 mL) was stirred at 100°C for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (PE/EtOAc 20/1 to 0/1) to give 4-chloro-2-(l -fluoropropan -2-yl)-6- methylpyrimidine (127 mg, 58.4% yield) as colorless oil. LCMS m/z = 189.1 [M+H] ⁺ . Preparation 201

2-(4-(benzyloxy)-6-methylpyrimidin-2-yl)propane-l,2-diol 2-(4-(Benzyloxy)-6-methylpyrimidin-2-yl)propane-l,2-diol was obtained as a yellow oil, 670 mg, 58.7% yield, from 4-(benzyloxy)-6-methyl-2-(prop-l-en-2-yl)pyrimidine (Preparation 196) and OsC following the procedure described in Preparation 187. 'H NMR: (500 MHz, CDCh) 8 ppm: 7.32-7.43 (m, 5H), 6.52 (s, 1H), 5.38-5.44 (m, 2H), 5.05 (s, 1H), 3.91 (d, J=10.5 Hz, 1H), 3.73 (d, J=11.0 Hz, 1H), 2.70 (br s, 1H), 2.44 (s, 3H), 1.48 (s, 3H).

Preparation 202

4-(benzyloxy)-2-(l,2-difluoropropan-2-yl)-6-m ethylpyrimidine

4-(Benzyloxy)-2-(l,2-difluoropropan-2-yl)-6-m ethylpyrimidine was obtained as a yellow oil, 220 mg, 35.0% yield, from 2-(4-(benzyloxy)-6-methylpyrimidin-2-yl)propane-l,2-diol (Preparation 201) and DAST following the procedure described in Preparation 188. 'H NMR: (400 MHz, CDCh) 6 ppm: 7.35-7.44 (m, 5H), 6.56 (s, 1H), 5.41 (s, 2H), 4.70-4.96 (m, 2H), 2.47 (s, 3H), 1.71-1.77 (m, 3H).

Preparation 203

2-(l,2-difluoropropan-2-yl)-6-methylpyrimidin-4-ol

A solution of 4-(benzyloxy)-2-(l,2-difluoropropan-2-yl)-6-methylpyrimidine (Preparation 202, 200 mg, 0.719 mmol) and TFA (4.47 g, 39.2 mmol, 3 mL) was stirred at 100°C for 3 h. The mixture was concentrated and the residue was purified by chromatography on silica gel (PE/EtOAc 10/1) to give 2-(l,2-difluoropropan-2-yl)-6-methylpyrimidin-4-ol (100 mg, 74.0% yield) as a yellow solid. 'H NMR: (400 MHz, CDCh) 6 ppm: 6.22 (s, 1H), 4.61-4.81 (m, 2H), 2.29 (s, 3H), 1.68-1.73 (m, 3H).

Preparation 204

4-chloro-2-(l,2-difluoropropan-2-yl)-6-methylpyrimidine

A solution of 2-(l,2-difluoropropan-2-yl)-6-methylpyrimidin-4-ol (Preparation 203, 90 mg, 0.473 mmol) and POCh (3.3 g, 21.5 mmol) was stirred at 100°C for 3 h, then quenched with H2O (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic phase was washed with brine (2 x 10 mL), dried over ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc) to give 4-chloro- 2-(l,2-difluoropropan-2-yl)-6-methylpyrimidine (100 mg) as a yellow oil. 'H NMR: (500 MHz, CDCh) 8 ppm: 7.23 (s, 1H), 4.73-4.97 (m, 2H), 2.10 (s, 3H), 1.75-1.80 (m, 3H).

Preparation 205

2-(4-(benzyloxy)pyrimidin-2-yl)propan-2-ol

To a solution of methyl 4-(benzyloxy)pyrimidine-2-carboxylate (Preparation 144, 1.5 g, 6.14 mmol) in THF (20.0 mL) was added dropwise CHsMgBr (3 M, 2.05 mL) at 0 °C. The mixture was stirred for 1 h, then warmed 25 °C for 12 h under N2. The mixture was quenched with NH4CI (sat. 20 mL), poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL), the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography (PE/EtOAc = 3/1) on silica gel to give 2-(4- (benzyloxy)pyrimidin-2-yl)propan-2-ol (358.2 mg, 23.9% yield) as a white solid. 'H NMR: (400 MHz, CDCh) 6 ppm: 8.40 (d, J=5.6 Hz, 1H), 7.34-7.46 (m, 5H), 6.65 (d, J=5.6 Hz, 1H), 5.44 (s, 2H), 4.68 (s, 1H), 1.56 (s, 6H).

Preparation 206

4-(benzyloxy)-2-(2-fluoropropan-2-yl)pyrimidine

4-(benzyloxy)-2-(2-fluoropropan-2-yl)pyrimidine was obtained as a yellow oil, 556.4 mg, 78.8%, from 2-(4-(benzyloxy)pyrimidin-2-yl)propan-2-ol, following the procedure described in Preparation 130. 1H NMR (500 MHz, CDCh) 6 ppm: 8.46-8.48 (m, 1H), 7.33-7.46 (m, 5H), 6.67 (d, J=5.5 Hz, 1H), 5.45 (s, 2H), 1.79 (s, 3H), 1.74 (s, 3H). Preparation 207

4-chloro-2-(2-fluoropropan-2-yl)pyrimidine

To a solution of 4-(benzyloxy)-2-(2-fluoropropan-2-yl)pyrimidine (Preparation 206, 556.4 mg, 2.26 mmol) in TFA (4.47 g, 39.2 mmol) was stirred at 100 °C for 12 h. The mixture was evaporated under reduced pressure to give 2-(2-fluoropropan-2-yl)pyrimidin-4-ol as a white solid.

A solution of 2-(2-fluoropropan-2-yl)pyrimidin-4-ol (100.0 mg, 0.640 mmol) in POCh (2.0 mL) was stirred at 100 °C for 2 h. The mixture was concentrated, diluted with H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous ISfeSCL, filtered and concentrated to give 4-chloro-2-(2-fluoropropan-2- yl)pyrimidine (82.0 mg, 73.34% yield) as colorless oil. ^J H NMR (500 MHz, CDCh) 8 ppm: 8.66 (d, J=5.5 Hz, 1H), 7.29 (d, J=5.5 Hz, 1H), 1.81 (s, 3H), 1.77 (s, 3H).

Preparations 208 to 219

The compounds in the following table were prepared from 2-bromo-5-fluoroisonicotinic acid and the aprropriate alcohol (SM), following a similar procedure to that described in Preparation 14.

Preparations 220 to 231

The compounds in the following table were obtained from the appropriate 2- bromoisonicotinic acid and DPP A, following a similar reaction to that described in Preparation 22.

Preparation 232 to 240

The compounds in the following table were prepared from the appropriate 2-bromo or 2- chloropyridine and acetamide, following a similar procedure to that described in Preparation 32.

Preparation 241 tert-butyl methyl (5 -(2 -methoxy ethoxy )pyridine-2,4-diyl)dicarbamate tert-Butyl methyl (5-(2-methoxyethoxy)pyridine-2,4-diyl)dicarbamate was obtained as a brwon oil, 570 mg, 58%, from tert-butyl (2-bromo-5-(2-methoxyethoxy)pyridin-4- yl)carbamate

(Preparation 22) and methyl carbamate, following the procedure described in Preparation 32.

'H N R: (400 MHz, CDCh) 8 ppm : 8.78 (s, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 4.12-4.14 (m,

2H), 3.79 (s, 3H), 3.68-3.71 (m, 2H), 3.47 (s, 3H), 1.53 (s, 9H).

Preparation 242 tert-butyl (5-(2-methoxyethoxy)-2-propionamidopyridin-4-yl)carbamate tert-Butyl (5-(2-methoxyethoxy)-2-propionamidopyridin-4-yl)carbamate was obtained, 950 mg, 97.2%, as a brown solid, from tert-butyl (2-bromo-5-(2-methoxyethoxy)pyridin-4- yl)carbamate (Preparation 22) and propionamide, following the procedure described in Preparation 32. 'H NMR: (400 MHz, CDCh) 6 ppm: 8.86 (s, 1H), 7.88 (s, 1H), 7.75 (s, 2H), 4.12-4.15 (m, 2H), 3.68-3.70 (m, 2H), 3.48 (s, 3H), 2.21-2.37 (m, 2H), 1.54 (s, 9H), 1.20- 1.24 (m, 3H).

Preparation 243 tert-butyl methyl (5-(2-(dimethylamino)ethoxy)pyridine-2,4-diyl)dicarbamate A mixture of (Preparation 30, 250 mg, 0.694 mmol), methyl carbamate (250 mg, 3.33 mmol), CS2CO3 (500 mg, 1.53 mmol), BrettPhos Pd G3 (25 mg, 27.6 umol) and dioxane (3 mL) was sealed and heated to 90 °C for 2 h. Additional BrettPhos Pd G3 (15 mg, 16.6 umol) was added and the reaction was stirred at 90 °C for 2 h. The reaction was cooled to rt, diluted with EtOAc (5 mL), filtered through Celite®, rinsing with EtOAc (10 mL) and the filtrate concentrated to dryness. The crude material was purified via silica gel chromatography (heptane to 3 : 1 EtOAc:EtOH with 2% DMEA) to give tert-butyl methyl (5-(2- (dimethylamino)ethoxy)pyridine-2,4-diyl)dicarbamate as a light tan oil, (170 mg, 69.1% yield) . LCMS m/z = 355.0 [M+ H]+. Preparations 244 to 246 The compounds in the following table were prepared from the appropriate 2-bromo or 2- chloropyridine and acetamide, following a similar procedure to that described in Preparation 41.

Preparation 247 tert-butyl (2-acetami do- 5 -hy droxypyri din-4-yl) carb am ate

To a solution of tert-butyl (2-acetamido-5-(benzyloxy)pyridin-4-yl)carbamate (Preparation 38, 500 mg, 1.26 mmol) in MeOH (5 mL) was added Pd/C (250 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with EE several times. The reaction mixture was stirred under EE (15 psi) at 20°C for 12 h, then filtered and concentrated to give tert-butyl (2-acetamido-5-hydroxypyridin-4-yl)carbamate (480 mg) as a gray solid. LCMS m/z = 212.3 [M+H] ⁺ .

Preparation 248 tert-butyl (2-acetamido-5-(2-(difluoromethoxy)ethoxy)pyridin-4-yl)carba mate

To a solution of tert-butyl (2-acetamido-5-hydroxypyridin-4-yl)carbamate (Preparation 247, 200 mg, 0.748 mmol) in DMF (10.0 mL) were added 2-(difluoromethoxy)ethyl 4- methylbenzenesulfonate (239 mg, 0.898 mmol) and CS2CO3 (731 mg, 2.24 mmol). The reaction mixture was stirred at 25°C for 2 h, then diluted with H2O (50 mL), extracted with EtOAc (100 mL) and washed with brine (50 mL). The combined organic layers were concentrated under reduced pressure and purified by chromatography on silica gel (PE/EtOAc 3/1 to 0/1) to give tert-butyl (2-acetamido-5-(2-(difluoromethoxy)ethoxy)pyridin- 4-yl)carbamate (170 mg, 62.9% yield) as a colourless oil. LCMS m/z = 362.0 [M+H] ⁺ .

Preparation 249 tert-butyl (2-acetamido-5-(3-methoxypropoxy)pyridin-4-yl)carbamate

To a solution of tert-butyl (2-acetamido-5-hydroxypyridin-4-yl)carbamate (Preparation 247, 330 mg, 1.11 mmol) in MeCN (6 mL) were added K2CO3 (461 mg, 3.33 mmol) and 3- methoxypropan-l-ol (680 mg, 4.44 mmol). The reaction mixture was stirred at 80°C for 12 h, then diluted with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over ISfeSCU, filtered and concentrated under reduced pressure to give a residue which was purified by chromatography on silica gel (DCM/MeOH 100/1 to 25/2) to yield tert-butyl (2-acetamido-5-(3-methoxypropoxy)pyridin-4-yl)carbamate (400 mg, 95.5% yield) as red oil. LCMS m/z = 340.2 [M+H] ⁺ .

Preparation 250 tert-butyl (2-acetamido-5-(2-morpholinoethoxy)pyridin-4-yl)carbamate

To a solution of tert-butyl (2-acetamido-5-hydroxypyridin-4-yl)carbamate (Preparation 247, 400 mg, 1.50 mmol) and K2CO3 (310 mg, 2.24 mmol) in MeCN (5.0 mL) was added 4-(2- chloroethyl)morpholine (HC1 salt, 336 mg, 2.24 mmol). The reaction mixture was stirred at 80°C for 1 h, then filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (DCM/MeOH 1/0 to 10/1) to give tert-butyl (2-acetamido-5- (2-morpholinoethoxy)pyridin-4-yl)carbamate (563 mg, 98.9% yield) as a yellow oil. LCMS m/z = 381.2 [M+H] ⁺ .

Preparation 251 tert-butyl (2-acetamido-5-(2-(4-methylpiperazin- 1 -yl)ethoxy)pyridin-4-yl)carbamate

A solution of tert-butyl (2-acetamido-5-hydroxypyridin-4-yl)carbamate (Preparation 247, 500 mg, 1.87 mmol), 2-(4-methylpiperazin-l-yl)ethan-l-ol (324 mg, 2.24 mmol) and (tributylphosphoranylidene)acetonitrile (2.3 g, 9.35 mmol) in toluene (5.0 mL) was stirred at 110°C under N2 for 1.5 h in a microwave. The mixture was hydrolysed with H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue which was purified by chromatography on silica gel (PE/EtOAc 1/0 to 3/1) to yield tert-butyl (2- acetamido-5-(2-(4-methylpiperazin-l-yl)ethoxy)pyridin-4-yl)c arbamate (200 mg, 27.2% yield) as a yellow oil. LCMS m/z = 394.2 [M+H] ⁺ .

Preparations 252 to 265

The compounds in the following table were prepared from the appropriate tert-butyl carbamate, following a similar procedure to that described in Preparation 63.

Preparation 266

N-(4-amino-5-(oxetan-3-ylmethoxy)pyridin-2-yl)acetamide trifluoroacetate To a solution of tert-butyl (2-acetamido-5-(oxetan-3-ylmethoxy)pyridin-4-yl)carbamate (Preparation 244, 430 mg, 1.27 mmol) in HFIP (2.5 mL) was added TFA (205 mg, 1.80 mmol). The reaction mixture was stirred at 25°C for 5 h, then concentrated under reduced pressure to obtain the N-(4-amino-5-(oxetan-3-ylmethoxy)pyridin-2-yl)acetamide, 740 mg, crude, TFA salt, as a white solid. LCMS m/z = 238.0 [M+H] ⁺ .

Preparations 267 to 268

The compounds in the following table were prepared as TFA salts from the appropriate tertbutyl carbamate, following a similar procedure to that described in Preparation 266. Preparation 269

N-(4-amino-5-(l-cyclopropylethoxy)pyridin-2-yl)acetamide

To a solution of tert-butyl (2-acetamido-5-(l-cyclopropylethoxy)pyridin-4-yl)carbamate (Preparation 235, 135 mg, 0.40 mmol) in DCM (2 mL) were added 2,6-lutidine (86.3 mg, 0.80 mmol) and TMSOTf (160 mg, 0.60 mmol). The reaction mixture was stirred at 25°C for 24 h under N2, then concentrated and purified by prep-HPLC (Method B) to give compound

N-(4-amino-5-(l-cyclopropylethoxy)pyndin-2-yl)acetamide (84 mg, 0.36 mmol) as a white solid. LCMS m/z = 236.1 [M+H] ⁺ .

Preparation 270 tert-butyl (2-acetamido-5-(2 -fluoroethoxy )pyridin-4-yl)carbamate

To a solution of 2-fluoroethanol (110 pL, 1.87 mmol) in THF (10 mL) was added PPI13 (736 mg, 2.81 mmol) followed by DIAD (553 pL, 2.81 mmol) and the solution stirred for 10 mins. tert- Butyl (2-acetamido-5-hydroxypyridin-4-yl)carbamate (Preparation 247, 0.500 g, 1.87 mmol) was added and the reaction was stirred at rt for 1 d. The reaction was diluted with water, extracted with EtOAc, the combined organic extracts washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel chromatography (0- 100% EtOAc in heptanes) to give tert-butyl (2-acetamido-5-(2-fluoroethoxy)pyridin-4- yl)carbamate (375 mg, 64% yield). LCMS m/z = 314.1 [M+H] ⁺ .

Preparation 271 tert-butyl (2-acetamido-5-(3-fluoropropoxy)pyridin-4-yl)carbamate tert-Butyl (2-acetamido-5-(3-fluoropropoxy)pyridin-4-yl)carbamate was obtained, 438 mg, 71% from tert-butyl (2-acetamido-5-hydroxypyridin-4-yl)carbamate (Preparation 247) and 3- fluoropropan-l-ol, following the procedure described in Preparation 270. LCMS m/z = 328.1 [M+H] ⁺ .

Preparation 272

N-(4-amino-5-(2-fluoroethoxy)pyridin-2-yl)acetamide hydrochloride

N-(4-amino-5-(2-fluoroethoxy)pyridin-2-yl)acetamide hydrochloride was obtained from tertbutyl (2-acetamido-5-(2-fluoroethoxy)pyridin-4-yl)carbamate (Preparation 270) following the procedure described in Preparation 63. LCMS m/z = 214.1 [M+H] ⁺ . Preparation 273

N-(4-amino-5-(3-fluoropropoxy)pyridin-2-yl)acetamide hydrochloride

N-(4-amino-5-(3-fluoropropoxy)pyridin-2-yl)acetamide hydrochloride was obtained from tert-butyl (2-acetamido-5-(3-fluoropropoxy)pyridin-4-yl)carbamate (Preparation 271), following the procedure described in Preparation 63. LCMS m/z = 228.1 [M+H] ⁺ .

Preparation 274

N-(2-chloro-5-(tri fluoromethoxy )pyri din-4-yl)-6-cycl opropoxy-2-(l,l - difluoroethyl)pyrimidin-4-amine

A vial containing 4-chloro-6-cyclopropoxy-2-(l, 1 -difluoroethyl )pyrimidine (Preparation 163, 325 mg, 1.4 mmol), 2-chloro-5-(trifluoromethoxy)pyridin-4-amine (196 mg, 0.923 mmol), CS2CO3 (889 mg, 2.7 mmol), BINAP (138 mg, 0.222 mmol) and KOAc (24 mg, 0.106 mmol) in dioxane (4 mL) was degassed then backfilled with N2 and heated to 95 °C. After 1 h, the mixture was cooled to rt then loaded onto a silica gel column. The mixture was purified with (5-35 % EtOAc in heptane) to afford N-(2-chl oro-5 - (trifluoromethoxy)pyridin-4-yl)-6-cyclopropoxy-2-(l, l-difluoroethyl)pyrimidin-4-amine as a white film (125 mg, 33 % yield). LCMS m/z = 410.8 [M+ H] ⁺ .

Preparation 275

N-(4-((6-bromo-4-methylpyridin-2-yl)amino)-5-ethoxypyridi n-2-yl)acetamide

To a mixture of N-(4-amino-5-ethoxypyridin-2-yl)acetamide hydrochloride

(Preparation 62, 1 g, 4.32 mmol) in dioxane (25 mL) was added DIPEA (1.12 g, 8.63 mmol) and the reaction mixture was sonicated for 1 min. 2,6-Dibromo-4-methylpyridine (1.62 g, 6.47 mmol) was added, followed by CS2CO3 (2.81 g, 8.63 mmol). A mixture of Pd(OAc)2 (97 mg, 0.432 mmol) and BINAP (564 mg, 0.906 mmol) in dioxane (5 mL) was sonicated and then added to the reaction. The reaction mixture was purged with N2, then heated at 90°C for 3h. The cooled reaction mixture was filtered through a Celite® plug, rinsing through with MeOH. The filtrate was concentrated and the crude was purified by chromatography on silica gel (50%EtOAc with 2%NH4OH in heptane) to give N-(4-((6- bromo-4-methylpyridin-2-yl)amino)-5-ethoxypyridin-2-yl)aceta mide (512 mg, 32% yield). LCMS m/z = 365, 367 [M+H] ⁺

Preparation 276 tert-butyl (2-acetamido-5-ethoxypyridin-4-yl)carbamate

To a solution of tert-butyl (2-bromo-5-ethoxypyridin-4-yl)carbamate (Preparation 23, 75 g, 236.5 mmol) in dioxane (1 L) was added acetamide (69.84 g, 1.18 mol), CS2CO3 (231.13 g, 709.4 mmol) and BrettPhos Pd G3 (4.29 g, 4.73 mmol) and the reaction was stirred at 100 °C for 1 h under N2. The cooled mixture was concentrated under reduced pressure. The residue was washed with water (500 mL) and extracted with EtOAC (500 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over ISfeSCU, filtered and concentrated. The residue was purified on silica gel column chromatography (PE/EtOAc = 5/1 to 1/1) to give tert-butyl (2-acetamido-5-ethoxypyridin-4-yl)carbamate (58 g, 83.1% yield) as yellow solid. 1H NMR (400MHz, DMSO-d ₆ ) 8 ppm 10.17 (s, 1H), 8.62 (s, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 4.11 (q, J = 6.8 Hz, 2H), 2.03 (s, 3H), 1.48 (s, 9H), 1.35 (t, J = 6.8 Hz, 3H).

Preparation 277 tert-butyl (2-acetamido-5-ethoxypyridin-4-yl)(6-chloro-2-(l,l-difluoroe thyl)pyrimidin-4- yl)carbamate A mixture of tert-butyl (2-acetamido-5-ethoxypyridin-4-yl)carbamate (Preparation 276, 1 g, 3.39 mmol), 4, 6-di chi oro-2-(l,l -difluoroethyl )pyrimidine (Preparation 91), CS2CO3 (4.5 g, 14 mmol), and DMF (10 mL) was heated to 40 °C for 6 h. The reaction was diluted with 1 : 1 heptane:EtOAc (50 mL) and washed with water (50 mL). The aqueous layer was extracted with 1 : 1 heptane:EtOAc (2 x 50 mL) and the combined organic layers were concentrated to dryness. The crude material was purified by silica gel chromatography (heptane to EtOAc) to give tert-butyl (2-acetamido-5-ethoxypyridin-4-yl)(6-chloro-2-(l,l-difluoroe thyl)pyrimidin- 4-yl)carbamate as a yellow solid. (880 mg, 55.1% yield). LCMS m/z = 472.1 [M+H] ⁺ .

Preparation 278 tert-butyl (2-acetamido-5-methoxypyridin-4-yl)(6-chloro-2-(l,l-difluoro ethyl)pyrimidin-4- yl)carbamate

A solution of tert-butyl (2-acetamido-5-methoxypyridin-4-yl)carbamate (Preparation 35, 1 g, 3.55 mmol), CS2CO3 (3.5 g, 10.74 mmol) and DMAC (20 mL) was stirred for 10 mins at rt then 4,6-dichloro-2-(l,l-difluoroethyl)pyrimidine (Preparation 91, 1.5 g, 7.04 mmol) was added and the reaction stirred at rt for 4 h. The reaction was diluted with EtOAc (50 mL) and filtered through Celite®. The filtrate was concentrated to a low volume, then dissolved in 1 : 1 heptane:EtOAc (100 mL) and washed with 10% brine/water (2 x 150 mL). The crude organic layer was concentrated to dryness and purified by silica gel chromatography (heptane to EtOAc) to give tert-butyl (2-acetamido-5-methoxypyridin-4-yl)(6-chloro-2-(l,l- difhjoroethyl)pyrimidin-4-yl)carbamate as a bright yellow oil (1 g, 61.4% yield).

Preparation 279

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-hydroxypyri din-2- yl)acetamide To a solution of N-(5-(benzyloxy)-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin -4- yl)amino)pyridin-2-yl)acetamide (Example 30, 12.6 g, 30.5 mmol) in EtOH (150 mL) was added Pd/C (324 mg, 3.05 mmol). The mixture was stirred under EE atmosphere (15 psi) at 25°C for 16 h, then filtered and concentrated to give a residue which was purified by column chromatography on silica gel (DCM/MeOH 1/0 to 10/1) to give N-(4-((2-( 1,1 -difhioroethyl)- 6-methylpyrimidin-4-yl)amino)-5-hydroxypyridin-2-yl)acetamid e (10 g, 79.2% yield) as white solid. LCMS m/z = 324.1 [M+H] ⁺ .

Preparation 280

N-(5-(benzyloxy)-4-((6-cyclopropoxy-2-(l,l-difluoroethyl) pyrimidin-4-yl)amino)pyri din-2- yl)acetamide

To a solution of N-(4-amino-5-(benzyloxy)pyridin-2-yl)acetamide hydrochloride (Preparation 82, 1.38 g, 4.69 mmol) and 4-chloro-6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidine (Preparation 163, 1 g, 4.26 mmol) in dioxane (60 mL) were added CS2CO3 (2.78 g, 8.52 mmol), BINAP (530.8 mg, 0.852 mmol) and Pd2(dba)3 (390.3 mg, 0.426 mmol) and the reaction degassed for 10 mins by bubbling N2. The reaction was stirred at 90 °C for 8 h. The cooled reaction was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (PEZEtOAc = 5/1 - 1/1) to give N- (5-(benzyloxy)-4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrim idin-4-yl)amino)pyri din-2- yl)acetamide (1.05 g, 54.1% yield) as a white solid. LCMS m/z = 456.2 [M+H]+

Preparation 281

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-hydroxypyri din-2- yl)acetamide To a solution of N-(5-(benzyloxy)-4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyr imidin-4- yl)amino)pyridin-2-yl)acetamide (Preparation 280, 15 g, 32.9 mmol) in EtOH (180 mL) was added Pd/C (3.50 g, 3.29 mmol, 10% purity). The reaction mixture was stirred at 30 °C, then purged by bubbling EE for 10 mins. The reaction was warmed to 50 °C and stirred under EE of 15 psi for 4 h. The reaction was purged by bubbling N2 for 10 mins, then filtered through Celite®, rinsing with EtOH (80 mL). The filtrate was evaporated under reduced pressure to give filtrate to give N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl)am ino)-5- hydroxypyridin-2-yl)acetamide (10.2 g, 84.8% yield) a tan solid. LCMS m/z = 366.0 [M+H]+; ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 10.08 (s, 2H), 9.30 (s, 1H), 8.90 (br s, 1H), 7.82 (s, 1H), 6.91 (s, 1H), 4.10-4.19 (m, 1H), 1.98-2.13 (m, 6H), 0.68-0.95 (m, 4H).

Preparation 282

4-iodo-2-(2-methoxyethoxy)pyrimidine

To a solution of 2-chloro-4-iodopyrimidine (142 mg, 1.87 mmol) in THF (5 mL) was added NaH (99.8 mg, 2.50 mmol, 60% purity) at 25 °C and the mixture stirred for 30 min before 2- methoxyethan-l-ol (300 mg, 1.25 mmol) was added and the mixture was stirred at 70 °C for 16 h. The mixture was concentrated and the residue purified by chromatography on silica gel (33% EtOAc/PE) to give 4-iodo-2-(2-methoxyethoxy)pyrimidine as a yellow oil (150 mg, 43%). ^X H NMR (400 MHz, CDCh) 6 ppm 8.01 (d, J=5.2 Hz, 1H), 7.39 (d, J=5.2 Hz, 1H), 4.50-4.52 (m, 2H), 3.75-3.77 (m, 2H), 3.42 (s, 3H).

Preparation 283

2-chloro-4-(2-methoxyethoxy)pyrimidine

To a solution of 2,4-dichloropyrimidine (1 g, 6.71 mmol) in DMF (15 mL) was added 2- methoxyethan-l-ol (511 mg, 6.71 mmol) and CS2CO3 (4.4 g, 13.42 mmol) and the mixture stirred at 100 °C for 4 h. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organics were washed with brine (20 mL x 2), dried (Na2SO4) and were concentrated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc) to give 2-chloro-4-(2-methoxyethoxy)pyrimidine as a yellow solid (700 mg, 55%). 'H NMR (400 MHz, CDCh) 6 ppm 8.30 (d, J=6.0 Hz, 1H), 6.73 (d, J=5.6 Hz, 1H), 4.52-4.56 (m, 2H), 3.71-3.79 (m, 2H), 3.43 (s, 3H).

Preparation 284

6-(2-methoxyethyl)pyrimidin-4-ol

To a solution of methyl 5 -m ethoxy-3 -ox opentanoate (1 g, 6.24 mmol) in MeOH (10 mL) was added formimidamide acetate (650 mg, 6.24 mmol) and NaOMe (674.6 mg, 12.49 mmol) and the mixture was stirred at 70 °C for 2 h. The mixture was concentrated and purified by Prep- HPLC (Method E, Gradient 0-30%) to give 6-(2-methoxyethyl)pyrimidin-4-ol (135 mg, 14.0% yield) as a yellow oil. 'H NMR (400 MHz, CDCh) 3 ppm 8.38 (s, 1H), 6.48 (s, 1H), 5.87-5.98 (m, 1H), 3.73 (t, J=5.8 Hz, 2H), 3.35 (s, 3H), 2.88 (t, J=5.8 Hz, 2H).

Preparation 285

4-chloro-6-(2-methoxyethyl)pyrimidine

To a solution of 6-(2-methoxyethyl)pyrimidin-4-ol (Preparation 284, 100 mg, 0.649 mmol) in DCM (3 mL) was added POCh (1.0 mL 10.73 mmol) and the mixture was stirred at 40 °C for 18 h. The mixture was evaporated, the residue diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified on silica gel column chromatography (PE/EtOAc=l/0 to 1/1) to give 4-chloro-6-(2- methoxyethyl)pyrimidine (40 mg, 35.7% yield) as a yellow oil. 'H NMR: (400 MHz, CDCh) 3 ppm 9.08 (s, 1H), 7.57 (s, 1H), 3.77-3.81 (m, 2H), 3.35 (s, 3H), 3.18-3.22 (m, 2H).

Preparation 286

2-chloro-5-(difluoromethoxymethyl)pyrazine

(5-Chloropyrazin-2-yl)methanol (500 mg, 3.46 mmol) and Cui (329.36 mg, 1.73 mmol) were dissolved in MeCN (5 mL) and the reaction mixture was heated to 45°C. A solution of 2,2- difhioro-2-fluorosulfonyl-acetic acid (924 mg, 5.19 mmol) in MeCN (3 mL) was added dropwise over 30 mins. The reaction was stirred for 3 h, cooled to rt and diluted with EtOAc. The organic layer was washed with sat. NaHCOs solution and dried over Na2SO4. The crude product was purified by silica gel column chromatography eluting with (0-100% heptane- EtOAc) to obtain 2-chloro-5-(difluoromethoxymethyl)pyrazine (120 mg, 14.3% yield).

Preparation 287 l-((2,6-dibromopyridin-3-yl)oxy)-2-methylpropan-2-ol

To a solution of 2,6-dibromopyridin-3-ol (10 g, 39.54 mmol) in DMF (150 mL) was added K2CO3 (16.40 g, 118.6 mmol) and 2,2-dimethyloxirane (5.70 g, 79.1 mmol). The mixture was stirred at 100 °C for 24 h under N2. The mixture was diluted with water (100 mL), extracted with EtOAc (lOOmL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PEZEtOAc = 100/1 to 3/1) to give l-((2,6-dibromopyridin-3-yl)oxy)-2-methylpropan-2-ol (8 g, 56.0% yield) as a brown oil. 1H NMR (400MHz, CDCh) 8 ppm 7.37 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 3.84 (s, 2H), 1.39 (s, 6H).

Preparation 288

6-bromo-2,2-dimethyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyrid ine

To a solution of l-((2,6-dibromopyridin-3-yl)oxy)-2-methylpropan-2-ol (Preparation 287, 8 g, 22.15 mmol) in DMF (120 mL) was added NaH (1.33 g, 33.23 mmol, 60% purity) at 0 °C. The mixture was stirred at 90 °C for 3 h under N2. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PEZEtOAc = 100/1 to 5/1) to give 6-bromo-2,2-dimethyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (4.2 g, 69.9% yield) as white solid. 1H NMR: (400MHz, CDCh) 6 ppm 6.99-7.03 (m, 2H), 4.06 (s, 2H), 1.36 (s, 6H).

Preparation 289

3 -bromo- 1 -(2-ethoxy ethyl)- 1 H-pyrazole To a solution of 3-bromo-lH-pyrazole (300 mg, 1.96 mmol) in MeCN (10 mL) was added 1- bromo-2-ethoxyethane (288.2 mg, 1.96 mmol), CS2CO3 (638.8 mg, 1.96 mmol) and KI (65.1 mg, 0.39 mmol) and the resulting mixture was stirred at 90 °C for 8 h. The mixture was concentrated under vacuum and the crude was purified by column chromatography (PE/EtOAc = 0/1 to 3/1) to give 3-bromo-l-(2-ethoxyethyl)-lH-pyrazole (230 mg, 53.6% yield) as white oil. 'H NMR (400 MHz, CDCh) 8 ppm 7.38 (d, ./=2,4 Hz, 1H), 6.24 (d, J=2.Q Hz, 1H), 4.24 (t, J=5.2 Hz, 2H), 3.74 (t, J=5.2 Hz, 2H), 3.41-3.47 (m, 2H), 1.15 (t, J=6.8 Hz, 3H).

Preparation 290

4-bromo-2-(2-methoxyethyl)-2H-l,2,3-triazole and 4-bromo- l-(2-methoxy ethyl)- 1H- 1,2,3 - tri azole

To a solution of 4-bromo-2H- 1,2, 3 -triazole (1.0 g, 6.76 mmol) in DMF (10 mL) was added 1- bromo-2-methoxyethane (1.03 g, 7.43 mmol) and CS2CO3 (4.4 g, 13.5 mmol) and the resulting mixture stirred at 80 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL x 3). The combined organics were washed with brine (30 mL x 2), dried (ISfeSCU) and evaporated to dryness to afford a mixture of 4-bromo-2-(2- methoxyethyl)-2H- 1,2, 3 -triazole and 4-bromo-l-(2-methoxyethyl)-lH-l,2,3-triazole as a yellow oil (1.2 g, 86%). ^X H NMR (400 MHz, CDCh) 6 ppm: 7.70 (s, 0.3H), 7.56 (s, 1H), 4.57 (t, J=5.6 Hz, 2H), 4.53 (t, J=4.8 Hz, 0.7H), 3.87 (t, J=5.6 Hz, 2H), 3.74 (t, J=4.8 Hz, 0.7H), 3.36 (s, 1H), 3.35 (s, 3H).

Preparation 291

3 -bromo- 1 -(2 -methoxy ethyl)- 1 H- 1 ,2,4-tri azole

3-Bromo-l-(2-methoxyethyl)-lH-l,2,4-triazole was obtained as a yellow solid, 500 mg,

71.8%, from 3-bromo-lH-l,2,4-triazole and l-bromo-2-m ethoxy ethane (469.7 mg, 3.38 mmol) following the procedure described in Preparation 290. 'H NMR (400 MHz, CDCh) 6: ppm 8.02 (s, 1H), 4.28-4.30 (m, 2H), 3.69-3.74 (m, 2H), 3.33 (s, 3H).

Preparation 292

2-(3-bromo-l-methyl-lH-pyrazol-5-yl)propan-2-ol

To a solution of l-(3-bromo-l-methyl-lH-pyrazol-5-yl)ethan-l-one (1 g, 4.93 mmol) in THF (10 mL) was added MeMgBr (3 M, 2.46 mL, 7.39 mmol) at 0 °C under N2. The mixture was stirred at 20 °C under N2 for 2 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (PE/EtOAc = 100/1 to 10/7) to give 2-(3-bromo-l-methyl-lH- pyrazol-5-yl)propan-2-ol (1 g, 92.7% yield) as a light yellow liquid. LCMS m/z = 219.1 [M+H] ⁺

Preparation 293

2-bromo-5-(methoxymethyl)thiazole

To a solution of 2-bromo-5-(hydroxymethyl)thiazole (1.0 g, 5.15 mmol) in THF (20 mL) was added NaH (309.2 mg, 7.73 mmol, 60% purity) at 0 °C and the mixture stirred at 25 °C for 1 h. Mel (877.8 mg, 6.18 mmol) was added and the reaction stirred at 25 °C for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (30 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (PE/ EtOAc = 1/0 to 5/1) to give 2-bromo-5-(methoxymethyl)thiazole (200.0 mg, 18.65% yield) as lightyellow oil. LCMS m/z = 207.9 [M+H] ⁺

Preparation 294 to 300

The compounds in the following table were prepared from the appropriate alcohol and Mel, following a similar procedure to that described in Preparation 293.

Preparation 301

5-bromo-N,N-dimethyl-l,3,4-thiadiazol-2-amine

To a solution of 2,5-dibromo-l,3,4-thiadiazole (500 mg, 2.05 mmol) and N- methylmethanamine hydrochloride (200.6 mg, 2.46 mmol) in dioxane (10 mL) was added TEA (414.9 mg, 4.10 mmol). The mixture was stirred at 100 °C for 2h. The mixture was concentrated and purified by chromatography on silica gel (PEZEtOAc = 100/1 to 3/1) to give 5-bromo-N,N-dimethyl-l,3,4-thiadiazol-2-amine (360 mg, 76.0% yield) as a white solid. LCMS m/z = 208.0 [M+H] ⁺

Preparation 302

4-bromo-N,N-dimethylthiazol-2-amine

To a solution of 2,4-dibromothiazole (500 mg, 2.06 mmol) in MeCN (1 mL) was added dimethylamine (928.0 mg, 20.58 mmol) and DBU (940.1 mg, 6.17 mmol) and the reaction mixture was stirred at 20 °C for 16 h. The mixture was concentrated under vacuum and the crude was purified by column chromatography (PE/EtOAc = 0/1 to 1/1) to give 4-bromo-N,N- dimethylthiazol-2-amine (300 mg, 70.4% yield) as a white solid. ^T H NMR (400 MHz, CDCh) 8 ppm 6.35 (s, 1H), 3.10 (s, 6H).

Preparation 303

2-(3-bromo-l-methyl-lH-pyrazol-5-yl)-N,N-dimethylpropan-2 -amine

Part A: To a solution of 2-(3-bromo-l-methyl-lH-pyrazol-5-yl)propan-2-ol (Preparation 292, 650 mg, 2.97 mmol) in MeCN (6 mL) was added sulfuric acid (1.5 mL) at 0 °C, and the mixture stirred at 25 °C for 15 h. After work-up, N-(2-(3-bromo-l-methyl-lH-pyrazol-5- yl)propan-2-yl)acetamide was obtained as a yellow solid (610 mg, 71%)

Part B: A solution of N-(2-(3-bromo-l-methyl-lH-pyrazol-5-yl)propan-2-yl)acetamide (500 mg, 1.92 mmol) in HC1 (4.8 mL), H2O (10 mL) and MeOH (10 mL) was stirred at 80 °C for 12 h. The mixture was concentrated and purified by prep-HPLC (Method X, Gradient 0- 25%) to give 2-(3-bromo-l-methyl-lH-pyrazol-5-yl)propan-2-amine as a yellow oil (205 mg, 44%). LCMS m/z = 220.1 [M+H] ⁺ .

Part C: A solution of 2-(3-bromo-l-methyl-lH-pyrazol-5-yl)propan-2-amine (170 mg, 0.78 mmol) and (CH2O)n (3.74 g, 3.12 mmol, 4.25 mL) in MeOH (2 mL) and H2O (0.2 mL) was stirred at 25 °C for Ih before NaBHsCN (196 mg, 3.12 mmol) and ZnCh (106 mg, 0.78 mmol) was added and the reaction stirred at 25 °C for 12 h. The reaction mixture was evaporated to dryness and purified by chromatography on silica gel (1-25% EtOAc/PE) to give 2-(3-bromo-l-methyl-lH-pyrazol-5-yl)-N,N-dimethylpropan-2-am ine as a yellow oil (110 mg, 57%) 'H NMR (500 MHz, DMSO-d ₆ ) 8 ppm 6.19 (s, IH), 3.96 (s, 3H), 2.08 (s, 6H), 1.30 (s, 6H).

Preparation 304

3-bromo-l-methyl-5-(pyrrolidin-l-ylmethyl)-lH-pyrazole

To a solution of 3-bromo-l-methyl-lH-pyrazole-5-carbaldehyde (300 mg, 1.59 mmol) in MeOH (6 mL) was added pyrrolidine (339 mg, 4.76 mmol) and NaBHsCN (499 mg, 7.94 mmol) and the resulting mixture was stirred at 70 °C for 16 h. The mixture was concentrated and the residue purified by prep-HPLC (Method R, Gradient 26-56%) to give 3-bromo-l- methyl-5-(pyrrolidin-l-ylmethyl)-lH-pyrazole as a yellow oil (266 mg, 69%). 'H NMR (500 MHz, CDCk) 6 ppm: 6.13 (s, IH), 3.85 (s, 3H), 3.57 (s, 2H), 2.47-2.49 (s, 4H), 1.76-1.80 (s, 4H).

Preparation 305 to 308

The title compounds were prepared from the appropriate aldehyde and amine using an analogous method to that described for Preparation 304.

Preparation 309

2-bromo-5-(2 -methoxy ethyl)- 1, 3, 4-thiadiazole Part A: A solution of 3 -methoxypropanenitrile (1 g, 11.7 mmol) and hydrazinecarbothioamide (1.29 g, 14.1 mmol) in TFA (10 mL) was stirred at 65 °C for 5 h. The mixture was concentrated and purified by chromatography on silica gel (1-50% EtOAc/PE) to give 5-(2-methoxyethyl)-l,3,4-thiadiazol-2-amine as a yellow oil (580 mg, 28%). Part B: Isopentyl nitrite (883 mg, 7.54 mmol) and TMSBr (865 mg, 5.65 mmol) were added to a solution of 5-(2-methoxyethyl)-l,3,4-thiadiazol-2-amine (300 mg, 1.88 mmol) in CtfeB (2 mL) at 0 °C and the reaction stirred for 30 min at 0 °C and at 25 °C for 2 h. The mixture was concentrated and purified by chromatography on silica gel (1-25% EtOAc/PE) to give 2- bromo-5-(2-methoxyethyl)-l,3,4-thiadiazole as a yellow oil (290 mg, 62%). LCMS m/z = 222.9 [M+H] ⁺ .

Preparation 310

2-bromo-5-(methoxymethyl)-l,3,4-thiadiazole

The title compound was prepared from 5-(methoxymethyl)-l,3,4-thiadiazol-2-amine using an analogous method used to prepare Preparation 309, Part B. LCMS m/z = 208.9 [M+H] ⁺ .

Preparation 311

3-bromo-N,N-dimethyl-l,2,4-thiadiazol-5-amine

Dimethylamine (186.5 mg, 1.65 mmol) and DIPEA (583 mg, 4.51 mmol) were added to a solution of 3-bromo-5-chloro-l,2,4-thiadiazole (300 mg, 1.50 mmol) in EtOH (10 mL) and the mixture stirred at 25 °C for 1 h. The mixture was concentrated and the residue purified by silica column (0-20% EtOAc/PE) to give 3-bromo-N,N-dimethyl-l,2,4-thiadiazol-5-amine as a colourless liquid (262 mg, 84%). LCMS m/z = 210.0 [M+H] ⁺ .

Preparation 312

5-bromo-3-(methoxymethyl)-l,2,4-thiadiazole

Part A: To a solution of 2-methoxyacetimidamide hydrochloride (500 mg, 4.01 mmol) in MeOH (15 mL) at 0 °C, under vigorous stirring, was added dropwise Br2 (641.4 mg, 4.01 mmol) and NaOMe (217 mg, 4.01 mmol) simultaneously over 30 min maintaining a slight bromine excess by color. To the resulting nearly colorless suspension was added dropwise a solution of potassium thiocyanate (390 mg, 4.01 mmol) in MeOH (5 mL) over 10 min at 0- 10 °C. The resulting mixture was stirred for 2 h at 0-10 °C. The solid was collected by filtration and washed with MeOH to afford a brown solid which was purified by chromatography on silica gel (DCM/MeOH=10/l) to give 3 -(methoxymethyl)- 1,2,4- thiadiazol-5-amine (280 mg, 48%). Part B: To a solution of 3-(methoxymethyl)-l,2,4-thiadiazol-5-amine (250mg, 1.72 mmol) in CFbB (5 mL) was added TMSBr (1.05 g, 6.89 mmol) and tert-butyl nitrite (533 mg, 5.17 mmol) and the mixture stirred at 0 °C for 3 h under N2. The mixture was concentrated and the residue purified by chromatography on silica gel (EtOAc) to give 5-bromo-3- (methoxymethyl)-l,2,4-thiadiazole as a yellow solid (50 mg, 14%). NMR (500 MHz, CDCL) 8 ppm 4.71 (s, 2H), 3.51 (s, 3H).

Preparation 313

4-bromo-2-(4-methylpiperazin- 1 -yl)thiazole

To a solution of 2,4-dibromothiazole (1 g, 4.12 mmol) in THF (10.0 mL) was added 1- methylpiperazine (2.5 g, 24.7 mmol) and TEA (2.5 g, 24.70 mmol) and the reaction mixture stirred at 90 °C for 12 h. The mixture was concentrated under reduced pressure and the residue purified by silica gel column chromatography (10-20% MeOH/DCM) to give 4- bromo-2-(4-methylpiperazin-l-yl)thiazole as a yellow oil (1.0 g, 93%). LCMS m/z = 262.0 [M+H] ⁺ .

Preparation 314

4-bromo-N-(2-methoxyethyl)-N-methylthiazol-2-amine

The title compound was prepared as a yellow oil (1.01 g, 93%) from 2,4-dibromothiazole and 2-methoxy-N-methylethan-l -amine using an analogous method to that described for Preparation 313. LCMS m/z = 252.9 [M+H] ⁺ .

Preparation 315

5-bromo-N-(2-methoxyethyl)-N-methyl-l,3,4-thiadiazol-2-am ine

A solution of 2,5-dibromo-l,3,4-thiadiazole (400 mg, 1.64 mmol) and 2-methoxy-N- methylethan-l -amine (146 mg, 1.64 mmol) in DMF (8 mL) was added K2CO3 (680 mg, 4.92 mmol) and the mixture stirred at 80 °C for 4h. The mixture was concentrated and the residue purified by chromatography on silica gel (1-25% EtOAc/PE) to give 5-bromo-N-(2- methoxyethyl)-N-methyl-l,3,4-thiadiazol-2-amine as a yellow oil (280 mg, 61%). LCMS m/z = 252.0 [M+H] ⁺ . Preparation 316

2-bromo-5-(4-methylpiperazin-l-yl)-l,3,4-thiadiazole

The title compound was prepared from 2,5-dibromo-l,3,4-thiadiazole and 1 -methylpiperazine using an analogous method to that described for 5-bromo-N-(2-methoxyethyl)-N-methyl- l,3,4-thiadiazol-2-amine (Preparation 315). LCMS m/z = 265.0 [M+H] ⁺ .

Preparation 317 l-(2-bromothiazol-5-yl)-N,N-dimethylmethanamine To a solution of 2-bromothiazole-5-carbaldehyde (200 mg, 1.04 mmol) in DCM (10 mL) was added Me2NH.HCl (169.9 mg, 2.08 mmol) and the solution stirred at 25 °C for 1 h before NaBH(OAc)3 (441.5 mg, 2.08 mmol) was added and stirring continued at 25 °C for 16 h. The mixture was concentrated and purified by prep-HPLC (Boston Prime C18 150 x 30 mm, 5 mm; 25-55% MeCN/H ₂ O (NH ₄ OH + NH4HCO3)) to give l-(2-bromothiazol-5-yl)-N,N- dimethylmethanamine as a yellow solid (66.0 mg, crude). LCMS m/z = 222.9 [M+H] ⁺ . Preparation 318 to 325

The title compounds were prepared from the appropriate aldehyde and amine using a similar method to that described for l-(2-bromothiazol-5-yl)-N,N-dimethylmethanamine (Preparation 317)

Preparation 326

2-(azetidin- 1 -yl)-4-bromothiazole

To a solution of azetidine (1 g, 4.12 mmol) in THF (10 mL) was added 2,4-dibromothiazole (1.41 g, 24.70 mmol, 1.66 mL) and TEA (2.50 g, 24.7 mmol) and the mixture stirred at 80 °C for 12 h. The mixture was diluted with H2O (20 ml), extracted with EtOAc (20 ml x 3), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica column chromatography (1-20% EtOAc/PE) to give 2-(azetidin-l-yl)-4-bromothiazole as a white solid (469 mg, 52%). LCMS m/z = 221.0 [M+H] ⁺ .

Preparation 327

6-(4-bromothiazol-2-yl)-2-oxa-6-azaspiro[3.3]heptane

The title compound was prepared using an analogous method to that described for

Preparation 326, from 2,4-dibromothiazole and 2-oxa-6-azaspiro[3.3]heptane. LCMS m/z = 262.0 [M+H] ⁺ .

Preparation 328

4-(2-(4-bromo-2H-l,2,3-triazol-2-yl)ethyl)morpholine

To a solution of 4-bromo-2H- 1,2, 3 -triazole (300 mg, 2.03 mmol) in DMF (10 mL) was added 4-(2-bromoethyl)morpholine (393.5 mg, 2.03 mmol), CS2CO3 (1.3 g, 4.06 mmol) and the reaction stirred at 90 °C for 3 h. The mixture was concentrated and H2O (20 mL) added and extracted with EtOAc (20 mL x 3). The combined organics were washed with brine (20 mL), dried (Na2SO4) and concentrated. The residue was purified on silica gel column chromatography (15-33% EtOAc/PE) to give 4-(2-(4-bromo-2H- 1,2,3 -triazol-2- 00 MHz, CDCL) 8 ppm 7.53 l-(2-(4-Bromo-2H-l,2,3-triazol-2-yl)ethyl)-4-methylpiperazin e was prepared using an analogous method to that described for Preparation 328, from 4-bromo-2H-l,2,3-triazole. LCMS m/z = 274.0 [M+H] ⁺ .

Preparation 330

6-bromo-2,3-dihydroimidazo[2,l-b]oxazole

Part A: To a solution of 2,4,5-tribromo-lH-imidazole (1.0 g, 3.28 mmol) in DMF (10.0 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (942 mg, 3.94 mmol) and CS2CO3 (3.2 g, 9.84 mmol) and the resulting mixture stirred at 70 °C for 16 h. The mixture diluted with water (60 mL) and extracted with EtOAc (50 mL x 3). The combined organics were washed with brine (50 mL), dried (ISfeSCh) and concentrated. The residue was purified by chromatography on silica gel (5-20% EtOAc/PE) to give 2,4,5-tribromo-l-(2-((tert- butyldimethylsilyl)oxy)ethyl)-lH-imidazole as a yellow oil (1.3 g, 86%).

Part B: To a solution of 2,4,5-tribromo-l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-lH- imidazole (1.3 g, 2.81 mmol) in dioxane (8.0 mL) was added HCl/dioxane (4 M, 8.0 mL) and the resulting mixture stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-(2,4,5-tribromo-lH-imidazol-l-yl)ethan-l-ol as a white solid (1.0 g, crude).

Part C: To a solution of 2-(2,4,5-tribromo-lH-imidazol-l-yl)ethan-l-ol (1.0 g, 2.87 mmol) in DMF (8.0 mL) was added NaH (229 mg, 5.73 mmol, 60% purity) at 0 °C and the reaction stirred at 0 °C for 2 h. The reaction was quenched with NH4CI aq. (20 mL), diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organics were washed with brine (30 mL), dried (Na2SO4) and concentrated to give 5,6-dibromo-2,3- dihydroimidazo[2,l-b]oxazole as yellow oil (580 mg, 75%) as yellow oil.

Part D: To a solution of 5,6-dibromo-2,3-dihydroimidazo[2,l-b]oxazole (580 mg, 2.16 mmol) in THF (8.0 mL) was added n-BuLi (2.5 M, 2.16 mmol, 0.86 mL) slowly at -70 °C under N2 and the resulting mixture stirred at -70 °C for 1 h under N2. The reaction was quenched with NH4CI (sat, 20 mL), diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organics was dried (Na2SO4), concentrated and the residue purified by chromatography on silica gel (5-25% EtOAc/PE) to give 6-bromo-2,3-dihydroimidazo[2,l- b]oxazole as a white solid (190 mg, 46%). ^T H NMR (400 MHz, CDCL) 8 ppm: 6.60 (s, 1H), 5.00 (d, J=7.6 Hz, 2H), 4.15 (d, J=8.0 Hz, 2H). Preparation 331

2-bromo-5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin e

To a solution of 2-bromo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (230 mg, 1.14 mmol) in MeOH (1 mL) was added NaBH ₃ CN (357.7 mg, 5.69 mmol), (CH ₂ O)n (2.73 g, 2.28 mmol) and the mixture was stirred at 25 °C for 16 h. The mixture was concentrated and purified by Prep-HPLC (Method R, Gradient 12-42%) to give 2-bromo-5-methyl-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazine (135 mg, 54.9% yield) as a white solid. LCMS m/z = 218.0 [M+H] ⁺

Preparation 332

2-bromo-7-methyl-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine

2-bromo-7-methyl-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine was obtained as a white solid, 120 mg, 46.8%, from 2-bromo-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine and (CH2O)n, following the procedure described in Preparation 331. LCMS m/z = 218.0 [M+H] ⁺

Preparation 333

2-bromo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine

N'l' ji NH

To a solution of 3-bromo-lH-pyrazol-5-amine (900 mg, 5.56 mmol) in dioxane (10 mL) was added 1,3-dibromopropane (1.4 g, 6.67 mmol) and DIPEA (2.2 g, 16.67 mmol). The resulting solution was heated at 120 °C for 12 h in a sealed tube. The mixture was concentrated and purified by Prep-HPLC (Method B, 15-35%) to give 2-bromo-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrimidine (328 mg, 29.2% yield) as a white solid. LCMS m/z = 202.0 [M+H] ⁺

Preparation 334

2-bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimid ine 2-Bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine was obtained as a yellow oil, 100 mg, 46.8% from 2-bromo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine (Preparation 333), following the procedure described in Preparation 293. LCMS m/z = 218.0 [M+H] ⁺ Preparation 335

2-bromo-5-(methyl-d3)-4,5,6,7-tetrahydropyrazolo[l,5-a]py razine

A vial containing 2-bromo-4, 5,6, 7-tetrahydropyrazolo[l,5-a]pyrazine trifluoroacetate (317 mg, 1.00 mmol) in anhydrous 2-MeTHF (4 mL) was cooled in an ice water bath, then DIPEA (0.9 mL, 5.2 mmol) and NaOtBu (299 mg, 3.1 mmol) were added under N2 at <5 °C. After 20 minutes, CD3I (0.2 mL, 3.2 mmol) was added and the reaction was maintained at <5 °C for 1.5 h. The reaction was quenched by slow addition of solid NaHCCL, the mixture was stirred at 23 °C for 1 h, then was concentrated under reduced pressure. The residue was loaded onto a silica gel column and purified with (50-100% 3: 1 EtOAc: EtOH in heptane) to afford 2-bromo-5- (methyl-d3)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (110 mg, crude). LCMS m/z = 219.0 [M+ H] ⁺ .

Preparation 336

2-Iodo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine hydrochloride

To a flask containing tert-butyl 2-iodo-6,7-dihydro-4H-pyrazolo[l,5-a]pyrazine-5- carboxylate (938 mg, 2.69 mmol) in DCM (11 mL) was added HC1 in dioxane (4M solution) (2 mL, 8.00 mmol). Upon complete addition of HC1, the reaction was stirred at 23 °C for 72 h. DCM (11 mL) then HC1 in dioxane (4 mL, 16.00 mmol) were added and the mixture stirred for 45 h then concentrated in vacuo. The crude product was diluted with EtOAc then sonicated for 5 mins. The heterogeneous mixture was filtered to afford a faint yellow white solid as 2-iodo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (HC1 Salt) (703 mg, crude). LCMS m/z = 249.9 [M+ H] ⁺ .

Preparation 337 l-(2-iodo-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)ethan-l -one To a vial containing 2-iodo-4, 5,6, 7-tetrahydropyrazolo[l,5-a]pyrazine hydrochloride (Preparation 336, 290 mg, 1.02 mmol) in DCM (5 mL) was added DIPEA (1.1 mL, 6.32 mmol) and the solution stirred for 15 mins. Acetic anhydride (0.2 mL, 2.12 mmol) was added dropwise at 23 °C and the reaction stirred for 3 h at this temperature. The reaction was diluted with DCM, then washed with saturated aqueous NaHCOs and the layers separated. The aqueous layer was extracted with DCM (3x) and the combined organic extracts dried over MgSCU, filtered and evaporated under reduced pressure to give l-(2-iodo-6,7- dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)ethan-l-one (287 mg, 97% yield). LCMS m/z = 291.9 [M+ H] ⁺ .

Preparation 338

Methyl 3 -b romo- 1 -(2 -((tert-butoxy carb onyl )ami no)ethyl )- 1 H-pyrazol e- 5 -carb oxy late

A vial containing tert-butyl N-(2-hydroxyethyl)carbamate (488 mg, 3.03 mmol) and PPhs (812 mg, 3.1 mmol) in anhydrous THF (10 mL) was degassed then backfilled with N2 and cooled in ice water bath. DEAD (2.1 mL, 5.33 mmol, 40% purity) was added dropwise at <5 °C, the solution allowed to warm to rt, then methyl 3-bromo-lH-pyrazole-5-carboxylate (507 mg, 2.5 mmol) was added in portions The reaction mixture was stirred at rt for 19 h, then diluted with heptane, the mixture stirred for 1 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with (5 to 55 % EtOAc in heptane) to give methyl 3-bromo-l-(2-((tert-butoxycarbonyl)amino)ethyl)- lH-pyrazole-5-carboxylate (537 mg, crude). LCMS m/z = 347.9 [M+H] ⁺ .

Preparation 339 l-(2-aminoethyl)-3-bromo-lH-pyrazole-5-carboxylic acid

^Hc ₀

BK 'N > H ₂ N

To a solution of methyl 5-bromo-lH-pyrazole-3-carboxylate (3 g, 14.63 mmol) in dry DMF (50 mL) at 0 °C was added NaH (1.17 g, 29.27 mmol, 60% purity) and the mixture was stirred at 0 °C for 15 min. tert-Butyl 2,2-dioxooxathiazolidine-3-carboxylate (3.92 g, 17.56 mmol) was added and the reaction was stirred at rt for 1 h. The mixture was cooled to 0 °C, slowly quenched with water, then extracted with EtOAc (3 x). The aqueous layer was concentrated in vacuo, the residue was taken up in MeOH, filtered with aid of MeOH and concentrated in vacuum to give 2-(2-aminoethyl)-5-bromo-pyrazole-3 -carboxylic acid. LCMS m/z = 234.0 [M+H] ⁺

Preparation 340

3-bromo-l-(2-((tert-butoxycarbonyl)amino)ethyl)-lH-pyrazo le-5-carboxylic acid

NaOH (512.7 mg, 12.82 mmol) and Boc anhydride (4.20 g, 19.23 mmol) were added to a solution of 2-(2-aminoethyl)-5-bromo-pyrazole-3 -carboxylic acid (Preparation 339, 3 g, 12.82 mmol) in water (25 mL) and dioxane (25 mL) and the resulting mixture was stirred at rt for 17 h. The reaction was concentrated in vacuo, acidified to pH=3 and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 3-bromo-l-(2-((tert-butoxycarbonyl)amino)ethyl)-lH- pyrazole-5-carboxylic acid (2.71 g, 63.3% yield) as a white solid. LCMS m/z = 334.0 [M+H] ⁺

Preparation 341 tert-butyl (2-(3-bromo-5-(methoxy(methyl)carbamoyl)-lH-pyrazol-l-yl)eth yl)carbamate

To crude 3-bromo-l-(2-((tert-butoxycarbonyl)amino)ethyl)-lH-pyrazole- 5-carboxylic acid (Preparation 340, 2.7 g, 8.08 mmol) in dry DMF (15 mL) was added TEA (2.45 g, 24.24 mmol) , N-methoxymethanamine HC1 (788.1 mg, 8.08 mmol) and HATU (3.07 g, 8.08 mmol). The resulting suspension was stirred at rt for 3h. The reaction was quenched with water and extracted with EtOAc (3 x) and the combined organic extracts were washed with brine (3x), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc in Hept) to give tert-butyl (2-(3-bromo-5- (methoxy(methyl)carbamoyl)-lH-pyrazol-l-yl)ethyl)carbamate (2.18 g, 71.5% yield) was obtained as a white solid. LCMS m/z = 399.2 [M+Na]+ Preparation 342 tert-butyl (2-(5-acetyl-3-bromo-lH-pyrazol-l-yl)ethyl)carbamate

To a solution of tert-butyl (2-(3-bromo-5-(methoxy(methyl)carbamoyl)-lH-pyrazol-l- yl)ethyl)carbamate (Preparation 341, 2.15 g, 5.70 mmol) in dry THF (20 mL) under N2 was added a solution of MeMgBr (3 M, 7.60 mL) in 2-THF, dropwise at 0°C. The resulting solution was stirred at rt overnight. The mixture was cooled to 0°C and was quenched with NH4CI solution and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over MgSCU and filtered. The filtrate was concentrated in vacuo and the residue was purified via silica gel column chromatography (PE/EtOAc 0-60%) to give tertbutyl (2-(5-acetyl-3-bromo-lH-pyrazol-l-yl)ethyl)carbamate (1.35 g, 71.3% yield) as a white solid. LCMS m/z = 332.1 [M+H]+

Preparation 343

Methyl l-(2-aminoethyl)-3-bromo-lH-pyrazole-5-carboxylate

To a vial containing methyl 3-bromo-l-(2-((tert-butoxycarbonyl)amino)ethyl)-lH-pyrazole- 5- carboxylate (Preparation 342, 537 mg, 1.54 mmol) in DCM (8 mL) was added TFA (1 mL, 13 mmol) and the reaction was stirred at 23 °C for 3.5 h. The mixture was diluted with DCM then neutralised by addition of 1.5 M aq. K2CO3 solution. The phases were separated, the organic dried over MgSCU, filtered and the filtrate evaporated under reduced pressure to give methyl l-(2-aminoethyl)-3-bromo-lH-pyrazole-5-carboxylate as a white solid (414 mg, crude). LCMS m/z = 248.0 [M+ H] ⁺ .

Preparation 344

2-Bromo-6, 7-dihydropyrazolo[ 1 , 5 -a]pyrazin-4(5H)-one To a vial containing methyl l-(2-aminoethyl)-3-bromo-lH-pyrazole-5-carboxylate (Preparation 343, 382 mg, 1.54 mmol) in anhydrous 2-MeTHF (12 mL) was added NaOtBu (303 mg, 3.16 mmol) under N2 and the homogeneous reaction was heated to 45 °C and stirred for 19 h. The mixture was cooled to 23 °C then diluted with water and EtOAc. The mixture was neutralized by dropwise addition of aq. 2 N HC1, the layers separated and the aqueous layer extracted with EtOAc (3x). The combined organic extracts were dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford 2-bromo-6,7- dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (349 mg, crude). LCMS m/z = 215.9 [M+H] ⁺ .

Preparation 345

2-bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin e

To tert-butyl (2-(5-acetyl-3-bromo-lH-pyrazol-l-yl)ethyl)carbamate (Preparation 342, 1.35 g, 4.06 mmol) was added MeOH (1 mL) followed by HC1 (4 M, 36.58 mmol, 9.14 mL) solution in dioxane and the resulting mixture was stirred at rt for 1 h. The solvents were removed in vacuo. To the solid residue was added TEA (4.11 g, 40.64 mmol) followed by NaBEECN (1 M, 16.26 mmol, 16.26 mL) solution in THF and the resulting slurry was stirred at rt overnight. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (DCM/MeOH 0-5%) to obtain 2-bromo-4-methyl-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazine (870 mg, crude) as a colorless oil. LCMS m/z = 216.0 [M+H]+

Preparation 346

2-bromo-4,5-dimethyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyr azine

To 2-bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (Preparation 345, 400 mg, 1.58 mmol) was added a solution of formaldehyde (7.70 g, 2.38 mmol, 37% purity) in water followed by NaBEECN (1 M, 4.75 mmol, 4.75 mL) in THF. The resulting mixture was stirred at 25°C for 16 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% MeOH in DCM) to give 2-bromo-4,5-dimethyl-6,7-dihydro-4H- pyrazolo[l,5-a]pyrazine (316 mg, 86.7% yield) as a white solid. LCMS m/z = 230.1 [M+H]+ Preparation 347

2-bromo-6-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin e

A suspension of 2-bromo-6-methyl-6,7-dihydro-5H-pyrazolo[l,5-a]pyrazin-4-one (commercial, 2.50 g, 10.87 mmol) in BH3-THF (1 M, 108.7 mmol, 108.7 mL) was stirred at 80°C for 16 h under N2. MeOH (20 mL) was added and the mixture stirred at 80°C for 1 h. The mixture was concentrated under vacuum to give 2-bromo-6-methyl-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazine as a yellow gum, LCMS m/z = 216.0 [M+H] ⁺ Preparation 348 2-bromo-5,6-dimethyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazi ne

2-Bromo-5,6-dimethyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyr azine was obtained as a white solid, 410 mg, 19%, from 2-bromo-6-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (Preparation 347) and formaldehyde, following a similar method to that described in Preparation 346. LCMS m/z = 230.1 [M+H] ⁺

Preparation 349

N-((3-Bromo-lH-pyrazol-5-yl)methyl)-2-chloro-2-fluoro-N-m ethylethan-l -amine

To a flask containing 2-chloro-2-fluoro-N-methyl-ethanamine hydrochloride (165 mg, 1.11 mmol) and 3-bromo-5-(chloromethyl)-lH-pyrazole hydrochloride (207 mg, 0.894 mmol) in anhydrous DMF (5 mL) was added DIPEA (1.1 mL, 6.32 mmol) under N2 and the reaction was stirred at 23 °C for 0.5 h, then at 40 °C for 14 h. The mixture was cooled to 23 °C, K2CO3 (333 mg, 2.4 mmol) was added and the mixture was heated to 65 °C for 6 days. The mixture was cooled to 23 °C then diluted with EtOAc. After filtration through a syringe filter, the filtrate was evaporated under reduced pressure to give N-((3-bromo-lH-pyrazol-5- yl)methyl)-2-chloro-2-fluoro-N-methylethan-l -amine (242 mg, crude).

Preparation 350

2-Bromo-7-fluoro-5-methyl-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine

To a vial containing N-((3-bromo-lH-pyrazol-5-yl)methyl)-2-chloro-2-fluoro-N- methylethan-1 -amine (Preparation 349, 242 mg, 0.894 mmol) in anhydrous DMF (2 mL) was added CS2CO3 (1.2 g, 3.7 mmol) and the reaction mixture stirred at 45 °C for 3 h. The mixture was diluted with EtOAc then filtered through a syringe filter. The filtrate was evaporated under reduced pressure to give 2-bromo-7-fluoro-5-methyl-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazine (209 mg, crude). LCMS m/z = 233.9 [M+H] ⁺ .

Preparation 351

2-bromo-7-methyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a ]pyrazine

Part A: LiBHj (333 mg, 15.3 mmol) was added to 2-bromo-[l,2,4]triazolo[l,5-a]pyrazine (760 mg, 3.82 mmol) in EtOH (10 mL) at 0°C and the temperature was slowly raised to 50 °C and stirred for 12 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue adjusted to pH 2-3 under ice-cooling using aqueous HC1 solution and washed with EtOAc. The aqueous solution was adjusted to pH 9-10 with Na2CO3 and extracted into DCM (30 mL x 3), washed with brine (3x 30 mL), dried (Na2SO4) and evaporated to dryness to give 2-bromo-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyrazine as a white solid (450 mg, crude).

Part B: Paraformaldehyde (13.3 g, 11.1 mmol) was added to a solution of 2-bromo-5,6,7,8- tetrahydro-[l,2,4]triazolo[l,5-a]pyrazine (450 mg, 2.22 mmol) in MeOH (5.0 mL) followed by NaBHsCN (696 mg, 11.1 mmol) and the reaction stirred at 25 °C for 2 h. The mixture was concentrated and the residue purified by prep-HPLC (Method Z, Gradient 0-10%) to afford 2-bromo-7-methyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]py razine as a white solid (210 mg, 44%). LCMS m/z = 218.0 [M+H] ⁺ .

Preparation 352

(3 -bromo- 1 -(2-(tert-butyldimethylsilyl)ethyl)- 1H- 1 ,2,4-triazol-5-yl)methyl 4- methylbenzenesulfonate

Part A: To a solution of methyl 3-bromo-lH-l,2,4-triazole-5-carboxylate (3.0 g, 14.6 mmol) in DMF (30 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (6.9 g, 29.1 mmol) and CS2CO3 (9.5 g, 29.1 mmol) and the resulting mixture stirred at 20 °C for 3 days. The mixture was added to water (60 mL) and extracted with EtOAc (50 mL x 3). The combined organics were washed with brine (50 mL x 2), dried (ISfeSCU) and concentrated. The residue was purified by chromatography on silica gel (5-20% EtOAc/PE) to give methyl 3-bromo-l- (2-(tert-butyldimethylsilyl)ethyl)-lH-l,2,4-triazole-5-carbo xylate as a colourless oil (1.7 g, 32%).

Part B: To a solution of methyl 3-bromo-l-(2-(tert-butyldimethylsilyl)ethyl)-lH-l,2,4- triazole-5-carboxylate (1.6 g, 4.39 mmol) in THF (20 mL) was added LiBHj (2 M, 17.57 mmol, 8.78 mL) slowly at 0 °C and the reaction stirred at 25 °C for 1 h. The mixture was quenched with sat. NH4CI (30 mL), poured into H2O (30 mL), extracted with EtOAc (30 mL x 3) and washed with brine (30 mL x 2). The combined organics was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (5-25% EtOAc/PE) to give (3-bromo-l-(2-(tert-butyldimethylsilyl)ethyl)-lH-l,2,4- triazol-5-yl)methanol as a white solid (1.1 g, 74%).

Part C: To a solution of (3-bromo-l-(2-(tert-butyldimethylsilyl)ethyl)-lH-l,2,4-triaz ol-5- yl)methanol (500 mg, 1.49 mmol) in DCM (5 mL) was added TsCl (340 mg, 1.78 mmol), DMAP (9.1 mg, 0.074 mmol) and TEA (752 mg, 7.43 mmol) at 0°C. The mixture was stirred at 20 °C for 2 h, poured into water (30 mL) and extracted with DCM (20 mL x 3). The combined organics were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated and the residue purified by chromatography on silica gel (5-20% EtOAc/PE) to give (3-bromo-l-(2-(tert-butyldimethylsilyl)ethyl)-lH-l,2,4-triaz ol-5-yl)methyl 4- methylbenzenesulfonate as a white solid (300 mg, 41%). ^T H NMR (400 MHz, CDCL) 8 ppm: 7.74 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 5.18 (s, 2H), 4.26 (t, J=4.8 Hz, 2H), 3.88 (t, J=4.8 Hz, 2H), 2.46 (s, 3H), 0.78 (s, 9H), -0.08 (s, 6H).

Preparation 353

2-bromo-5,6-dihydro-8H-[l,2,4]triazolo[5,l-c][l,4]oxazine

Part A: To a solution of (3-bromo-l-(2-(tert-butyldimethylsilyl)ethyl)-lH-l,2,4-triaz ol-5- yl)methyl 4-methylbenzenesulfonate (Preparation 352, 300 mg, 0.611 mmol) in dioxane (2 mL) was added HCl/dioxane (4 M, 2.0 mL) and the resulting mixture was stirred at 20 °C for 1 h. The reaction was concentrated under reduced pressure to give (3 -bromo- 1 -(2- hydroxyethyl)-lH-l,2,4-triazol-5-yl)methyl 4-methylbenzenesulfonate as a colourless oil (220.5 mg, crude).

Part B: To a solution of (3-bromo-l-(2-hydroxyethyl)-lH-l,2,4-triazol-5-yl)methyl 4- methylbenzenesulfonate (220.5 mg, 0.59 mmol) in MeOH (3 mL) and EtOH (0.3 mL) was added NaOMe (63.3 mg, 1.17 mmol) and the reaction stirred at 60 °C for 2 h. The mixture was evaporated to dryness, added to water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organics were washed with brine (20 mL x 2), dried over ISfeSCU, filtered and concentrated to give 2-bromo-5,6-dihydro-8H-[l,2,4]triazolo[5,l-c][l,4]oxazine as a white solid (90 mg, crude). LCMS m/z = 205.6 [M+H] ⁺ .

Preparation 354

4-chloro-6-(4-methylpiperazin-l-yl)pyrimidine

To a solution of 4,6-dichloropyrimidine (500 mg, 3.36 mmol) and 1 -methylpiperazine (302.6 mg, 3.02 mmol) in EtOH (20 mL) was added TEA (373.6 mg, 3.69 mmol) at 0 °C. The mixture was stirred at 20 °C for 5 h. The reaction mixture was diluted with EtOAc (100 mL) and concentrated under reduced pressure to give 4-chloro-6-(4-methylpiperazin-l- yl)pyrimidine (700 mg, crude) as a white solid. LCMS m/z = 213.3 [M+H] ⁺

Preparation 355

2-bromo-6-(2-methoxyethoxy)pyrazine

To a stirring solution of 2,6-dibromopyrazine (300 mg, 1.26 mmol) and 2-methoxyethanol (105.6 mg, 1.39 mmol) in anhydrous THF (12 mL) was added NaH (30.26 mg, 1.26 mmol) at 0°C and the reaction was allowed to warm to rt and stirred for 3 h. The reaction mixture was quenched with NH4CI at 0°C and was extracted with EtOAc. The solvent was evaporated and the crude product was purified by silica gel column chromatography (0-100% heptane-EtOAc) to yield 2-bromo-6-(2 -methoxy ethoxy )pyrazine (268 mg, 91.2% yield) as a clear liquid; 'H NMR (500 MHz, DMSO-d ₆ ) 8 8.41 (d, J= 1.3 Hz, 1H), 8.37 (s, 1H), 4.42 - 4.40 (m, 2H), 3.69 - 3.66 (m, 2H), 3.29 (s, 3H).

Preparation 356

2 -bromo-6-(ox etan-3 -yl oxy )pyrazine

2-Bromo-6-(oxetan-3-yloxy)pyrazine was obtained as a white solid, 217 mg, 74.5%, from 2,6-dibromopyrazine and oxetan-3-ol, following the method described in Preparation 355. 'H NMR (500 MHz, CD2CI2) 6 8.27 (d, J= 1.9 Hz, 1H), 8.22 (d, J= 1.9 Hz, 1H), 5.60 (p, J= 5.6 Hz, 1H), 4.95 (t, J= 7.0 Hz, 2H), 4.71 - 4.66 (m, 2H).

Preparation 357

4-chloro-6-(2-methoxyethoxy)pyrimidine

NaH (525.6 mg, 13.14 mmol, 60% purity) was dissolved in THF (10 mL), the solution stirred at 0 °C for 15 mins, then a solution of 2-methoxyethanol (1.0 g, 13.14 mmol) in THF (10 mL) was added dropwise. The mixture was warmed to 25 °C for 30 mins, then a solution of 4,6-dichloropyrimidine (3.1 g, 21.03 mmol) in THF (10 mL) was added dropwise and the reaction was stirred at 25 °C for 2 h. The mixture was diluted with H2O (200 mL) and extracted with EtOAc (100 mL x 3), dried over ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PEZEtOAc =100/1 to 3/1) to give 4-chloro-6-(2-methoxyethoxy)pyrimidine (1.8 g, 72.6% yield) as a colorless oil. 'H NMR (400 MHz, CDCI3) 6 ppm: 8.54 (s, 1H), 6.80 (s, 1H), 4.52-4.55 (m, 2H), 3.69- 3.72 (m, 2H), 3.40 (s, 3 H).

Preparation 358

6-chloro-3-(2-methoxyethyl)pyrimidin-4(3H)-one

To a solution of 6-chloropyrimidin-4(3H)-one (500 mg, 3.83 mmol) and l-bromo-2- methoxyethane (585.6 mg, 4.21 mmol) in DMF (15 mL) was added K2CO3 (1.1 g, 7.66 mmol) and the reaction mixture was stirred at 50 °C for 16 h. The mixture was diluted with H2O (200 mL), extracted with EtOAc (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc = 1/1) to give 6-chloro-3-(2-methoxyethyl)pyrimidin-4(3H)-one (400.0 mg, 55.4% yield) as a white solid. LCMS m/z = 189.2 [M+H] ⁺

Preparation 359

6-chloro-N-(2-methoxyethyl)pyrazin-2-amine

To a solution of 2,6-dichloropyrazine (500 mg, 3.36 mmol) in DMF (30 mL) was added 2- m ethoxy ethan-1 -amine (378.1 mg, 5.03 mmol) and CS2CO3 (3.3 g, 10.07 mmol). The resulting mixture was stirred at 100 °C for 2 h. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (PE /EtOAc = 1/1) to give 6-chloro-N-(2-methoxyethyl)pyrazin-2-amine (150 mg, 23.8% yield) as yellow oil. ^T H NMR (400 MHz, CDCh) 8 ppm: 7.79 (s, 1H), 7.78 (s, 1H), 5.07 (br s, 1H), 3.54-3.60 (m, 4H), 3.39 (s, 3H).

Preparation 360

6-chloro-N-(2-methoxyethyl)-N-methylpyrazin-2-amine

6-Chloro-N-(2-methoxyethyl)-N-methylpyrazin-2-amine was obtained as a yellow oil, 400 mg, 59.1% yield, from 2,6-dichloropyrazine and 2-methoxy-N-methylethan-l -amine, following the procedure described in Preparation 359. 'H NMR (400 MHz, CDCh) 6 ppm: 7.89 (s, 1H), 7.76 (s, 1H), 3.72 (t, ./=5,2 Hz, 2H), 3.59 (t, ./=5,2 Hz, 2H), 3.35 (s, 3H), 3.14 (s, 3H).

Preparation 361 l,3-dioxoisoindolin-2-yl l,4-dioxane-2-carboxylate A mixture of l,4-dioxane-2-carboxylic acid (500 mg, 3.78 mmol), 2-hydroxyisoindoline-l,3- dione (625 mg, 3.83 mmol), and DMAP (50 mg, 0.409 mmol) in DCM (10 mL) was stirred at rt for 5 mins, then N,N'-diisopropylcarbodiimide (500 mg, 3.96 mmol) was added dropwise over 5 mins and the reaction was stirred for 2 h at rt. The reaction was filtered through a 0.2 um syringe filter and purified directly via silica gel chromatography (heptane to EtOAc) to give (l,3-dioxoisoindolin-2-yl) l,4-dioxane-2-carboxylate (900 mg, 72.1% yield) as a white solid. ^X H NMR (500 MHz, DMSO-d ₆ ) 8 (ppm) = 8.05 - 7.94 (m, 4H), 4.98 (br d, J= 1.2 Hz, 1H), 3.97 (br d, J= 3.7 Hz, 2H), 3.93 - 3.87 (m, 1H), 3.71 (br d, J= 4.9 Hz, 3H).

Preparation 362

2-chloro-5-(l,4-dioxan-2-yl)pyrazine

A mixture of 2-bromo-5 -chloro-pyrazine (251.3 mg, 1.30 mmol), (l,3-dioxoisoindolin-2-yl), l,3-dioxoisoindolin-2-yl l,4-dioxane-2-carboxylate (Preparation 361, 300 mg, 0.909 mmol),

2-(2-pyridyl)pyridine (30 mg, 0.192 mmol), AgNCh (80 mg, 0.471 mmol) and NiCh-dme (40 mg, 0.182 mmol) in DMF (6 mL) was electrolyzed on an IKA Electrasyn at 12mA for 4 electron equivs. The reaction was diluted with EtOAc (15 mL), filtered through a 0.2 um syringe filter, and concentrated to dryness. The crude material was purified via silica gel chromatography (heptane to EtOAc) to give 2-chloro-5-(l,4-dioxan-2-yl)pyrazine as a white solid. (80 mg, 19.3% yield). LCMS m/z = 201.0 [M+H] ⁺ .

Preparation 363

3-methyl-6-(tributylstannyl)pyrimidin-4(3H)-one

To a solution of 6-chloro-3-methylpyrimidin-4(3H)-one (1.0 g, 6.92 mmol) in toluene (10 mL) was added Pd2(dba)3 (633.5 mg, 0.691 mmol) and PCy3 (485.0 mg, 1.73 mmol) at 25 °C. (Bu3Sn)2 (8.0 g, 13.74 mmol) was added slowly and the reaction mixture was stirred at 100 °C under N2 for 16 h. The mixture was allowed to cool to rt and then was poured into an aqueous solution of KF. The aqueous mixture was extracted with EtOAc (100 mL x 2), the combined organic layers concentrated and the crude purified by silica gel column (PE/EtOAc = 1/0 to 1/1) to afford 3-methyl-6-(tributylstannyl)pyrimidin-4(3H)-one (720 mg, 26.1% yield) as yellow oil. LCMS m/z = 401.1 [M+H] ⁺ Preparation 364 tert-butyl (2-acetamido-5-(3-(dimethylamino)prop-l-yn-l-yl)pyridin-4-yl )carbamate

To a solution of tert-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (Preparation 53, 1.0 g, 3.03 mmol) and N,N-dimethylprop-2-yn-l -amine (377.7 mg, 4.54 mmol) in DMF (10 mL) was added TEA (459.7 mg, 4.54 mmol), Cui (57.7 mg, 0.303 mmol) and Pd(PPh3)2C12 (106.3 mg, 0.151 mmol) and the reaction mixture was stirred at 90 °C for 12 h under N2. The mixture was treated with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over ISfeSCU and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (PE/EtOAc = 20/1 to 0/1) to give tert-butyl (2-acetamido-5-(3- (dimethylamino)prop-l-yn-l-yl)pyridin-4-yl)carbamate (590.6 mg, 58.7% yield) as a white solid. ^X H NMR (500 MHz, CDCh) 8 ppm: 8.93 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.32 (s, 1H), 3.57 (s, 2H), 2.38 (s, 6H), 2.19 (s, 3H), 1.54 (s, 9H).

Preparation 365 tert-butyl (2-acetamido-5 -(3 -meth oxyprop- l-yn-l-yl)pyridin-4-yl)carbamate tert-Butyl (2-acetamido-5-(3-methoxyprop-l-yn-l-yl)pyridin-4-yl)carbama te was obtained as a yellow solid, 605 mg, 62.6% yield, from tert-butyl (2-acetamido-5-bromopyridin-4- yl)carbamate (Preparation 53) and 3 -methoxyprop- l-yne, following the procedure described in Preparation 364. 'H NMR (400 MHz, CDCh) 6 ppm: 8.94 (s, 1H), 8.21 (s, 1H), 8.19 (s, 1H), 4.39 (s, 2H), 3.47 (s, 3H), 2.19 (s, 3H), 1.55 (s, 9H).

Preparation 366 tert-butyl (2-acetamido-5-(3-(dimethylamino)propyl)pyridin-4-yl)carbama te To a solution of tert-butyl (2-acetamido-5-(3-(dimethylamino)prop-l-yn-l-yl)pyridin-4- yl)carbamate (Preparation 364, 570.6 mg, 1.72 mmol) in THF (8 mL) was added Pd/C (182.7 mg, 0.172 mmol, 10% purity). The resulting mixture was stirred at 20 °C for 2 h under H2 (15 psi). The reaction was filtered, the filtrate concentrated under reduced pressure and the residue was purified by chromatography on silica gel (DCM/MeOH = 20/1 to 10/1) to give tert-butyl (2-acetamido-5-(3-(dimethylamino)propyl)pyridin-4-yl)carbama te (547.2 mg, 94.8% yield) as a white solid. 1H NMR (400 MHz, CDCh) 6 ppm: 10.88 (s, 1H), 8.70 (s, 1H), 8.35 (s, 1H), 7.92 (s, 1H), 2.57-2.60 (m, 2H), 2.24 (s, 6H), 2.13-2.16 (m, 3H), 2.10-2.12 (m, 2H), 1.76-1.80 (m, 2H), 1.52 (s, 9H).

Preparation 367 tert-butyl (2-acetamido-5-(3-methoxypropyl)pyridin-4-yl)carbamate tert-Butyl (2-acetamido-5-(3-methoxypropyl)pyridin-4-yl)carbamate was obtained as a white solid, 532 mg, 90.4%, from tert-butyl (2-acetamido-5-(3-methoxyprop-l-yn-l-yl)pyridin-4- yl)carbamate (Preparation 365), following a similar procedure to that described in Preparation 366. 'H NMR (400 MHz, CDCh) 8 ppm: 8.86 (s, 1H), 8.08 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 3.41 (s, 3H), 3.29-3.32 (m, 2H), 2.61-2.65 (m, 2H), 2.18 (s, 3H), 1.80-1.87 (m, 2H), 1.54 (s, 9H).

Preparation 368

Tert-butyl (2-acetamido-5-cyclopropylpyridin-4-yl)carbamate

A vial containing tert-butyl N-(2-acetamido-5-bromo-4-pyridyl)carbamate (329 mg, 0.998 mmol), potassium cyclopropyltrifluoroborate (299 mg, 2.02 mmol), cataCXium A (74 mg, 0.205 mmol), KO Ac (24 mg, 0.108 mmol) and CS2CO3 (1.03 g, 3.16 mmol) in toluene (4.5 mL) and water (0.45 mL) was degassed then backfilled with N2 then heated at 90 °C for 17 h. The cooled mixture was filtered through Celite®, washing through with EtOAc. The filtrate was concentrated in vacuo and the residue purified by silica gel column eluting with (20-85 % EtOAc in heptane) to give tert-butyl (2-acetamido-5-cyclopropylpyridin-4-yl)carbamate (234 mg, 81% yield) as a white solid. LCMS m/z = 292.1 [M+H] ⁺ .

Preparation 369

N-(4-amino-5-(3-(dimethylamino)propyl)pyridin-2-yl)acetam ide

To a solution of tert-butyl (2-acetamido-5-(3-(dimethylamino)propyl)pyridin-4-yl)carbama te (Preparation 366, 527.2 mg, 1.57 mmol) in DCM (5 mL) was added HCl/dioxane (4 M, 2 mL) and the reaction mixture was stirred at 20 °C for 3 h. The mixture was adjusted to pH 6 with NH3 H2O, the mixture was concentrated and was purified by Prep-HPLC (Method D, 0- 20%) to give N-(4-amino-5-(3-(dimethylamino)propyl)pyridin-2-yl)acetamide (345.2 mg, 80.8% yield) as a white solid. 'H NMR (400 MHz, DMSO ) 8 ppm: 13.00 (s, 1H), 11.77 (s, 1H), 10.65 (s, 1H), 7.75 (s, 1H), 6.65 (s, 1H), 3.03-3.08 (m, 2H), 2.72 (s, 6H), 2.51-2.52 (m, 2H), 2.17 (s, 3H), 1.79-1.87 (m, 2H).

Preparation 370

N-(4-amino-5-(3-methoxypropyl)pyridin-2-yl)acetamide hydrochloride

To a solution of tert-butyl (2-acetamido-5-(3-methoxypropyl)pyridin-4-yl)carbamate (Preparation 367, 521.7 mg, 1.61 mmol) in DCM (5 mL) was added HCl/dioxane (4 M, 2 mL). The resulting mixture was stirred at 20 °C for 3 h. The reaction was concentrated to give N-(4-amino-5-(3-methoxypropyl)pyridin-2-yl)acetamide hydrochloride (425.6 mg, crude) as a yellow solid. LCMS m/z = 224.1 [M+H] ⁺

Preparation 371

N-(4-amino-5-cyclopropylpyridin-2-yl)acetamide

To a vial containing tert-butyl (2-acetamido-5-cyclopropylpyridin-4-yl)carbamate (Preparation 368, 234 mg, 0.804 mmol) in DCM (4 mL) was added TFA (0.6 mL, 7.8 mmol) and the reaction was stirred at 23 °C for 19 h. The mixture was diluted with DCM then neutralized by addition of 1.5 M aqueous K2CO3 solution. After 15 minutes of stirring at 23 °C, the organic layer was separated, then dried over anhydrous MgSC . The mixture was filtered and the filtrate evaporated under reduced pressure to give N-(4-amino-5- cyclopropylpyridin-2-yl)acetamide (131 mg, crude). LCMS m/z = 192.1

[M+H] ⁺ . Preparation 372

4,6-dichloro-N-methoxy-N-methylnicotinamide

Cl O

A -

To a solution of 4,6-dichloronicotinic acid (25.0 g, 130 mmol) and N,O- dimethylhydroxylamine (13.9 g, 143.2 mmol) in THF (250 mL) was added TEA (19.5 g, 195.3 mmol) and EDCI (37.4 g, 195.3 mmol) and the reaction mixture was stirred at 25 °C for 12 h. The mixture was concentrated, diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (PEZEtOAc = 15/1 to 3/1) on silica gel to give 4,6-dichloro-N-methoxy-N-methylnicotinamide (5.4 g, 17.6% yield) as yellow oil. LCMS m/z = 235.0 [M+H]

Preparation 373 cyclopropyl(4,6-dichloropyridin-3-yl)methanone

To a solution of 4,6-dichloro-N-methoxy-N-methylnicotinamide (Preparation 372, 1.0 g, 4.25 mmol) in THF (30 mL) was added dropwise cyclopropyl magnesium bromide (0.5 M, 51.1 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h under N2. The mixture was quenched at 0 °C with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (PEZEtOAc = 15/1 to 5/1) on silica gel to give cyclopropyl(4,6-dichloropyridin-3- yl)methanone (590 mg, 64.2% yield) as yellow oil. LCMS m/z = 216.1 [M+H] ⁺

Preparation 374

1 -(4,6-dichloropyridin-3 -yl)propan- 1 -one

To a solution of 4,6-dichloronicotinic acid (2.0 g, 10.42 mmol) in THF (5 mL) was added ethyl magnesium bromide (1 M, 39.58 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h under N2. The mixture was quenched with NH4CI (sat, 50 mL) and extracted with EtOAc (60 mL x 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (PE/EtOAc = 1/0 to 3/1) to give l-(4,6-dichloropyridin-3-yl)propan-l-one (458.3 mg, 21.6% yield) as a light-yellow solid. LCMS m/z = 204.0 [M+H] ⁺

Preparation 375

2.4-dichloro-5-(cyclopropyldifluoromethyl)pyridine

A solution of cyclopropyl(4,6-dichloropyridin-3-yl)methanone (Preparation 373, 2.8 g, 12.87 mmol) in DAST (20.0 mL) was stirred at 80 °C for 32 h. The mixture was diluted with H2O (200 mL), extracted with DCM (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography (PE/EtOAc = 100/1 to 20/1) to give 2,4-dichloro-5-(cyclopropyldifluoromethyl)pyridine (900 mg, 29.4% yield) as brown oil. 'H NMR (400 MHz, CDCh) 8 ppm: 8.52 (s, 1H), 7.47 (s, 1H), 1.71-1.83 (m, 1H), 0.81-0.85 (m, 2H), 0.71-0.75 (m, 2H).

Preparation 376

2.4-dichloro-5-(l,l-difhioropropyl)pyridine

To a solution of l-(4,6-dichloropyridin-3-yl)propan-l-one (Preparation 374, 458.0 mg, 2.24 mmol) in DCM (1 mL) was added DAST (3.7 g, 22.7 mmol) and the reaction mixture was stirred at 50 °C for 7 h. The mixture was diluted with water (10 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (PE) to give 2,4-dichloro-5-(l,l-difluoropropyl)pyridine (352.2 mg, 69.4% yield) as light-yellow oil. 'H NMR (500 MHz, CDCh) 6 ppm: 8.54 (s, 1H), 7.45 (s, 1H), 2.27-2.37 (m, 2H), 1.01 (t, J=7.5 Hz, 3H).

Preparation 377

2-chloro-5-(cyclopropyldifluoromethyl)-N-(4-methoxybenzyl )pyridin-4-amine

To a solution of 2,4-dichloro-5-(cyclopropyldifluoromethyl)pyridine (Preparation 375, 600 mg, 2.52 mmol) in DMSO (10 mL) was added PMBNH2 (484.0 mg, 3.53 mmol) and TEA (510.1 mg, 5.04 mmol) and the reaction mixture was stirred at 70 °C for 16 h. The mixture was purified by prep-HPLC (Method P, Gradient 45-75%) to give 2-chloro-5- (cyclopropyldifluoromethyl)-N-(4-methoxybenzyl)pyridin-4-ami ne (232.8 mg, 27.3% yield) as a light-yellow solid. LCMS m/z = 339.1 [M+H] ⁺

Preparation 378

2-chloro-5-(l,l-difluoropropyl)-N-(4-methoxybenzyl)pyridi n-4-amine

2-Chloro-5-(l,l-difluoropropyl)-N-(4-methoxybenzyl)pyridi n-4-amine was obtained as a white solid, 111.3 mg, 38.5% from 2, 4-di chi oro-5-(l,l -difluoropropyl )pyridine (Preparation 376), following a similar procedure to that described in Preparation 377. LCMS m/z = 327.1 [M+H] ⁺

Preparation 379

N-(5-(cyclopropyldifluoromethyl)-4-((4-methoxybenzyl)amin o)pyridin-2-yl)acetamide

To a solution of 2-chloro-5-(cyclopropyldifluoromethyl)-N-(4-methoxybenzyl)py ridin-4- amine (Preparation 377, 50.0 mg, 0.148 mmol) in dioxane (5 mL) was added acetamide (43.6 mg, 0.738 mmol), BrettPhos Pd G3 (13.4 mg, 14.8 umol) and CS2CO3 (120.2 mg, 0.369 mmol). The mixture was stirred at 90 °C for 30 min under N2. The mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (PEZEtOAc = 1/0 to 1/2) to give N-(5- (cyclopropyldifluoromethyl)-4-((4-methoxybenzyl)amino)pyridi n-2-yl)acetamide (50.0 mg, crude) as a light-yellow solid. LCMS m/z = 362.0 [M+H] ⁺

Preparation 380

N-(5-(l,l-difluoropropyl)-4-((4-methoxybenzyl)amino)pyrid in-2-yl)acetamide

N-(5-(l,l-Difluoropropyl)-4-((4-methoxybenzyl)amino)pyrid in-2-yl)acetamide was obtained, 120 mg, as a light yellow-solid, from 2-chloro-5-(l,l-difluoropropyl)-N-(4- methoxybenzyl)pyridin-4-amine (Preparation 378) and acetamide, following the procedure described in Preparation 379. LCMS m/z = 350.1 [M+H] ⁺

Preparation 381

N-(4-amino-5-(cyclopropyldifluoromethyl)pyridin-2-yl)acet amide

To a solution of N-(5-(cyclopropyldifluoromethyl)-4-((4-methoxybenzyl)amino)p yridin-2- yl)acetamide (Preparation 379, 50.0 mg, 0.138 mmol) in MeCN (3 mL) and water (0.3 mL) was added ceric ammonium nitrate (227.6 mg, 0.415 mmol) and the reaction mixture stirred at 25 °C for 16 h. The mixture was purified by prep-HPLC (Method W, Gradient: 0-35%) to give N-(4-amino-5-(cyclopropyldifluoromethyl)pyridin-2-yl)acetami de (20.6 mg, 61.7% yield) as a white solid. LCMS m/z = 242.1 [M+H] ⁺

Preparation 382

N-(4-amino-5-(l,l -difluoropropyl )pyridin-2-yl)acetamide trifluoroacetate

To a solution of N-(5-(l,l-difluoropropyl)-4-((4-methoxybenzyl)amino)pyri din-2 - yl)acetamide (Preparation 380, 60.0 mg, 0.172 mmol) in DCM (1 mL) was added TFA (3 mL) and the reaction mixture stirred at 25 °C for 16 h. The mixture was concentrated and purified by prep-TLC (PE/ EtOAc = 1/2) to give N-(4-amino-5-(l,l-difluoropropyl)pyridin- 2-yl)acetamide trifluoroacetate (32.5 mg, crude) as a white solid. LCMS m/z = 230.2 [M+H] ⁺

Preparation 383 methyl 2-chloro-5-(dimethylamino)isonicotinate

To a solution of methyl 2-chloro-5-fluoroisonicotinate (1 g, 5.28 mmol) in DMSO (8 mL) was added dimethylamine hydrochloride (473 mg, 5.80 mmol) and DIPEA (2.1 g, 15.83 mmol) and the mixture stirred at 25 °C for 16 h. The reaction was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organics were washed with brine (20 mL x 2), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (33% EtOAc/PE) to afford methyl 2-chloro-5- (dimethylamino)isonicotinate as a yellow oil (960 mg, 84%). LCMS m/z = 214.9 [M+H] ⁺ .

Preparation 384 to 385

The compounds I the following table were prepared from methyl 2-chloro-5- fluoroisonicotinate and the appropriate amine using an analogous method to that described for Preparation 383. Preparation 386

2-chloro-5-(dimethylamino)isonicotinic acid

To a solution of methyl 2-chloro-5-(dimethylamino)isonicotinate (Preparation 383, 960 mg, 4.47 mmol) in H2O (4 mL) and THF (12 mL) was added LiOH.PhO (321 mg, 13.42 mmol) and the resulting mixture stirred at 25 °C for 16 h. The mixture was concentrated and purified by prep-HPLC (Boston Green ODS 150 x 30 mm, 5 mm; 18-38% MeCN/PBO (TFA)) to give 2-chloro-5-(dimethylamino)isonicotinic acid as a white solid (300 mg, 28%). 'H NMR (400 MHz, CDCh) 6 ppm: 8.63 (s, 1H), 8.11 (s, 1H), 2.92(s, 6H). Preparation 387 to 388

The title compounds were prepared from the corresponding ester using an analogous method to that described for Preparation 386.

Preparation 389 2-bromo-5-(4-methyl-lH-pyrazol-l-yl)isonicotinic acid

To a solution of methyl 2-bromo-5-fluoroisoni cotinate (1.0 g, 4.27 mmol) in DMF (10 mL) was added 4-methyl-lH-pyrazole (1.0 g, 4.27 mmol) and CS2CO3 (4.2 g, 12.82 mmol) and the reaction stirred at 80 °C for 16 h. The mixture was diluted with H2O (200 mL) and the pH adjusted to pH ~2 with aqueous 10% HC1. The mixture was extracted with EtOAc (100 mL x 3), dried (Na2 SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC (Method Y, Gradient 12-42%) to give 2-bromo-5-(4-methyl-lH-pyrazol-l- yl)isonicotinic acid as a white solid (220 mg, 18%). LCMS m/z = 282.0 [M+H] ⁺ .

Preparation 390 to 393 The title compounds were prepared from methyl 2-bromo-5-fluoroisonicotinate and the appropriate heterocycle using an analogous method to that described for Preparation 389.

Preparation 394

2-bromo-5-(4-(2-methoxyethyl)-lH-pyrazol-l-yl)isonicotini c acid

2-Bromo-5-(4-(2-methoxyethyl)-lH-pyrazol-l-yl)isonicotini c acid was obtained as a white solid, 800 mg, 96%, from 2-bromo-5-(4-(2-hydroxyethyl)-lH-pyrazol-l-yl)isonicotinic acid (Preparation 393) and Mel, following a similar procedure to that described in Preparation 293. LCMS m/z = 326.1 [M+H] ⁺ .

Preparation 395 tert-butyl (2-chloro-5-(dimethylamino)pyridin-4-yl)carbamate

EtsN (756 mg, 7.48 mmol) and DPPA (2.1 g, 7.48 mmol) were added to a solution of 2- chloro-5-(dimethylamino)isonicotinic acid (Preparation 386, 750 mg, 3.74 mmol) in t-BuOH (10 mL) and stirred at 90 °C for 3 h under N2. The reaction was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organics were washed with brine (20 mL x 2), dried (ISfeSCU) and evaporated to dryness. The residue was purified by chromatography on silica gel (100% EtOAc) to give tert-butyl (2-chloro-5- (dimethylamino)pyridin-4-yl)carbamate as a yellow oil (1 g, 98%). ^X H NMR (400 MHz, CDCL) 8 ppm: 8.09 (s, 1H), 8.08 (s, 1H), 2.69 (s, 6H), 1.55 (s, 9H).

Preparation 396 tert-butyl (2-acetamido-5-(dimethylamino)pyridin-4-yl)carbamate

To a solution of tert-butyl (2-chloro-5-(dimethylamino)pyridin-4-yl)carbamate (Preparation 395, 1 g, 3.68 mmol) in dioxane (10 mL) was added acetamide (1.5 g, 25.8 mmol), CS2CO3 (2.4 g, 7.36 mmol), Xantphos (852 mg, 1.47 mmol) and Pd2(dba)3 (337 mg, 0.37 mmol) and the reaction stirred at 100 °C for 16 h under N2. The reaction mixture was concentrated and the residue purified by prep-HPLC (Method T, Gradient 18-38%) to afford tert-butyl (2- acetamido-5-(dimethylamino)pyridin-4-yl)carbamate as a yellow solid (300 mg, 28%). LCMS m/z = 295.2 [M+H] ⁺ .

Preparation 397 N-(4-amino-5-(dimethylamino)pyridin-2-yl)acetamide hydrochloride

To a solution of tert-butyl (2-acetamido-5-(dimethylamino)pyridin-4-yl)carbamate (Preparation 396, 120 mg, 0.41 mmol) in DCM (2 mL) was added HCl/dioxane (4 M, 0.4 mL) and the mixture stirred at 25 °C for 3 h. The reaction was concentrated to give N-(4- amino-5-(dimethylamino)pyridin-2-yl)acetamide hydrochloride as a yellow solid (110 mg).

LCMS m/z = 195.1 [M+H] ⁺ .

Preparation 398 to 405

The following compounds were prepared from the appropriate carboxylic acid, following a similar 3 step synthesis to that described for the synthesis of Preparation 397

Preparation 406 tert-butyl (6'-acetamido-5-cyano-[2,3'-bipyridin]-4'-yl)carbamate To a solution of tert-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (Preparation 53, 1.0 g, 3.03 mmol) in MeOH (25 mL), toluene (25 mL) and water (10 mL) was added 6- bromonicotinonitrile (554.3 mg, 3.03 mmol), (BPin)2 (1.5 g, 6.06 mmol), Pd(OAc)2 (136.0 mg, 0.606 mmol), CsF (2.8 g, 18.17 mmol) and bis(l-adamantyl)-butyl-phosphane (434.4 mg, 1.21 mmol) and the reaction mixture was stirred at 100 °C for 2 h under N2. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous TsfeSCU, filtered and concentrated. The crude was purified by column chromatography (PEZEtOAc = 0/1 to 1/2) to give tert-butyl (6'-acetamido-5-cyano-[2,3'-bipyridin]-4'-yl)carbamate (147.0 mg, 13.7% yield) as a yellow solid. ^X H NMR (500 MHz, CDCh) 8 ppm : 11.39 (s, 1H), 9.26 (s, 1H), 8.94 (d, J=2.Q Hz, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 8.07-8.10 (m, 1H), 7.87 (d, J=8.5 Hz, 1H), 2.25 (s, 3H), 1.55 (s, 9H).

Preparation 407 to 419 The compounds in the following table were prepared from tert-butyl (2-acetamido-5- bromopyridin-4-yl)carbamate (Preparation 53) and the appropriate halo heterocycle, following a similar procedure to that described in Preparation 406.

Preparation 420

(6-acetamido-4-((tert-butoxycarbonyl)amino)pyridin-3-yl)b oronic acid To a solution of tert-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (Preparation 53, 500 mg, 1.51 mmol) in dioxane (5 mL) was added (BPin)2 (769.1 mg, 3.03 mmol), KO Ac (297.2 mg, 3.03 mmol) and Pd(dppf)C12 (110.8 mg, 0.151 mmol). The resulting mixture was stirred at 90 °C for 1 h under N2. The mixture was concentrated under reduced pressure to give (6- acetamido-4-((tert-butoxycarbonyl)amino)pyri din-3 -yl)boronic acid (600 mg, crude) as a brown solid. LCMS m/z = 296.1 [M+H] ⁺

Preparation 421 tert-butyl (2-acetamido-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyridin-4- yl)carbamate

To a solution of tert-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (Preparation 53, 2 g, 6.1 mmol) in dioxane (60 mL) was added KO Ac (1.2 g, 12.1 mmol), XPhos Pd G3 (512.7 mg, 0.606 mmol) and (BPin)2 (1.5 g, 6.1 mmol). The resulting mixture was stirred at 90 °C for 16 h under N2. The mixture was concentrated to give tert-butyl (2-acetamido-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-yl)carbamate (6 g, crude), which was used directly in the next step.

Preparation 422 tert-butyl (2-acetamido-5-(l-methyl-6-oxo-l,6-dihydropyridazin-3-yl)pyr idin-4-yl)carbamate

To a solution of tert-butyl (2-acetamido-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-4-yl)carbamate (Preparation 421, 3.7 g, 2.0 mmol) in dioxane (40 mL) and water (8 mL) was added 6-chloro-2-methylpyridazin-3(2H)-one (340.3 mg, 2.4 mmol), Pd(dppf)C12.DCM (160.2 mg, 0.196 mmol) and K2CO3 (542.2 mg, 3.9 mmol) and the mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to give residue, which was partitioned between H2O (15mL) and EtOAc (15 mL) and the layers separated. The aqueous was extracted with EtOAc (15 mL x 3), dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (ISCO®, EtOAc) to give tert-butyl (2-acetamido-5-(l-methyl-6-oxo-l,6-dihydropyridazin-3-yl)pyr idin- 4-yl)carbamate (335 mg, 39.9% yield) as a yellow solid. LCMS m/z = 360.0 [M+H] ⁺

Preparation 423 to 428

The compounds in the following table were prepared from tert-butyl (2-acetamido-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-yl)carbamate (Preparation 421) or (6- acetamido-4-((tert-butoxycarbonyl)amino)pyri din-3 -yl)boronic acid (Preparation 420) and the appropriate halo heterocycle, following a similar procedure to that described in Preparation 422.

Preparation 429 tert-butyl (2-acetamido-5-(6-methoxypyridazin-3-yl)pyridin-4-yl)carbama te and tert-butyl (2- acetamido-5-(6-oxo-l,6-dihydropyridazin-3-yl)pyridin-4-yl)ca rbamate

To a solution of (6-acetamido-4-((tert-butoxycarbonyl)amino)pyridin-3-yl)boro nic acid (Preparation 420, 300 mg, 1.02 mmol) in dioxane (5 mL) and H2O (1 mL) was added 3- bromo-6-methoxypyridazine (288 mg, 1.52 mmol), Pd(dppf)C12 DCM (83 mg, 0.10 mmol), K2CO3 (281 mg, 2.03 mmol) and the mixture was stirred at 90 °C for 2 h under N2. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated and the residue purified by chromatography on silica gel (5-66% EtOAc/PE) to give a mixture of tert-butyl (2-acetamido-5-(6-methoxypyridazin-3-yl)pyridin-4-yl)carbama te and tert-butyl (2-acetamido-5-(6-oxo-l,6-dihydropyridazin-3-yl)pyridin-4-yl )carbamate as a yellow solid (180 mg, 49%) which was used in the next step. ^T H NMR (400 MHz, MeOH-d4) 6 ppm: 9.07 (s, 1H), 8.58 (s, 1H), 8.12 (d, J=9.6 Hz, 1H), 7.31 (d, J=9.2 Hz, 1H), 4.16 (s, 3H), 2.20 (s, 3H), 1.55 (s, 9H).

Preparation 430

Tert-butyl (2-acetamido-5-(6-methylpyridazin-3-yl)pyridin-4-yl)carbamat e

A vial containing tert-butyl (2-acetamido-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-4-yl)carbamate (Preparation 421, 378 mg, 1.0 mmol), 3-bromo-6-methyl- pyridazine (173 mg, 1.0 mmol), Pd(dppf)C12 : DCM (12 mg, 15 umol) and K3PO4 (646 mg, 3.0 mmol) in dioxane (4 mL) and water (0.4 mL) was degassed, then backfilled with N2 and heated to 90 °C for 22 h. The mixture was cooled to rt then filtered through a Celite® plug, washing through with EtOAc. The filtrate was concentrated and the residue purified by column chromatography on silica gel eluting with (15-100 % EtOAc in heptane) to give tertbutyl (2-acetamido-5-(6-methylpyridazin-3-yl)pyridin-4-yl)carbamat e (160 mg, 46% yield) as a white solid. LCMS m/z = 343.9 [M+ H] ⁺ .

Preparation 431 tert-butyl (2-acetamido-5-(l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)pyr idin-4-yl)carbamate

To a solution of 3-methyl-6-(tributylstannyl)pyrimidin-4(3H)-one (Preparation 363, 500 mg, 1.51 mmol) and tert-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (Preparation 53, 604.5 mg, 1.51 mmol) in DMF (5 mL) was added PdC12(PPh3)2 (53.2 mg, 0.076 mmol) and the reaction mixture was stirred at 100 °C for 4 h under N2. The mixture was quenched with aq. KF (20 mL), diluted with H2O (10 mL) and extracted with DCM (15 mL x 3). The combined organic phase was washed with brine (20 mL), dried with Na2SO4, filtered and concentrated in vacuo. The crude was purified by column chromatography (DCM/MeOH = 1/0 to 10/1) on silica gel to give tert-butyl (2-acetamido-5-(l-methyl-6-oxo-l,6-dihydropyrimidin-4- yl)pyridin-4-yl)carbamate (220 mg, 40.4% yield) as yellow solid. LCMS m/z = 360.1 [M+H] ⁺

Preparation 432

Tert-butyl (2-acetamido-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]py razin-2-yl)pyridin- 4-yl)carbamate

A vial containing 2-bromo-5-methyl-4, 5,6, 7-tetrahydropyrazolo[l,5-a]pyrazine (Preparation 331, 439 mg, 2.03 mmol), tert-butyl (2-acetamido-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridin-4-yl)carbamate (Preparation 421, 1.15 g, 3.05 mmol), SPhos-Pd-G3 (157.4 mg, 0.202 mmol), and K3PO4 (1.5 M aqueous solution, 4.1 mL, 6.15 mmol) in 2-MeTHF (8 mL) was degassed then backfilled with N2 then heated to 75 °C. After 3 h, the mixture was cooled to rt then filtered through Celite®, rinsing through with EtOAc, and the filtrate was washed with brine. The organic layer was dried over anhydrous Na2SO4 then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20- 100 % 3 : 1 EtOAc: EtOH in heptane) to afford tert-butyl (2-acetamido-5- (5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyri din-4-yl)carbamate (160 mg, 20 % yield)as a white solid. LCMS m/z = 387.2 [M+H] ⁺ .

Preparation 433

2-chloro-5-(6-methoxypyridazin-3-yl)pyridin-4-amine

A mixture of 2-chloropyridin-4-amine (1 g, 7.78 mmol), 2-MeTHF (10 mL) and HBPin (1.20 g, 9.38 mmol) was heated at 90 °C for 2 h in a MW reactor. The reaction was cooled to rt, vented, (BPin)2 (1 g, 3.94 mmol), (lZ,5Z)-cycloocta-l,5-diene;2,4-dimethyl- BLAHbicyclo[1.1.0]butane (50 mg, 75.43 mmol), and 3,4,7,8-tetramethyl-l,10- phenanthroline (50 mg, 211.59 mmol) were added and the reaction was sealed and heated to 90 °C for 90 mins. The cooled reaction mixture was diluted with water (5 mL), the mixture stirred for 15 mins and sparged with N2. K3PO4 (3.30 g, 15.56 mmol), Pd(0Ac)2 (45 mg, 0.20 mmol), PC\3 (110 mg, 0.392 mmol) and 3-chloro-6-methoxy-pyndazine (2 g, 13.84 mmol) were added, the reaction then sealed and heated to 100 °C for 16 h. The cooled reaction mixture was diluted with water (5 mL) and EtOAc (5 mL), and the biphasic mixture was filtered through Celite®, rinsing with 10 mL EtOAc. The crude solid was suspended in MeOH (30-40 mL), and passed through Celite®, leaving residual black solids. The filtrate was concentrated to dryness and the residue re-crystallised from hot IPA to give 2-chloro-5-(6-methoxypyridazin-3-yl)pyridin-4- amine (1.25 g, 67.9% yield). LCMS m/z = 236.9 [M+H] ⁺ .

Preparation 434

N-(4-amino-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetam ide

A mixture of 2-chloro-5-(6-methoxypyridazin-3-yl)pyridin-4-amine (Preparation 433, 1.25 g, 5.28 mmol), acetamide (1.60 g, 27.04 mmol), CS2CO3 (5.32 g, 16.34 mmol) and BrettPhos Pd G3 (100 mg, 0.110 mmol) in 2-MeTHF (5 mL) was stirred at 95 °C overnight. Additional BrettPhos Pd G3 (100 mg, 0.110 mmol) was added and the reaction stirred for a further 3 h. The cooled reaction mixture was diluted with water (10 mL) and stirred vigorously. The mixture was filtered through filter paper, rinsing with EtOAc (10 mL) and dried under vacuum to give N-(4-amino-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide (550 mg, 40.16% yield). LCMS m/z = 260.0 [M+H ^]+

Preparation 435 tert-butyl (tert-butoxycarbonyl)(2-chloro-5-cyanopyridin-4-yl)carbamate

To a solution of 4-amino-6-chloronicotinonitrile (600 mg, 3.91 mmol) in DCM (10 mL) was added TEA (1.09 mL, 7.81 mmol), Boc ₂ O (3.4 g, 15.63 mmol) and DMAP (47.7 mg, 0.391 mmol) and the reaction mixture was stirred at 25 °C for 16 h. The mixture was concentrated and the residue was purified by chromatography on silica gel (PE/EtOAc=3/l) to give tertbutyl (tert-butoxycarbonyl)(2-chloro-5-cyanopyridin-4-yl)carbamate (1.1 g, 76.7% yield) as a yellow solid. ^X H NMR (500 MHz, DMSO-d ₆ ) 8: ppm 9.06 (s, 1H), 8.14 (s, 1H), 1.40 (s, 18H).

Preparation 436 tert-butyl (2-acetamido-5-cyanopyridin-4-yl)(tert-butoxycarbonyl)carbam ate

To a solution tert-butyl (tert-butoxycarbonyl)(2-chl oro-5 -cyanopyridin-4-yl)carbamate (Preparation 435, 1.1 g, 2.97 mmol) in dioxane (10 mL) was added acetamide (876.5 mg, 14.84 mmol), Pd2(dba)3 (271.8 mg, 0.297 mmol), Xantphos (343.4 mg, 0.594 mmol) and K2CO3 (820.3 mg, 5.94 mmol) and the reaction mixture was stirred at 120 °C for 4 h under N2. The mixture was concentrated and the residue was purified by chromatography on silica gel (PE/EtOAc=l/l) to give tert-butyl (2-acetamido-5-cyanopyridin-4-yl)(tert- butoxycarbonyl)carbamate (800 mg, 71.6% yield) as a yellow solid. ^T H NMR (400 MHz, DMSO-d ₆ ) 8: ppm 11.2 (s, 1H), 8.87 (s, 1H), 8.12 (s, 1H), 2.15 (s, 3H), 1.40 (s, 18H).

Preparation 437 tert-butyl (2-acetamido-5-(N-hydroxycarbamimidoyl)pyridin-4-yl)carbamat e

To a solution of tert-butyl (2-acetamido-5-cyanopyridin-4-yl)(tert-butoxycarbonyl)carbam ate (Preparation 436, 790 mg, 2.10 mmol) in EtOH (12 mL) was added NH2OH.HCI (291.7 mg, 4.20 mmol) and TEA (585 uL, 4.20 mmol) and the reaction was stirred at 90 °C for 16 h. The mixture was concentrated and the residue was purified by chromatography on silica gel (PE/EtOAc=l/l) to give tert-butyl (2-acetamido-5-(N-hydroxycarbamimidoyl)pyridin-4- yl)carbamate (400 mg, 61.6% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-de) 6: ppm 10.91 (s, 1H), 10.45 (s, 1H), 10.06 (s, 1H), 8.93 (s, 1H), 8.45 (s, 1H), 6.22 (s, 2H), 2.08 (s, 3H), 1.49 (s, 9H).

Preparation 438 tert-butyl (2-acetamido-5-(5-methyl-l,2,4-oxadiazol-3-yl)pyridin-4-yl)c arbamate

To a solution of tert-butyl (2-acetamido-5-(N-hydroxycarbamimidoyl)pyridin-4-yl)carbamat e (Preparation 437, 350 mg, 1.13 mmol) in dioxane (10 mL) was added l,l-dimethoxy-N,N- dimethyl ethan-1 -amine (753.5 mg, 5.66 mmol) and the reaction was stirred at 80 °C for 16 h.

The mixture was concentrated and the residue was purified by chromatography on silica gel (EtOAc) to give tert-butyl (2-acetamido-5-(5-methyl-l,2,4-oxadiazol-3-yl)pyridin-4- yl)carbamate (300 mg, 79.5% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-de) 8: ppm 10.69 (s, 1H), 9.55 (s, 1H), 9.04 (s, 1H), 8.83 (s, 1H), 2.70 (s, 3H), 2.11 (s, 3H) , 1.51 (s, 9H).

Preparation 439 tert-butyl (2-amino-5-bromopyridin-4-yl)carbamate

To a flask containing tert-butyl (2-(acetamido-2,2,2-d3)pyridin-4-yl)carbamate (1.2 g, 4.7 mmol) in MeCN (12 mL) was added NBS (873 mg, 4.91 mmol) in portions at 23 °C. After 5 mins, the mixture was heated at 70 °C for 1 h. The cooled reaction mixture was concentrated under reduced pressure, the residue was diluted with EtOAc then washed once with saturated aqueous NaHCOs. The organic layer was dried over anhydrous Na2SO4 then filtered and concentrated under reduced pressure. The residue was purified by silica gel column (5-50 % EtOAc in heptane) to give tert-butyl (2-amino-5-bromopyridin-4-yl)carbamate (729.2 mg, crude). LCMS m/z = 287.9 [M+ H] ⁺ .

Preparation 440

Tert-butyl (2-(acetamido-2,2,2-d3)-5-bromopyridin-4-yl)carbamate

To a vial containing tert-butyl (2-amino-5-bromopyridin-4-yl)carbamate (Preparation 439, 729 mg, 2.53 mmol) in anhydrous THF (8 mL) was added DIPEA (1.4 mL, 8.04 mmol) dropwise at <-15 °C. After 5 mins, 2,2, 2-trideuterioacetyl chloride (209 mg, 2.6 mmol) was added dropwise to the cold homogeneous solution. Upon complete addition, the reaction was warmed to 23 °C and stirred for 18 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in EtOAc and rinsed with aqueous saturated NaHCOs. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography with (5-60 % EtOAc in heptane) to afford a white solid as tert-butyl (2-(acetamido-2,2,2-d3)-5-bromopyridin-4- yl)carbamate (206 mg, 25% yield). LCMS m/z = 332.9 [M+ H] ⁺ .

Preparation 441

Tert-butyl (2-(acetamido-2,2,2-d3)-5-(4,4,5,5-tetramethyl-l,3,2-dioxabo rolan-2-yl)pyridin-4- yl)carbamate

Tert-butyl (2-(acetamido-2,2,2-d3)-5-(4,4,5,5-tetramethyl-l,3,2-dioxabo rolan-2-yl)pyridin-4- yl)carbamate was obtained from tert-butyl (2-(acetamido-2,2,2-d3)-5-bromopyridin-4- yl)carbamate

(Preparation 440), following the method described in Preparation 421.

Preparation 442

Tert-butyl (2-(acetamido-2,2,2-d3)-5-(6-methoxypyridazin-3-yl)pyridin-4 -yl)carbamate

A vial containing tert-butyl (2-(acetamido-2,2,2-d3)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-4-yl)carbamate (Preparation 441, 312 mg, 0.820 mmol), 3-chloro- 6-methoxy-pyridazine (78 mg, 0.542 mmol), KO Ac (13 mg, 60 umol), PCy3 (36 mg, 0.129 mmol), and K2CO3 (1.5 M, 1.1 mL) in dioxane (4 mL) was degassed then backfilled with N2 then heated to 95 °C and stirred for 2 h. The mixture was cooled to rt then filtered through a Celite® plug, rinsing through with EtOAc. The combined organic filtrate was concentrated in vacuo, and the residue was loaded onto a silica gel column and purified with (25-95 % EtOAc in heptane) to afford an off white solid as tert-butyl (2-(acetamido-2,2,2-d3)-5-(6- methoxypyridazin-3-yl)pyridin-4-yl)carbamate (124 mg, 64% yield) LCMS m/z = 363.1 [M+

H] ⁺ .

Preparation 443 tert-butyl (6'-acetamido-5-(l-fluoroethyl)-[2,3'-bipyridin]-4'-yl)carba mate

A mixture of tert-butyl (2-acetamido-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyridin- 4-yl)carbamate (Preparation 421, 500 mg, 0.663 mmol), 2-bromo-5-(l-fluoroethyl)pyridine (Preparation 183, 159 mg, 0.994 mmol), Pd(PCys)2 (44 mg, 66 pmol) and aq. K2CO3 (2 M, 1.99 mmol, 994 pL) in dioxane (5 mL) was heated at 100°C for 2h. The cooled mixture was filtered and the filtrate was purified directly on silica gel (0-70% EtOAc-EtOH 3: 1 with 2%NEUOE1 in heptane) to give tert-butyl (6'-acetamido-5-(l-fluoroethyl)-[2,3'-bipyridin]-4'- yl)carbamate (105 mg, 42% yield). LCMS m/z = 375 [M+H] ⁺

Preparation 444

N-(4'-amino-5-(l-fluoroethyl)-[2,3'-bipyridin]-6'-yl)acet amide hydrochloride

To a solution of tert-butyl (6'-acetamido-5-(l-fluoroethyl)-[2,3'-bipyridin]-4'-yl)carba mate (Preparation 443, 100 mg, 267 pmol) in DCM (2 ml) was added HC1 (4 M, 1.34 mmol, 334 pL) and the reaction stirred at rt for Ih. The mixture was evaporated under reduced pressure to give N-(4'-amino-5-(l-fluoroethyl)-[2,3'-bipyridin]-6'-yl)acetami de hydrochloride (crude). LCMS m/z = 275[M+H] ⁺

Preparations 445 to 449

The compounds in the following table were prepared from tert-butyl (2-acetamido-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-yl)carbamate (Preparation 421) and appropriate halopyridine, following a similar 2 step synthesis to that described for Preparation 444.

Preparation 450

N-(4-amino-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetam ide hydrochloride and N-(4- amino-5-(6-oxo-l,6-dihydropyridazin-3-yl)pyridin-2-yl)acetam ide hydrochloride.

To a solution of a mixture of tert-butyl (2-acetamido-5-(6-methoxypyridazin-3-yl)pyridin-4- yl)carbamate and tert-butyl (2-acetamido-5-(6-oxo-l,6-dihydropyridazin-3-yl)pyridin-4- yl)carbamate (Preparation 429, 180 mg, 0.50 mmol) in DCM (1 mL) was added HCl/dioxane (4 M, 0.2 mL) and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a mixture of N-(4-amino-5-(6- methoxypyridazin-3-yl)pyridin-2-yl)acetamide and N-(4-amino-5-(6-oxo-l,6- dihydropyridazin-3-yl)pyridin-2-yl)acetamide as a white solid (150 mg, HC1 salt) Preparation 451

N-(4'-amino-5-cyano-[2,3'-bipyridin]-6'-yl)acetamide hydrochloride

To a solution of tert-butyl (6'-acetamido-5-cyano-[2,3'-bipyridin]-4'-yl)carbamate (Preparation 406, 147.0 mg, 0.416 mmol) in DCM (1.0 mL) was added HCl/EtOAc (4 M, 2.0 mL) and the reaction mixture was stirred at 25 °C for 1 h. The mixture was evaporated under reduced pressure to give N-(4'-amino-5-cyano-[2,3'-bipyridin]-6'-yl)acetamide hydrochloride (130.0 mg, crude) as a yellow solid. LCMS m/z = 254.2 [M+H] ⁺

Preparation 452 to 470

The compounds in the following table were prepared from the appropriate protected amine, following the procedure described in Preparation 451.

Preparation 471

N-(4-amino-5-(6-methylpyridazin-3-yl)pyridin-2-yl)acetami de hydrochloride

A solution of tert-butyl (2-acetamido-5-(6-methylpyridazin-3-yl)pyridin-4-yl)carbamat e (Preparation 430, 160 mg, 0.465 mmol) in dioxane (4 mL) and HC1 (4 M in dioxane, 1 mL) was stirred for 1 h, then the heterogeneous mixture was heated to 50 °C and stirred for 4 days. The reaction was cooled to rt then diluted with EtOAc. The mixture was filtered, the filter cake was rinsed with EtOAc to afford a tan solid as N-(4-amino-5-(6-methylpyridazin-3- yl)pyridin-2-yl)acetamide hydrochloride (161 mg). LCMS m/z = 243.9 [M+ H] ⁺ .

Preparation 473

N-(4-amino-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetam ide-2,2,2-d3 trifluoroacetate

To a vial containing tert-butyl (2-(acetamido-2,2,2-d3)-5-(6-methoxypyridazin-3-yl)pyridin- 4-yl)carbamate (Preparation 442, 124 mg, 0.343 mmol) in DCM (2 mL) was added TFA (0.2 mL, 2.61 mmol) and the reaction was stirred at 23 °C for 23 h. The mixture was concentrated under reduced pressure to afford N-(4-amino-5-(6-methoxypyridazin-3-yl)pyridin-2- yl)acetamide-2,2,2-d3 trifluoroacetate as an off-white residue (132 mg, crude). LCMS m/z = 263.1 [M+H] ⁺ .

Preparation 474

N-(4-amino-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]p yrazin-2-yl)pyridin-2- yl)acetamide trifluoroacetate

N-(4-amino-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]p yrazin-2-yl)pyridin-2- yl)acetamide trifluoroacetate was obtained as an orange oil from tert-butyl (2-acetamido-5-(5- methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin -4-yl)carbamate (Preparation 432) following the procedure described in Preparation 473. LCMS m/z = 287.1 [M+ H] ⁺ .

Preparation 475

N-(4-amino-5-(l-methyl-6-oxo-l,6-dihydropyridazin-3-yl)py ridin-2-yl)acetamide

To a solution of tert-butyl (2-acetamido-5-(l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)pyridin-4-yl)carbamate (Preparation 422, 160 mg, 0.445 mmol) in HFiPA (2 mL) was added TFA (595.6 mg, 5.2 mmol) and the reaction mixture was stirred at 25 °C for 12 h. The reaction was slowly quenched with ammonia until pH=7~8. The reaction mixture was concentrated under reduced pressure and the residue was purified by Prep-HPLC (Method B, 3-30%) to give N-(4-amino-5-(l-methyl-6-oxo-l,6-dihydropyridazin-3-yl)pyrid in-2-yl)acetamide (80 mg, 69.3% yield) as a white solid. LCMS m/z = 260.1 [M+H] ⁺

Preparation 476

N-(4-amino-5-(l-methyl-2-oxo-l,2-dihydropyrimidin-4-yl)py ridin-2-yl)acetamide tri fluoroacetate

To a solution of tert-butyl (2-acetamido-5-(l -methyl -2-oxo-l, 2-dihydropyrimidin-4- yl)pyridin-4-yl)carbamate (Preparation 424, 120 mg, 0.33 mmol) in HFIPA (3 mL) was added TFA (0.6 mL) and the mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give N-(4-amino-5-(l-methyl-2-oxo-l,2-dihydropyrimidin-4- yl)pyridin-2-yl)acetamide trifluoroacetate (120 mg, crude) as white solid. LCMS m/z = 260.2 [M+H] ⁺

Preparation 477

N-(4'-amino-5-((difluoromethoxy)methyl)-[2,3'-bipyridin]- 6'-yl)acetamide hydrochloride

A mixture of tert-butyl (2-acetamido-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyridin- 4-yl)carbamate (Preparation 421, 500 mg, 0.663 mmol), 2-chloro-5- ((difluoromethoxy)methyl)pyridine (Preparation 182, 192 mg, 0.994 mmol), Pd(PCys)2 (44 mg, 66 pmol) and aq. K2CO3 (2 M, 1.99 mmol, 0.994 mL) in dioxane (5.0 mL) was heated at 100°C for 2h. The cooled mixture was filtered, the filtrate was diluted with EtOAc, washed with water, then brine. The organic layer was dried and concentrated. The crude was purified by chromatography on silica gel (0-70% EtOAc-EtOH 3: 1 with 2%NEUOE1 in heptane) to give tert-butyl (6'-acetamido-5-((difluoromethoxy)methyl)-[2,3'-bipyridin]-4 '- yl)carbamate (91 mg) (m/z: [M+H]+ = 409) as a white powder which was then dissolved in DCM (5.0 mL). HC1 (4 M, 4.00 mmol, 1.00 mL) was then added and the mixture stirred at rt overnight. The mixture was concentrated in vacuo and the product dried under vacuum to give N-(4'-amino-5-((difluoromethoxy)methyl)-[2,3'-bipyridin]-6'- yl)acetamide hydrochloride (81 mg). LCMS m/z = [M+H] ⁺

Preparation 478 tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate

To a mixture of 5-bromo-2-chloropyridin-4-amine (20 g, 96.41 mmol) in DCM (150 mL) was added TEA (29.27 g, 289.2 mmol), Boc ₂ O (25.25 g, 115.7 mmol) and DMAP (1.18 g, 9.64 mmol) and the mixture was stirred at 20 °C for 12 h under N ₂ . The mixture was concentrated and then the residue diluted with water (200 mL). The mixture was extracted with EtOAc (150 mL), the combined organic layers were washed with brine (150 mL), dried over Na ₂ SO4, filtered and concentrated. The crude material was purified by chromatography (PEZEtOAc = 5/1 to 2/1) to yield tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (21 g, 70.8% yield) as a white solid. 1H NMR: (400MHz, CDCh) 8 ppm 8.37 (s, 1H), 8.27 (s, 1H), 1.57 (s, 9H).

Preparation 479 tert-butyl (2-chloro-5-(l-methyl-lH-pyrazol-3-yl)pyridin-4-yl)carbamate

To a mixture of tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (Preparation 478, 16 g, 52.0 mmol) in dioxane (200 mL) and water (20 mL) was added l-methyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (10.82 g, 52.0 mmol), K3PO4 (5.52 g, 26.0 mmol) and Pd(dppf)Cl ₂ (3.81 g, 5.20 mmol) and the reaction was stirred at 100 °C for 12 h under N ₂ . The cooled mixture was concentrated and the residue was diluted with water (200 mL). The resulting solution was extracted with EtOAc (150 mL x 3) and the combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc = 10: 1 to 3: 1) to give tert-butyl (2-chloro-5-(l-methyl-lH-pyrazol-3-yl)pyridin-4- yl)carbamate (8.6 g, 53.5% yield) as a yellow solid. 'H N R: (400MHz, CDCh) 8 ppm 10.87 (s, 1H), 8.53 (s, 1H), 8.41 (s, 1H), 7.47 (d, J= 2.4 Hz, 1H), 6.65 (d, J= 2.0 Hz, 1H), 4.01 (s, 3H), 1.58 (s, 9H).

Preparation 480 tert-butyl (2-acetamido-5-(l-methyl-lH-pyrazol-3-yl)pyridin-4-yl)carbam ate

To a mixture of tert-butyl (2-chloro-5-(l-methyl-lH-pyrazol-3-yl)pyridin-4-yl)carbamate (Preparation 479, 8.6 g, 27.9 mmol) in dioxane (150 mL) was added acetamide (3.29 g, 55.71 mmol), CS2CO3 (27.23 g, 83.7 mmol), Xantphos (3.22 g, 5.57 mmol) and Pd2(dba)3 (2.55 g, 2.79 mmol) and the reaction mixture was stirred at 110 °C for 12 h under N2. The cooled mixture was concentrated in vacuo and the residue was diluted with water (100 mL). The resulting solution was extracted with EtOAc (80 mL x 3), the combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc = 1/1 to 0/1) to give tert-butyl (2-acetamido-5-(l-methyl-lH-pyrazol-3-yl)pyridin-4-yl)carbam ate (7 g, 75.8% yield) as a yellow solid.

Preparation 481

N-(4-amino-5-(l-methyl-lH-pyrazol-3-yl)pyridin-2-yl)aceta mide

To a mixture of tert-butyl (2-acetamido-5-(l-methyl-lH-pyrazol-3-yl)pyridin-4-yl)carbam ate (Preparation 480, 6 g, 18.11 mmol) in DCM (50 mL) was added TFA (23.6 mL) and the reaction stirred at 20 °C for 3 h. The solvent was removed in vacuo and the residue was diluted with water, then sat. NaHCCL was added to adjust the pH to 11. The resulting mixture was extracted with EtOAc (50 mL x 3) and the combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated and the residue purified by Prep-HPLC (Method A, Gradient 15-45%) to give N-(4-amino-5-(l-methyl-lH-pyrazol-3-yl)pyridin-2- yl)acetamide (2 g, 47.8% yield) as a yellow solid. LCMS m/z = 232.2 [M+H] ⁺

Preparation 482

N-(4-amino-5-bromopyridin-2-yl)acetamide hydrochloride

To a solution of tert-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (Preparation 53, 10 g, 30.29 mmol) in DCM (80 mL) was added HCl/dioxane (4 M, 15 mL) and the mixture was stirred at 25 °C for 16 h under N2. The mixture was concentrated under reduced pressure to give N-(4-amino-5-bromopyridin-2-yl)acetamide hydrochloride (9.0 g, crude) as a white solid. LCMS m/z = 229.9 [M+H] ⁺

Preparation 483

N-(5-bromo-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide

To a solution of N-(4-amino-5-bromopyridin-2-yl)acetamide hydrochloride (Preparation 482, 5 g, 18.76 mmol) in dioxane (50 mL) was added 4-chloro-2-(l,l-difhioroethyl)-6- methylpyrimidine (Preparation 92, 3.97 g, 20.64 mmol), Xantphos (1.09 g, 1.88 mmol), K3PO4 (7.96 g, 37.52 mmol) and Pd2(dba)3 (1.72 g, 1.88 mmol) and the mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was filtered and concentrated in vacuo. The mixture was diluted with water (500 mL) and extracted with EtOAc (55 mL x 3). The combined organic layers were washed with brine (55 mL), dried over ISfeSCU, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE/EtOAc=l/0 to 1/2) to give N-(5-bromo-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl) amino)pyri din-2- yl)acetamide (4.56 g, 62.9% yield) as a white solid. ^T H NMR (400 MHz, DMSO-de) 8: ppm 10.52 (s, 1H), 9.33 ( s, 1H), 8.79 (s, 1H), 8.40 (s, 1H), 7.05 (s, 1H), 2.40 (s, 3H), 2.07 (s, 3H), 1.98 (t, ./= I 9,O Hz, 3H).

Preparation 484

N-(5-bromo-4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino) pyridin-2-yl)acetamide

N-(5-Bromo-4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino) pyridin-2-yl)acetamide was obtained as a white solid, 1.93 g, 69.1% yield, from N-(4-amino-5-bromopyridin-2- yl)acetamide hydrochloride (Preparation 482) and 4-chloro-2-(l, 1 -difluoroethyl )pyrimidine (Preparation 148), following the procedure described in Preparation 483. 1H NMR (400 MHz, DMSO-de) 8: ppm 10.59 (s, 1H), 9.52 ( s, 1H), 8.83 (s, 1H), 8.56 (d, J=5.6 Hz, 1H), 8.44 (s, 1H), 7.25 (d, J=6.0 Hz, 1H), 2.08 (s, 3H), 2.00 (t, J=19.2 Hz, 3H).

Preparation 485

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4,4, 5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)acetamide

To a microwave vial, N-(5-bromo-4-((2-(l,l -di fluoroethyl )pyrimidin-4-yl)amino)pyridin-2- yl)acetamide (Preparation 484, 500 mg, 1.34 mmol), KO Ac (527 mg, 5.37 mmol) and (BPin)2 (750 mg, 2.96 mmol) were added, followed by 2-MeTHF (12 mL). In a different vial, XPhos (64 mg, 134 pmol) and Pd(OAc)2 (15 mg, 67 pmol) were suspended in 2-MeTHF (4 mL) and both vials stirred for 30 min under N2. The solution of catalyst was added to the first vial and the reaction was heated at 75°C overnight. The cooled reaction mixture was filtered through a plug of Celite®, rinsing through with 2-MeTHF. The filtrate was concentrated and diluted with MeCN. The solid formed was filtered off, and the filtrate was concentrated in vacuo to give N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4,4,5,5 -tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)acetamide crude (920 mg).

Preparation 486

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)acetamide

The title compound was synthesized in the similar way as described in Example 15, start with N-(5-bromo-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl) amino)pyridin-2-yl)acetamide (Preparation 483) to give the title compound as a crude which was used in the next step without further purification. LCMS m/z = 352 [M+H] ⁺ (boronic acid)

Preparation 487

(6-acetamido-4-((2-(l, l-difluoroethyl)pyrimidin-4-yl)amino)pyri din-3 -yl)boronic acid

To a solution of N-(5-bromo-4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)pyr idin-2- yl)acetamide (Preparation 484, 1.0 g, 2.69 mmol) in dioxane (10 mL) was added (BPin)2 (1.71 g, 6.72 mmol), cataCXiumA Pd G3 (195.7 mg, 0.269 mmol), KOAc (1.05 g, 10.75 mmol) and the mixture was stirred at 90 °C for 2 h under N2. The mixture was concentrated under reduced pressure to give (6-acetamido-4-((2-( 1,1 -difluoroethyl )pyrimidin-4- yl)amino)pyri din-3 -yl)boronic acid (3.2 g, crude) as black solid. LCMS m/z = 338.0 [M+H] ⁺

Preparation 488

(6-acetamido-4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyri din-3 -yl)boronic acid

To a solution ofN-(5-bromo-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-y l)amino)pyridin- 2-yl)acetamide (Preparation 483, 3 g, 7.77 mmol) in dioxane (40 mL) was added (BPin)2 (4.93 g, 19.42 mmol), KOAc (3.05 g, 31.1 mmol) and Pd(dppf)C12 (568.4 mg, 0.777 mmol) and the mixture was stirred at 90 °C for 2 h under N2. The mixture was concentrated under reduced pressure to give (6-acetamido-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)pyri din-3 -yl)boronic acid (9.8 g, crude) as a black solid. LCMS m/z = 352.0 [M+H] ⁺

Preparation 489

N-(5-bromo-4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-y l)amino)pyridin-2-yl)acetamide

To a solution of N-(4-amino-5-bromopyridin-2-yl)acetamide hydrochloride (Preparation 482, 500 mg, 1.88 mmol) in dioxane (6 mL) was added 4-chloro-2-(l,l-difluoroethyl)-6- ethylpyrimidine (Preparation 94, 465 mg, 2.25 mmol), Xantphos (217.1 mg, 0.375 mmol), Pd2(dba)3 (171.8 mg, 0.188 mmol), K3PO4 (796 mg, 3.75 mmol) and the mixture stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure and the residue diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organics were washed with brine (50 mL), dried (ISfeSCU), concentrated and the residue purified on silica gel column chromatography (0-50% EtOAc/PE) to give N-(5-bromo-4-((2- (l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl )acetamide as a white solid (577.5 mg, 77%). 'H NMR (400 MHz, CDCh) 8 ppm: 9.03 (s, 1H), 8.29 (s, 1H), 7.91 (br s, 1H), 7.38 (s, 1H), 6.94 (s, 1H), 2.84 (q, J=7.6 Hz, 2H), 2.22 (s, 3H), 2.13 (t, J=18.8 Hz, 3H), 1.35 (t, J=7.6 Hz, 3H).

Preparation 490

(6-acetamido-4-((2-(l, l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyri din-3 -yl)boronic acid

To a solution of N-(5-bromo-4-((2-(l, l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2- yl)acetamide (Preparation 489, 550 mg, 1.37 mmol) in dioxane (5 mL) was added (BPin)2 (698 mg, 2.75 mmol), KO Ac (540 mg, 5.50 mmol), cataCXIumA Pd G3 (100 mg, 0.14 mmol) and the mixture stirred at 100 °C for 2 h under N2. The mixture was concentrated under reduced pressure to give (6-acetamido-4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl )amino)pyridin- 3-yl)boronic acid as a black solid (1.2 g, crude) as black solid. LCMS m/z = 366.2 [M+H]+.

Preparation 491

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)acetamide

A vial containing N-(5-bromo-4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)a mino)pyridin- 2-yl)acetamide (Preparation 489, 1 g, 2.50 mmol), (BPin)2 (1.40 g, 5.50 mmol), XPhos Pd G3 (266.3 mg, 0.315 mmol), and KO Ac (986.51 mg, 10.05 mmol) in anhydrous 2-MeTHF (12 mL) was degassed then backfilled with N2 and heated at 75 °C for 4 h. The cooled mixture was diluted with EtOAc and washed with brine, dried and concentrated in vacuo to give N-(4-((2- (l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridin-2-yl)acetamide (2.3 g, crude). LCMS m/z = 366.2 [Boronic acid]

Preparation 492 methyl 6-acetamido-4-aminonicotinate

To a solution of methyl 4-amino-6-chloronicotinate (500 mg, 2.68 mmol) in dioxane (15 mL) was added acetamide (633.1 mg, 10.72 mmol), CS2CO3 (2.6 g, 8.04 mmol) and BrettPhos Pd G3 (485.8 mg, 0.536 mmol) and the reaction mixture was stirred at 90 °C for 16 h under N2. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (PEZEtOAc = 1/0 to 1/1) to give methyl 6-acetamido-4-aminonicotinate (290.2 mg, 51.8% yield) as a yellow solid. LCMS m/z = 210.2 [M+H] ⁺

Preparation 493 methyl 6-acetamido-4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl) amino)nicotinate

To a solution of methyl 6-acetamido-4-aminonicotinate (Preparation 492, 299.0 mg, 1.43 mmol) in dioxane (10 mL) was added 4-chloro-2-(l,l-difluoroethyl)-6-ethylpyrimidine (Preparation 94, 324.8 mg, 1.57 mmol), Pd2(dba)3 (130.88 mg, 0.143 mmol), Xantphos (165.4 mg, 0.286 mmol) and CS2CO3 (1.4 g, 4.29 mmol) and the reaction was stirred at 70 °C for 2 h under N2. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (PEZEtOAc = 1/0 to 1/1) to give methyl 6-acetamido-4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl) amino)nicotinate (499.5 mg, 92.1% yield) as a light-yellow solid. LCMS m/z = 380.2 [M+H] ⁺

Preparation 494

6-acetamido-4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4- yl)amino)nicotinic acid

To a solution of methyl 6-acetamido-4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4- yl)amino)nicotinate

(Preparation 493, 100 mg, 0.264 mmol) in THF (4 mL) and water (2 mL) was added LiOH.EEO (31.6 mg, 1.32 mmol) and the reaction stirred at 25 °C for 1 h. The mixture was concentrated and adjusted to pH= 5 using HC1 (4 M). The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (60 mL) and concentrated to give 6-acetamido-4-((2-(l,l-difluoroethyl)-6- ethylpyrimidin-4-yl)amino)nicotinic acid (100.0 mg, crude) as a white solid. LCMS m/z = 366.0 [M+H] ⁺

Preparation 495 2-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyri din-4-amine

To a solution of 5-bromo-2-chloropyridin-4-amine (4 g, 19.28 mmol) and (BPin)2 (14.69 g, 57.84 mmol) in dioxane (50 mL) was added KOAc (3.78 g, 38.56 mmol) and Pd(dppf)C12 (1.41 g, 1.93 mmol) under N2 and the reaction was stirred at 80 °C for 12 h under N2. The mixture was diluted with water (50 mL), extracted with EtOAc (50mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-chloro-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-amine (1.4 g, crude) as brown oil.

Preparation 496

2-chloro-5-(2,2-dimethyl-2,3-dihydrobenzo[b][l,4]dioxin-6 -yl)pyridin-4-amine

To a solution of 2-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyri din-4-amine (Preparation 495, 1.4 g, 8.12 mmol) and 6-bromo-2,2-dimethyl-2,3-dihydro-[l,4]dioxino[2,3- b]pyridine (Preparation 288, 2.20 g, 8.12 mmol) in dioxane (40 mL) and H2O (10 mL) was added Pd(dppf)C12 (1.01 g, 1.38 mmol) and K3PO4 (2.93 g, 13.81 mmol) and the reaction mixture was stirred at 75 °C for 2 h under N2 atmosphere. The mixture was diluted with water (100 mL), extracted with EtOAc (lOOmL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PEZEtOAc = 100/1 to 1/1) to give 2-chloro-5-(2,2-dimethyl-2,3-dihydrobenzo[b][l,4]dioxin-6-yl )pyridin- 4-amine (1.5 g, 63.3% yield) as white solid. 1H NMR: (400MHz, DMSO-de) 8 ppm 8.31 (s, 1H), 9.14 (s, 1H), 7.36-7.47 (m, 4H), 6.69 (s, 1H), 4.17 (s, 2H), 1.33 (s, 6H).

Preparation 497

2-chloro-5-(2,2-dimethyl-2,3-dihydrobenzo[b][l,4]dioxin-6 -yl)pyridin-4-amine

2-Chloro-5-(2,2-dimethyl-2,3-dihydrobenzo[b][l,4]dioxin-6 -yl)pyridin-4-amine was obtained as a brown solid, 6.3 g, 87.7%, from 2-chloro-5-(2,2-dimethyl-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)pyridin-4-amine (Preparation 496) and acetamide, followng a similar procedure to that described in Preparation 480. LCMS m/z = 314.9 [M+H] ⁺ . Preparation 498

2-chloro-5-(l -methyl- lH-pyrazol-3-yl)pyridin-4-amine

To a solution of 2-chloro-5-iodopyridin-4-amine (1 g, 3.93 mmol) in dioxane (45 mL) and H2O (5 mL) was added l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (1.64 g, 7.86 mmol), Pd(dppf)C12 (287.6 mg, 0.393 mmol) and K2CO3 (1.09 g, 7.86 mmol). The reaction was stirred at 100 °C for 12 h under N2. The mixture was diluted with H2O (30 ml) and extracted with EtOAc (20 ml x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EtOAc = 100/1 to 4/1) to give 2-chloro-5-(l-methyl-lH-pyrazol-3-yl)pyridin-4-amine (576 mg, 70.3% yield) as a brown solid. LCMS m/z = 209.2 [M+H] ⁺

Preparation 499

4'-amino-6'-chloro-[2,3'-bipyridine]-5-carbonitrile

To a solution of 2-chloro-5-iodopyridin-4-amine (1 g, 3.93 mmol) in toluene (5.0 mL), MeOH (5.0 mL) and H2O (0.5 mL) was added 6-bromonicotinonitrile (863.0 mg, 4.72 mmol), (BPin)2 (2.0 g, 7.86 mmol) Pd(OAc)2 (176.5 mg, 0.786 mmol), CsF (1.6 g, 23.58 mmol) and bis(l-adamantyl)-butyl-phosphane (281.8 mg, 0.786 mmol) and the reaction was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure and the residue partitioned between H2O (15mL) and EtOAc (15 mL) and the layers separated. The aqueous phase was extracted with EtOAc (15 mL x 3), the combined organic extracts dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (EtOAc/PE ) to give 4'-amino-6'-chloro-[2,3'-bipyridine]-5-carbonitrile (500 mg, crude) as a yellow solid. LCMS m/z = 231.0 [M+H] ⁺

Preparation 500

6'-chloro-5-fhioro-[2,3'-bipyridin]-4'-amine 6'-Chloro-5-fluoro-[2,3'-bipyridin]-4'-amine was obtained as a brown solid, 2.5 g, 94.8%, from 2-chloro-5-iodopyridin-4-amine and 2-bromo-5-fluoropyridine, following a similar procedure to that described in Preparation 499. 'H NMR (400 MHz, CDCh) 8 ppm 8.47 (d, J=2.8 Hz, 1H), 8.42 (s, 1H), 7.73-7.77 (m, 1H), 7.55-7.56 (m, 1H), 6.62-6.67 (m, 3H).

Preparation 501

N-(2-chloro-5-(l -methyl- lH-pyrazol-3-yl)pyri din-4-yl)-2-(l, 1 -difluoroethyl)-6- methylpyrimidin-4-amine

To a solution of 2-chloro-5-(l-methyl-lH-pyrazol-3-yl)pyridin-4-amine (Preparation 498, 500 mg, 2.40 mmol) in dioxane (35 mL) was added 4-chloro-2-(l,l-difluoroethyl)-6- methylpyrimidine (Preparation 92, 923.1 mg, 4.79 mmol), Pd2(dba)3 (219.44 mg, 0.24 mmol), Xantphos (138.7 mg, 0.24 mmol) and K3PO4 (1.02 g, 4.79 mmol) and the reaction mixture was stirred at 100°C for 16 h under N2. The mixture was diluted with H2O (50 ml), extracted with EtOAc (30 ml x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EtOAc = 100/1 to 2/1) to give N-(2- chloro-5-(l-methyl-lH-pyrazol-3-yl)pyridin-4-yl)-2-(l,l-difl uoroethyl)-6-methylpyrimidin- 4-amine (438 mg, 50.1% yield) as a yellow solid. LCMS m/z = 365.2 [M+H] ⁺

Preparation 502

6'-chloro-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)-[2,3'-bipyridine]-5- carbonitrile

6'-Chloro-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)-[2,3'-bipyridine]-5- carbonitrile was obtained as a yellow solid, 360 mg, crude from 4'-amino-6'-chloro-[2,3'- bipyridine]-5-carbonitrile (Preparation 499) and 4-chloro-2-(l, 1 -difluoroethyl )pyrimidine (Preparation 148), following the procedure described in Preparation 501. LCMS m/z = 387.1 [M+H] ⁺

Preparation 503

6'-chloro-N-(2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl )-5-fluoro-[2,3'-bipyridin]-4'-amine

6'-Chloro-N-(2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl )-5-fluoro-[2,3'-bipyridin]-4'- amine was obtained as a yellow solid, 320 mg, 18.8%, from 6'-chloro-5-fluoro-[2,3'-bipyridin]- 4'-amine (Preparation 500) and 4-chloro-2-( 1,1 -difluoroethyl )pyrimidine (Preparation 148), following the procedure described in Preparation 502. 1H NMR (400 MHz, CDCh) 8 ppm 12.19 (s, 1H), 8.90 (s, 1H), 8.59-8.61 (m, 2H), 7.86 (dd, J=9.2 Hz, 4.0 Hz, 1H), 7.65-7.67 (m, 1H), 6.64 (s, 1H), 2.54 (s, 3H), 2.09 (t, J=18.4 Hz, 3H).

Preparation 504

N-(2-(2-oxabicyclo[2.1. l]hexan-l-yl)-6-methylpyrimidin-4-yl)-6'-chloro-5- (methoxymethyl)-[2,3'-bipyridin]-4'-amine

A mixture of 6'-chloro-5-(methoxymethyl)-[2,3'-bipyridin]-4'-amine (100 mg, 0.40 mmol), 2- (2-oxabicyclo[2.1.1]hexan-l-yl)-4-chloro-6-methylpyrimidine (Preparation 176, 126 mg, 0.60 mmol), Xantphos Pd G3 (38 mg, 40 pmol) and NaOtBu (115 mg, 1.20 mmol) in dioxane (4 mL) was degassed with N2, and heated to 90 °C for 30 min. The cooled mixture was filtered, the filtrate concentrated and the residue was purified by chromatography on silica gel (0-80% EtOAc-EtOH 3 : 1 with 2%NH4OH in heptane) to give N-(2-(2- oxabicyclo[2.1. l]hexan-l-yl)-6-methylpyrimidin-4-yl)-6'-chloro-5-(methoxyme thyl)-[2,3'- bipyridin]-4'-amine (88 mg, 51% yield) as an off-white solid. LCMS m/z =424 [M+H] ⁺ Preparation 505 N-(2-chloro-5-iodopyridin-4-yl)-2-(l,l-difluoroethyl)pyrimid in-4-amine

To a solution of 2-chloro-5-iodopyridin-4-amine (500 mg, 1.96 mmol) in DMF (5 mL) was added 4-chloro-2-( 1,1 -difluoroethyl )pyrimidine (Preparation 148, 351 mg, 1.96 mmol), Pd2(dba)3 (180 mg, 0.197 mmol), Xantphos (113.7 mg, 0.197 mmol) and CS2CO3 (1.28 g, 3.93 mmol) and the mixture stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organics were washed with brine (30 mL), dried (Na2SO ₄ ) and concentrated to give a residue which was purified on silica gel column chromatography (0-25% EtOAc/PE) to give N-(2-chloro-5-iodopyridin-4-yl)-2-(l,l- difhioroethyl)pyrimidin-4-amine as a yellow solid (480 mg, 61%). ¹ H NMR (400 MHz, MeOH-d ₄ ) 8 ppm 8.65 (s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.47 (s, 1H), 7.24 (d, J=6.0 Hz, 1H), 2.00 (t, J=18.8 Hz, 3H).

Preparation 506

N-(2-chloro-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a] pyrazin-2-yl)pyridin-4-yl)-2-(l,l- difhioroethyl)pyrimidin-4-amine

To a solution of N-(2-chloro-5-iodopyridin-4-yl)-2-(l,l-difluoroethyl)pyrimid in-4-amine

(Preparation 505, 350 mg, 0.88 mmol) in toluene (3 mL), water (0.6 mL) and MeOH (3 mL) was added 2-bromo-5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (Preparation 331, 286 mg, 1.32 mmol), (BPin)2 (448 mg, 1.77 mmol), Pd(OAc)2 (39.63 mg, 0.18 mmol), bis(l- adamantyl)-butyl-phosphane (127 mg, 0.35 mmol), CsF (536 mg, 3.53 mmol) and the mixture stirred at 90 °C for 2 h under N2. The reaction mixture was evaporated to dryness and the residue diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organics were washed with brine (20 mL), dried (Na2SO ₄ ) and concentrated to give a residue which was purified on silica gel column chromatography (0-5% MeOH/DCM) to give N-(2-chloro-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyr azin-2-yl)pyridin-4-yl)-2- (l,l-difluoroethyl)pyrimidin-4-amine as a yellow solid (80 mg, 22%). ^T H NMR (400 MHz, MeOH-d ₄ ) 8 ppm 9.04 (s, 1H), 8.60 (s, 1H), 8.53 (d, J=6.0 Hz, 1H), 7.07 (d, J=6.0 Hz, 1H), 6.66 (s, 1H), 4.35 (t, J=5.6 Hz, 2H), 3.77 (s, 2H), 3.04 (t, J=5.6 Hz, 2H), 2.01-2.10 (m, 6H).

Preparation 507 to 508

The title compounds were prepared using N-(2-chloro-5-iodopyridin-4-yl)-2-(l,l- difhioroethyl)pyrimidin-4-amine (Preparation 505) and the appropriate halo-hetereocycle using an analogous method to that described for Preparation 506.

Preparation 509

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-formyl-l-methyl-lH- pyrazol-3-yl)pyridin-2-yl)acetamide

To a solution of N-(5-bromo-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide (Preparation 483, 410 mg, 1.06 mmol) in H2O (1 mL), toluene (5 mL) and MeOH (5 mL) was added 3-bromo-l-methyl-lH-pyrazole-5- carbaldehyde (301 mg, 1.59 mmol), (BPin)2 (539 mg, 2.12 mmol), CsF (968 mg, 6.37 mmol), di(adamantan-l-yl)(butyl)phosphane (152 mg, 0.425 mmol) and Pd(OAc)2 (47.7 mg, 0.212 mmol) and the resulting mixture stirred at 80 °C for 2 h under N2. The mixture was concentrated and the residue purified by prep-HPLC (Method R, Gradient 31-61%) to give N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(5-formyl-l-methyl-lH- pyrazol-3-yl)pyridin-2-yl)acetamide as a white solid (60 mg, 13.6 %). LCMS m/z = 416.2 [M+H] ⁺ .

Preparation 510 tert-butyl 2-(6-acetamido-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4 -yl)amino)pyri din-3- yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a solution of N-(4-((2-(l,l-difhjoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (Preparation 486, 300 mg, 0.854 mmol) in dioxane (5.0 mL) and H2O (1.0 mL) was added tert-butyl 2-bromo-6,7- dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (327.3 mg, 1.03 mmol), Pd(dppf)C12 DCM (69.8 mg, 85.4 pmol), K2CO3 (236.2 mg, 1.71 mmol) and the mixture was stirred at 90 °C for 2 hours under N2. The mixture was concentrated and purified by / c -HPLC (Method R, Gradient 57-87%) to give tert-butyl 2-(6-acetamido-4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-3-yl)-6,7-dihydrothiazolo [5,4-c]pyridine-5(4H)- carboxylate (60.0 mg, 12.9% yield) as a white solid. 'H NMR (400 MHz, CDCh) 8 ppm: 12.31 (s, 1H), 9.53 (br s, 1H), 8.55 (s, 1H), 8.09 (br s, 1H), 6.69 (s, 1H), 4.70 (s, 2H), 3.82- 3.83 (m, 2H), 3.00-3.01 (m, 2H), 2.56 (s, 3H), 2.16-2.26 (m, 6H), 1.51 (s, 9H).

Preparation 511

N-(4-acetyl-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin- 4-yl)amino)-[2,3'-bipyridin]-6'- yl)acetamide

N-(4-acetyl-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin- 4-yl)amino)-[2,3'-bipyridin]-6'- yl)acetamide was obtained (210 mg, 34%) from l-(2-chloropyridin-4-yl)ethan-l-one and N- (4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-( 4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)acetamide (Preparation 486), following a similar procedure to that described in Preparation 510. LCMS m/z = 427.2 [M+H] ⁺

Preparation 512

N-(4-((2-(l,l-difluoroethyl)-6-rnethylpyrimidin-4-yl)amin o)-5-(5-forrnylthiazol-2-yl)pyridin- 2-yl)acetamide

To a solution of (6-acetamido-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)pyri din-3 -yl)boronic acid (Preparation 488, 1.5 g, 4.27 mmol) in dioxane (20 mL) and H2O (4.0 mL) was added 2-bromothiazole-5-carbaldehyde (273.5 mg, 1.42 mmol), Pd(dppf)C12.DCM (116.3 mg, 0.142 mmol) and K2CO3 (590 mg, 4.27 mmol) and the mixture stirred at 90 °C for 2 h under N2. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organics were washed with brine (60 mL), dried (Na2SO4), concentrated and the residue purified by column chromatography (0-100% EtOAc/PE) to give N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(5- formylthiazol-2-yl)pyridin-2-yl)acetamide as a yellow solid (70 mg, crude) which was used without further purification. LCMS m/z = 419.1 [M+H] ⁺ ; ^T H NMR (500 MHz, MeOH-d4) 8 ppm: 10.08 (s, 1H), 9.48 (s, 1H), 8.83 (s, 1H), 8.67 (s, 1H), 7.05 (s, 1H), 2.53 (s, 3H), 2.21 (s, 3H), 2.14 (t, J=18.5 Hz, 3H).

Preparation 513 tert-butyl 2-(6-acetamido-4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino )pyridin-3-yl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate tert-butyl 2-(6-acetamido-4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino )pyridin-3-yl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate was obtained as a yellow solid, 160 mg, 69.9%, from (6-acetamido-4-((2-( 1,1 -difluoroethyl)pyrimidin-4-yl)amino)pyri din-3 - yl)boronic acid (Preparation 487) and tert-butyl 2-bromo-6,7-dihydropyrazolo[l,5- a]pyrazine-5(4H)-carboxylate following a similar procedure to that described in Preparation 512. 'H NMR (500 MHz, CDCh) 8 ppm 11.43 (s, 1H), 9.38 (s, 1H), 8.54 (d, J=4.4 Hz, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 6.91 (s, 1H), 6.46 (s, 1H), 4.67-4.74 (m, 2H), 4.20-4.28 (m, 2H), 3.90-3.98 (m, 2H), 2.14-2.25 (m, 6H), 1.52 (s, 9H)

Preparation 514 tert-butyl 2-(6-acetamido-4-((2-( 1,1 -difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyri din-3 - yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate

A vial containing tert-butyl tert-butyl 2-bromo-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (201 mg, 0.665 mmol), N-(4-((2-( 1,1 -difluoroethyl)-6-methylpyrimidin-4- yl)amino)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyr idin-2-yl)acetamide

(Preparation 486, 650 mg, 1.50 mmol), PCy3-Pd-G3 (96 mg, 0.130 mmol) and KO Ac (1.5 M, 2.40 mmol, 1.6 mL) in dioxane (6 mL) was degassed then backfilled with N2 then heated to 75 °C for 9 h. The mixture was cooled to rt then loaded onto a silica gel column and purified with (20-85 % EtOAc with 2% dimethyl ethylamine in heptane then 100% 3: 1 EtOAc) to afford tert-butyl 2-(6-acetamido-4-((2-( 1,1 -difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyri din-3 - yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (350 mg, crude) as a white solid. LCMS m/z = 529.2 [M+H] ⁺ .

Preparation 515 tert-butyl 2-(6-acetamido-4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino )pyridin-3-yl)-4,6- dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate tert-butyl 2-(6-acetamido-4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino )pyridin-3-yl)-4,6- dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate was obtained from N-(4-((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin- 2-yl)acetamide (Preparation 485) and tert-butyl 2-bromo-4,6-dihydro-5H-pyrrolo[3,4- d]thiazole-5-carboxylate, following the procedure described in Preparation 514.

Preparation 516 tert-butyl 2-(6-acetamido-4-((2-( 1,1 -difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyri din-3 - yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate

To suspension of N-(4-((2-(l,l-difhjoroethyl)-6-ethylpyrimidin-4-yl)amino)-5- (4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (Preparation 491, 200 mg, 0.447 mmol) in 2-Me-THF (2 mL) and water (0.4 mL) were added tert-butyl 2-bromo-6,7- dihydro-4H-pyrazolo[l,5-a]pyrazine-5-carboxylate (202.7 mg, 0.671 mmol) and K PC (284.7 mg, 1.34 mmol). The resulting mixture was sparged with N2 for 10 min. SPhos Pd G3 (34.9 mg, 44.7 pmol) was added and the reaction was stirred at 80°C for 16 h under N2. The cooled mixture was filtered, washing through with water and EtOAc and the filtrate separated. The aqueous phase was extracted with EtOAc (2) and the combined organic extracts washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc in Hept) to give tert-butyl 2-(6- acetamido-4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)am ino)pyridin-3-yl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (170 mg) as an off-white solid. LCMS [M+l]=543.5

Preparation 517

N-(5-(5-acetylpyrazin-2-yl)-4-((2-(l,l-difluoroethyl)-6-m ethylpyrimidin-4-yl)amino)pyridin- 2-yl)acetamide

To a solution of N-(4-((2-(l,l-difhjoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (Preparation 486, 500 mg, 1.15 mmol) in 2-MeTHF (10 mL) and H2O (2 mL) was added l-(5-chloropyrazin-2-yl)ethan-l- one (361 mg, 2.31 mmol), XPhos Pd G3 (97.7 mg, 0.115 mmol) and K3PO4 (735 mg, 3.46 mmol) and the mixture stirred at 80 °C for 1 h under N2. The mixture was concentrated under reduced pressure and the residue purified by column chromatography (100% EtOAc followed by 16% MeOH/DCM) to give N-(5-(5-acetylpyrazin-2-yl)-4-((2-(l,l-difluoroethyl)- 6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide as a yellow solid (286 mg, 58%). LCMS m/z = 428.2 [M+H] ⁺ .

Preparation 518

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazin-2-yl)pyridin-2-yl)acetamide tri fluoroacetate

To tert-butyl 2-(6-acetamido-4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4- yl)amino)pyridin- 3-yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (Preparation 516, 170 mg, 0.313 mmol) in DCM (2 mL) was added TFA (369.88 mg, 3.24 mmol) at 23 °C. The reaction was stirred at 23 °C for 16 h, then evaporated under reduced pressure to give N-(4-((2-(l,l- difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(4,5,6,7-tetra hydropyrazolo[l,5-a]pyrazin-2- yl)pyridin-2-yl)acetamide trifluoroacetate. LCMS m/z = 443.4 [M+H] ⁺

Preparation 519

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4, 5,6,7- tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyridin-2-yl)acetamide

To a solution of tert-butyl 2-(6-acetamido-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4 - yl)amino)pyridin-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5( 4H)-carboxylate (Preparation 510, 55 mg, 0.10 mmol) in DCM (2 mL) was added HCl/dioxane (4 M, 0.5 mL). The reaction was concentrated under reduced pressure to give N-(4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)-5-(4,5,6,7-tetrahydrothiazolo[5, 4-c]pyridin-2-yl)pyridin-2- yl)acetamide hydrochloride as a yellow solid (50 mg, crude) which was used without purification. ^X H NMR (400 MHz, MeOH-d ₄ ) 6 ppm: 8.95 (s, 1H), 8.73 (s, 1H), 7.18 (s, 1H), 3.72 (t, J=6.0 Hz, 2H), 3.66 (s, 2H), 3.38 (t, J=5.6 Hz, 2H), 2.60 (s, 3H), 2.33 (s, 3H), 2.11 (t, J=18.4 Hz, 3H).

Preparation 520

N-(5-bromo-2-chloropyridin-4-yl)-6-chloro-2-(l,l-difluoro ethyl)pyrimidin-4-amine

A mixture of 5-bromo-2-chloro-pyridin-4-amine (250 mg, 1.21 mmol), CS2CO3 (1 g, 3.07 mmol) and DMF (5 mL) was stirred for 5 mins, then 4,6-dichloro-2-(l,l- difluoroethyl)pyrimidine (300 mg, 1.41 mmol) was added and the reaction mixture stirred at rt for 1 h. The reaction was warmed to 35 °C for 2 h, then MeOH (3 mL) added. The reaction was warmed to 50 °C and stirred overnight. The cooled reaction was concentrated in vacuo, the residue diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated to dryness and purified via chromatography (heptane to 50% EtOAc) to give N-(5-bromo-2-chloro-4-pyridyl)-6-chloro-2-(l,l-difluoroethyl )pyrimidin-4- amine (415 mg, 89.7% yield). LCMS m/z = 383.1 [M+ H]+.

Preparation 521

N-(5-bromo-2-chloropyridin-4-yl)-2-(l,l-difluoroethyl)-6- methoxypyrimidin-4-amine

N-(5-Bromo-2-chloro-4-pyridyl)-6-chloro-2-(l,l-difluoroet hyl)pyrimidin-4-amine was treated with MeOH (10 mL) and K2CO3 (400 mg), then heated to 70 °C and the reaction was stirred overnight. The cooled reaction was concentrated in vacuo, diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated to dryness and purified via silica gel chromatography (heptane to 50% EtOAc) to give N-(5- bromo-2-chloropyridin-4-yl)-2-( 1 , 1 -difluoroethyl)-6-methoxypyrimidin-4-amine (390 mg, 85.3% yield). LCMS m/z = 379.1 [M+ H]+. Preparation 522

N-(2-chloro-5-(l -methyl- lH-pyrazol-3-yl)pyri din-4-yl)-2-(l, 1 -difluoroethyl)-6- methoxypyrimidin-4-amine

A mixture of N-(5-bromo-2-chloropyridin-4-yl)-2-(l, l-difluoroethyl)-6-methoxypyrimidin-4- amine (Preparation 521, 150 mg, 0.395 mmol), l-methyl-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazole (100 mg, 0.481 mmol), K2CO3 (150 mg, 1.09 mmol) and Pd(dppf)C12 (15 mg, 20.5 umol) in dioxane (3 mL) and water (1 mL) was sealed and warmed to 80 °C for 20 h. The cooled reaction was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated to dryness, then purified via silica gel chromatography (heptane to EtOAc) to give N-(2-chloro-5-(l-methyl-lH- pyrazol-3-yl)pyridin-4-yl)-2-(l,l-difluoroethyl)-6-methoxypy rimidin-4-amine as a white solid, (30 mg, 19.9% yield). LCMS m/z = 381.1 [M+ H] ⁺ .

Example 1

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-ethoxyp yridin-2-yl)acetamide

To a solution of N-(4-amino-5-ethoxypyridin-2-yl)acetamide hydrochloride (Preparation 62, 100 mg, 0.432 mmol) in DMF (5 mL) was added 2-bromo-6-( 1,1 -difluoroethyl )pyridine (144 mg, 0.647 mmol), BrettPhos Pd G3 (39.1 mg, 0.043 mmol) and CS2CO3 (422 mg, 1.29 mmol) and the reaction was stirred at 100 °C for 1.5 h under N2. The mixture was concentrated and purified by prep-HPLC (Method B, Gradient 23-53%) to give N-(4-((6-(l,l- difluoroethyl)pyridin-2-yl)amino)-5-ethoxypyridin-2-yl)aceta mide (31.0 mg, 21.4% yield) as a white solid. LCMS m/z = 337.4 [M+H] ⁺ . 'H NMR: (500 MHz, DMSO-d ₆ ) 6 ppm: 10.09 (s, 1H), 9.09 (s, 1H), 8.59 (s, 1H), 7.91 (s, 1H), 7.80 (t, =8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.18 (d, ,/=7.5 Hz, 1H), 4.20-4.15 (m, 2H), 2.14-2.03 (m, 6H), 1.40 (t, J=7.0 Hz, 3H). Examples 2 to 5

The compounds in the following table were prepared from N-(4-amino-5-ethoxypyridin-2- yl)acetamide hydrochloride (Preparation 62) and the appropriate substituted pyridine or pyrimidine (Het) following a similar procedure to that described in Example 1.

Examples 6 to 8

The compounds in the following table were prepared from the appropriate acetamide and 4- chloro-2-(l,l-difluoroethyl)pyrimidine, following a similar procedure to that described in Example 1.

Example 9

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-ethoxypyri din-2- yl)propionamide

N-(4-((2-(l,l-Difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-ethoxypyridin-2- yl)propionamide was obtained as a white solid, 28 mg, 16% yield from N-(4-amino-5-ethoxypyri din-2 - yl)propionamide hydrochloride (Preparation 73) and 4-chloro-2-(l,l-difluoroethyl)-6- methylpyrimidine (Preparation 92) following a similar procedure to that described in Example 1. The crude was purified by prep-HPLC (Method B, Gradient 30-60%). LCMS m/z = 366.1 [M+H] ⁺ 'H NMR: (500 MHz, CDCh) 8 ppm : 8.96 (s, 1H), 7.81 (s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 6.90 (s, 1H), 4.18 (q, J=7.0 Hz, 2H), 2.57 (s, 3H), 2.41 (q, J=7.5 Hz, 2H), 2.14 (t, J=19.0 Hz, 3H), 1.50 (t, J=7.0 Hz, 3H), 1.26 (t, J=7.5 Hz, 3H).

Example 10N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino) -5-ethoxypyri din-2- yl)acetamide To a solution of N-(4-amino-5-ethoxypyridin-2-yl)acetamide hydrochloride (Preparation 62, 1.5 g, 6.47 mmol) and 4-chloro-2-(l,l-difluoroethyl)-6-methylpyrimidine (Preparation 92, 1.3 g, 6.47 mmol) in dioxane (10.0 mL) was added CS2CO3 (6.3 g, 19.42 mmol) and BrettPhos Pd G3 (587 mg, 0.647 mmol) at 25 °C. The mixture was stirred at 100 °C for 2 h under N2. The mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (Method A, Gradient 25 to 55%) to give N-(4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide (1.1 g, 49.7% yield) as a white solid. LCMS m/z = 352.1 [M+H] ⁺ . 'H NMR: (400 MHz, CDCh) 6 ppm: 9.00 (s, 1H), 7.88 (br s, 1H), 7.80 (s, 1H), 7.53 (s, 1H), 6.88 (s, 1H), 4.18 (q, J=7.2 Hz, 2H), 2.55 (s, 3H), 2.21 (s, 3H), 2.15 (t, .7=18.8 Hz, 3H), 1.50 (t, 7=6.8 Hz, 3H).

Example llN-(5-(cyclopropylmethoxy)-4-((2-(l,l-difluoroethyl)-6-meth ylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide

To a solution of N-(4-amino-5-(cyclopropylmethoxy)pyridin-2-yl)acetamide hydrochloride (Preparation 64, 70.0 mg, 0.272 mmol) in dioxane (5 mL) was added 4-chloro-2-(l,l- difhjoroethyl)-6-methylpyrimidine (Preparation 92, 62.7 mg, 0.326 mmol), BrettPhos Pd G3 (24.6 mg, 0.0272 mmol) and CS2CO3 (265 mg, 0.815 mmol). The mixture was stirred at 100 °C for 2 h under N2. The mixture was concentrated and purified by prep-HPLC (Method C, Gradient 36 to 68%) to give N-(5-(cyclopropylmethoxy)-4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide (19.0 mg, 18.5% yield) as a white solid LCMS m/z = 378.1 [M+H] ⁺ . 'H NMR: (500 MHz, CDCh) 8 ppm: 8.99 (s, 1H), 8.26 (s, 1H),

7.79 (s, 1H), 7.61 (s, 1H), 6.87 (s, 1H), 3.92 (d, J=6.5 Hz, 2H), 2.54 (s, 3H), 2.18-2.10 (m,

6H), 1.31-1.26 (m, 1H), 0.70-0.68 (m, 2H), 0.38-0.36 (m, 2H).

Examples 12 to 19

The compounds in the following table were prepared from N-(4-amino-5-ethoxypyridin-2- yl)acetamide hydrochloride (Preparation 62) or N-(4-amino-5-methoxypyridin-2- yl)acetamide hydrochloride (Preparation 61) and the appropriate substituted pyridine or pyrimidine (Het) following a similar procedure to that described in Example 10.

Example 20

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(2-methoxyethoxy)pyridin-2- yl)acetamide

To a solution of N-(4-amino-5-(2-methoxyethoxy)pyridin-2-yl)acetamide hydrochloride (Preparation 63, 70.0 mg, 0.311 mmol) in dioxane (5.0 mL) was added 4-chloro-2-(l,l- difhioroethyl)-6-ethylpyrimidine (Preparation 94, 64.2 mg, 0.311 mmol), CS2CO3 (303.8 mg, 0.932 mmol) and BrettPhos Pd G3 (28.2 mg, 0.031 mmol). The mixture was stirred at 100 °C for 1 h under N2. The mixture was concentrated and purified by prep-HPLC (Method B, Gradient 25 to 55%) to give N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5- (2- methoxyethoxy)pyridin-2-yl)acetamide (54.3 mg, 43.9% yield) as a white solid. LCMS m/z = 396.2 [M+H] ⁺ . 'H NMR: (400 MHz, CDCh) 6 ppm: 9.11 (s, 1H), 8.16 (s, 2H), 7.92 (s, 1H), 6.78 (s, 1H), 4.20-4.18 (m, 2H), 3.75-3.73 (m, 2H), 3.51 (s, 3H), 2.81 (q, J=7.6 Hz, 2H), 2.20-2.11 (m, 6H), 1.33 (t, ./=7,6 Hz, 3H).

Example 21

N-(4-((2-(l -difluoroethyl)-6-methoxypyrimidin-4-yl)amino)-5-(2-methoxye thoxy)pyri din-

N-(4-((2-(l,l-Difluoroethyl)-6-methoxypyrimidin-4-yl)amin o)-5-(2-methoxyethoxy)pyridin- 2-yl)acetamide was obtained, as a white solid, 7.3 mg, 18% yield, from 4-chloro-2-(l,l- difluoroethyl)-6-methoxypyrimidine (Preparation 97) and N-(4-amino-5-(2- methoxyethoxy)pyridin-2-yl)acetamide hydrochloride (Preparation 63), following the procedure described in Example 20. LCMS m/z = 398.2 [M+H] ⁺ . 'H NMR: (500 MHz, CDCh) 8 ppm: 8.92 (s, 1H), 8.09-8.06 (m, 2H), 7.90 (s, 1H), 6.36 (s, 1H), 4.19-4.17 (m, 2H), 4.01 (s, 3H), 3.74-3.72 (m, 2H), 3.50 (s, 3H), 2.19 (s, 3H), 2.11 (t, J=18.5 Hz, 1H). Example 22

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-methoxyethoxy)pyri din-2-

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(2-methoxyethoxy)pyridin-2- yl)acetamide was obtained as a white solid, 42.2 mg, 41% yield, from 4-chloro-2-(l,l- difluoroethyl)-6-methylpyrimidine (Preparation 92) and N-(4-amino-5-(2- methoxyethoxy)pyridin-2-yl)acetamide hydrochloride (Preparation 63), following the procedure described in Example 20. LCMS m/z = 382.2 [M+H] ^{+ 1} H NMR: (500 MHz, CDCh) 8 ppm: 9.12 (br s, 1H), 8.21-8.12 (m, 2H), 7.93 (s, 1H), 6.76 (s, 1H), 4.20-4.14 (m, 2H), 3.75-3.52 (m, 2H), 3.50 (s, 3H), 2.53 (s, 3H), 2.19-2.12 (m, 6H).

Example 23 to 29 The compounds in the following table were prepared from 4-chloro-2-(l,l-difluoroethyl)-6- methylpyrimidine (Preparation 92) and the appropriate acetamide following a similar procedure to that described in Example 20.

Example 30

N-(5-(benzyloxy)-4-((2-(l,l-difluoroethyl)-6-methylpyrimi din-4-yl)amino)pyridin-2- yl)acetamide

To a mixture of N-(4-amino-5-(benzyloxy)pyridin-2-yl)acetamide hydrochloride (Preparation 82, 250 mg, 0.851 mmol), CS2CO3 (900 mg, 2.76 mmol) and dioxane (5 mL) which was degassed by bubbling N2 for 15 mins at rt was added 4-chloro-2-(l,l- difhjoroethyl)-6-methylpyrimidine (Preparation 92, 175 mg, 0.908 mmol) and BrettPhos Pd G3 (35 mg, 0.0386 mmol) and the reaction sealed and heated to 110 °C for 2 h. The cooled reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated to dryness, then purified by silica gel chromatography (heptane to EtOAc) to give N-(5-(benzyloxy)-4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide as a white solid, (53 mg, 15.1% yield). LCMS m/z = 414.4 [M+H] ⁺ . 1H NMR (DMSO-d ₆ ) 8: 10.22 (s, 1H), 9.28 (s, 1H), 8.96 (br s, 1H), 8.04 (s, 1H), 7.49 (br d, J=7.3 Hz, 2H), 7.38 (t, J=7.5 Hz, 2H), 7.33 (br d, J=7.6 Hz, 1H), 7.13 (s, 1H), 5.29 (s, 2H), 2.40 (s, 3H), 2.05 (s, 6H).

Example 31

N-(5-ethoxy-4-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)ami no)pyridin-2-yl)acetamide

To a solution of N-(4-amino-5-ethoxypyridin-2-yl)acetamide hydrochloride (Preparation 62, 50.0 mg, 0.216 mmol) in DMF (2 mL) was added 4-chloro-2-(2-fluoropropan-2- yl)pyrimidine (37.7 mg, 0.216 mmol), CS2CO3 (141 mg, 0.432 mmol), Pd2(dba)3 (19.8 mg, 0.0216 mmol) and Xantphos (12.5 mg, 0.216 mmol). The resulting mixture was stirred at 120 °C for 12 h under N2. The mixture was concentrated and purified by prep-HPLC (Method C, Gradient 34% to 64%) to give N-(5-ethoxy-4-((2-(2-fluoropropan-2-yl)pyrimidin-4- yl)amino)pyridin-2-yl)acetamide (3.8 mg, 5.3% yield) as a white solid. LCMS m/z = 334.2 [M+H] ⁺ . 'H NMR: (400 MHz, CDCh) 6 ppm: 9.04 (s, 1H), 8.52 (d, J=6.0 Hz, 1H), 7.81 (s, 1H), 7.75 (s, 1H), 7.52 (s, 1H), 6.86 (d, J=6.0 Hz, 1H), 4.20 (q, ./=7.2 Hz, 2H), 2.20 (s, 3H), 1.89 (s, 3H), 1.84 (s, 3H), 1.51 (t, J=6.8 Hz, 3H).

Example 32

N-(4-((2-(l,l-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin -4-yl)amino)-5-ethoxypyri din-2- yl)acetamide

N-(4-((2-(l, l-Difluoroethyl)-6-(2 -methoxy ethoxy )pyrimidin-4-yl)amino)-5-ethoxypyri din-2 - yl)acetamide was obtained, 39 mg, 37% yield, as a white solid, using a similar method to that described in Example 31, from N-(4-amino-5-ethoxypyridin-2-yl)acetamide hydrochloride (Preparation 62) and 4-chloro-2-(l,l-difluoroethyl)-6-(2-methoxyethoxy)pyrimidine (Preparation 112). LCMS m/z = 412.1 [M+H] ⁺ . ^ NMR: (500 MHz, MeOH-d ₄ ) 6 ppm: 8.93 (s, 1H), 7.89 (s, 1H), 6.54 (s, 1H), 4.51-4.53 (m, 2H), 4.22 (q, J=7.0 Hz, 2H), 3.76-3.75 (m, 2H), 3.41 (s, 3H), 2.15 (s, 3H), 2.04 (t, J=18.5 Hz, 3H) 1.49 (t, J=7.0 Hz, 3H).

Example 33

N-(4-((6-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-ethox ypyridin-2-yl)acetamide

To a solution of N-(4-amino-5-ethoxypyridin-2-yl)acetamide hydrochloride (Preparation 62, 60.0 mg, 0.307 mmol) in dioxane (2 mL) was added 4-chloro-6-(l,l-difluoroethyl)pyrimidine (82.3 mg, 0.461 mmol), Xantphos (71.1 mg, 0.123 mmol), Pd2(dba)3 (56.3 mg, 0.0615 mmol) and CS2CO3 (200.3 mg, 0.615 mmol). The resulting mixture was stirred at 100 °C for 1 h under N2. The mixture was concentrated and purified by prep-HPLC (Method B, Gradient 31 to 61%) to give N-(4-((6-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypy ri din-2 - yl)acetamide (34.2 mg, 33.0% yield) as a yellow solid. LCMS m/z = 338.0 [M+H] ⁺ . 'H NMR: (400 MHz, CDCh) 8 ppm: 9.26 (s, 1H), 8.96 (s, 1H), 7.83 (s, 1H), 7.80 (s, 1H), 7.59 (s, 1H), 7.16 (s, 1H), 4.20 (d, J=6.8 Hz, 2H), 2.21 (s, 3H), 2.00 (t, J=18.8 Hz, 3H), 1.51 (t, ,/=6.8 Hz, 3H).

Examples 34 to 37 The compounds in the following table were prepared from N-(4-amino-5-ethoxypyridin-2- yl)acetamide hydrochloride (Preparation 62) or N-(4-amino-5-methoxypyridin-2- yl)acetamide hydrochloride (Preparation 61) and the appropriate substituted pyridine or pyrimidine (Het) following a similar procedure to that described in Example 33

Example 38

N-(5-cyclopropoxy-4-((2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)pyridin-2-yl)acetamide To a solution of N-(4-amino-5-cyclopropoxypyridin-2-yl)acetamide hydrochloride (Preparation 67, 70 mg, 0.34 mmol) in dioxane (2 mL) was added 4-chloro-2-(l,l- difluoroethyl)pyrimidine (66.35 mg, 0.37 mmol), CS2CO3 (330.18 mg, 1.01 mmol), Pd2(dba)3 (61.86 mg, 0.07 mmol) and Xantphos (39.09 mg, 0.07 mmol) and the mixture was stirred at 120°C for 16 h under N2. The cooled mixture was concentrated in vacuo and the residue purified by Prep-HPLC (Method B, Gradient: 20 to 55%) to give N-(5-cyclopropoxy-4-((2- (l,l-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetami de (10.2 mg, 8.6% yield) as a white solid. LCMS m/z = 350.1 [M+H] ⁺ . 'H NMR: (500 MHz, CDCh) 8: ppm 9.02 (s, 1H), 8.58 (d, J=5.5 Hz, 1H), 8.14 (s, 1H), 7.49 ( s, 1H), 7.02 (d, J=6.Q Hz, 1H), 3.90-3.85 (m, 1H), 2.22 (s, 3H), 2.14 (t, J=18.5 Hz, 3H), 0.91-0.88 (m, 4H).

Examples 39 to 44

The compounds in the following table were prepared from 4-chloro-2-(l,l-difluoroethyl)-6- methylpyrimidine (Preparation 92) and the appropriate substituted acetamide following a similar procedure to that described in Example 38.

Example 45

N-(5-cyclopropoxy-4-((2-(l,l-difluoroethyl)-6-methylpyrim idin-4-yl)amino)pyri din-2- yl)acetamide

To a solution of 4-chloro-2-(l,l-difluoroethyl)-6-methylpyrimidine (Preparation 92, 50.0 mg, 0.241 mmol), N-(4-amino-5-cyclopropoxypyridin-2-yl)acetamide hydrochloride (Preparation 67, 51.2 mg, 0.265 mmol) and K3PO4 (71.7 mg, 0.338 mmol) was added Pd2(dba)3 (22.1 mg, 0.024 mmol) and Xantphos (14.0 mg, 0.024 mmol) and the reaction was stirred at 80 °C for 16 h. The mixture was quenched with H2O (30.0 mL) and extracted with EtOAc (20.0 mL x 3).

The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude was purified by Prep-HPLC (Method B, Gradient: 25 to 55%) to give N-(5-cyclopropoxy-4-((2-(l,l-difluoroethyl)-6-methylpyrimidi n-4- yl)amino)pyridin-2-yl)acetamide (20.0 mg, 22.8% yield) as a white solid. LCMS m/z = 364.1 [M+H] ⁺ . 1H NMR (500 MHz, CDCh) 6 ppm: 8.96 (s, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.38 (s, 1H), 6.86 (s, 1H), 3.86 (s, 1H), 2.54 (s, 3H), 2.20 (s, 3H), 2.14 (t, J= 18.5 Hz, 3H), 0.87 (s, 4H).

Example 46

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-methoxypyri din-2- yl)acetamide

To a solution of N-(4-amino-5-cyclopropoxypyridin-2-yl)acetamide hydrochloride (Preparation 67, 100.0 mg, 0.552 mmol), Pd2(dba)3 (50.6 mg, 0.0552 mmol), Xantphos (31.9 mg, 0.0552 mmol) and K3PO4 (234.3 mg, 1.10 mmol) in dioxane (2.0 mL) was added 4-chloro- 2-(l,l-difluoroethyl)-6-methylpyrimidine (Preparation 92, 127.6 mg, 0.662 mmol) and the reaction was stirred at 80 °C for 5 h. The mixture was filtered and concentrated under vacuum to give the crude, which was purified by /c -HPLC (Method C, Gradient: 20 to 50%) to give N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -methoxypyri din-2- yl)acetamide (29.5 mg, 15.9% yield) as a white solid. LCMS m/z = 338.1 [M+H] ⁺ 'H NMR: (400 MHz, CDCh) 8 ppm: 9.02 (s, 1H), 8.11 (s, 1H), 7.81 (s, 1H), 7.55 (s, 1H), 6.85 (s, 1H), 3.96 (s, 3H), 2.54 (s, 3H), 2.20-2.10 (m, 6H).

Example 47

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(methoxymethyl)pyri din-2- yl)acetamide

To a stirring solution of N-(4-chloro-5-(methoxymethyl)pyridin-2-yl)acetamide (Preparation 50, 16 mg, 0.0745 mmol) and 2-(l,l-difluoroethyl)-6-methylpyrimidin-4-amine (Preparation 93, 12.91 mg, 0.0745 mmol) in dioxane (1 mL) was added CS2CO3 (48.57 mg, 0.149 mmol). The resulting mixture was degassed with N2, BrettPhos Pd G3 (13.51 mg, 0.0149 mmol) was added and the reaction mixture was stirred at reflux at 100 °C for 48 h. The cooled mixture was filtered through Celite® and purified using Combiflash ((0-100% heptane/EtOAc: EtOH (3 : 1) with 2% NH4OH)) to give N-(4-((2-(l, l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)-5-(methoxymethyl)pyridin-2-yl)ac etamide (2.9 mg, 11.1% yield). LCMS m/z = 351.0 [M+H] ⁺ . flT NMR (500 MHz, CDCh) 6 8.91 (s, 1H), 8.35 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H), 6.81 (s, 1H), 4.53 (s, 2H), 3.42 (s, 3H), 2.54 (s, 3H), 2.21 (s, 3H), 2.12 (t, J = 18.8 Hz, 3H)

Example 48

N-(4-((6-methoxy-5-(l -methyl- lH-pyrazol-3-yl)pyri din-2 -yl)amino)-5- (methoxymethyl)pyridin-2-yl)acetamide

N-(4-((6-Methoxy-5-(l -methyl-lH-pyrazol-3-yl)pyri din-2 -yl)amino)-5- (methoxymethyl)pyridin-2-yl)acetamide was obtained, 15.7 mg, 18.5% yield, from N-(4- chloro-5-(methoxymethyl)pyridin-2-yl)acetamide (Preparation 50) and 6-methoxy-5-(l- methyl-lH-pyrazol-3-yl)pyridin-2-amine (Preparation 123) following the procedure described in Example 47. LCMS m/z = 382.0 [M+H] ⁺ . 1H NMR (500 MHz, CDCh) 8 9.07 (s, 1H), 8.58 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.37 (d, J = 2.2 Hz, 1H), 6.77 (d, J = 2.2 Hz, 1H), 6.51 (d, J = 8.1 Hz, 1H), 4.54 (s, 2H), 4.15 (s, 3H), 3.94 (s, 3H), 3.40 (s, 3H), 2.17 (s, 3H).

Example 49

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(ethoxy-d5)pyridin-2- yl)acetamide

A mixture of N-(4-amino-5-(ethoxy-d5)pyridin-2-yl)acetamide hydrochloride (Preparation 83, 1 g, 4.22 mmol), Cs ₂ CO ₃ (3 g, 9.21 mmol), DMA (10 mL), DIPEA (742.0 mg, 5.74 mmol) and 4-chloro-2-(l,l-difluoroethyl)-6-m ethylpyrimidine (Preparation 92, 1.22 g, 6.34 mmol) was degassed while stirring for 30 mins at rt and bubbling N ₂ . MolDalPhos Pd G3 (350 mg, 420 pmol) was added, the vial sealed and heated to 100 °C. The reaction mixture was diluted with EtOAc (20 mL), filtered through Celite®, rinsing with EtOAc (20 mL) and the filtrate concentrated to dryness. The crude material was purified by silica gel chromatography (80 g, heptane to EtOAc) to give an off-white solid. The obtained material was treated with EtOAc (25 mL) and diluted with heptane (200 mL). The mixture was heated to reflux, then stirred while cooling to rt over 2 h. The resulting white crystalline solids were collected via filtration to give N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 - (ethoxy-d5)pyridin-2-yl)acetamide (985 mg, 65.4% yield) . LCMS m/z = 357.1 [M+H] ⁺ . NMR (DMSO-d ₆ ) 8: 10.22 (br s, 1H), 9.11 (s, 1H), 9.00 (br s, 1H), 8.01 (s, 1H), 7.15 (s, 1H), 2.40 (s, 3H), 2.05 (m, 6H).

Example 50

N-(4-((2-(l,l-difluoroethyl)-6-methoxypyrimidin-4-yl)amin o)-5-(l -methyl- lH-pyrazol-3- yl)pyridin-2-yl)acetamide

To a solution of N-(2-chloro-5-(l-methyl-lH-pyrazol-3-yl)pyridin-4-yl)-2-(l,l - difhjoroethyl)-6-methoxypyrimidin-4-amine (Preparation 119, 30 mg, 0.0789 mmol) in dioxane (3 mL) was added Cs ₂ CO ₃ (30 mg, 0.092 mmol), acetamide (30 mg, 0.508 mmol) and BrettPhos Pd G3 (30 mg, 0.033 mmol), the vial sealed and heated at 90 °C for 20 h. The cooled reaction was diluted with water (10 mL), extracted with EtOAc (3 x 10 mL) and the combined organic layer was concentrated to dryness. The residue was purified by reverse phase prep-HPLC (Method J, Gradient: 5% to 60%), to give N-(4-((2-(l,l-difluoroethyl)-6- methoxypyrimidin-4-yl)amino)-5-(l-methyl-lH-pyrazol-3-yl)pyr idin-2-yl)acetamide (3.40 mg, 10.7% yield) as a white solid. LCMS m/z = 404.3 [M+H] ⁺ .

Example 51

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-ethoxypyridin-2- yl)acetamide

To a mixture of N-(4-((2-(l,l-difluoroethyl)-6-(prop-l-en-2-yl)pyrimidin-4-y l)amino)-5- ethoxypyridin-2-yl)acetamide (Preparation 122, 50 mg, 0.132 mmol) in MeOH (50 mL) was added Pd/C (42.30 mg, 39.75 pmol, 10% purity) and the reaction stirred at 20°C under H2 (15 psi) for 1 h. The reaction mixture was filtered and concentrated in vacuo. The crude was purified by prep-HPLC (Method B, Gradient: 30 to 60%) to give N-(4-((2-(l,l- difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-ethoxypyri din-2-yl)acetamide (21.7 mg, 43.2% yield) as a white solid. LCMS m/z = 380.2 [M+H] ⁺ 1H NMR: (500 MHz, DMSO-d ₆ ) 6 ppm: 10.20 (s, 1H), 9.10 (s, 1H), 9.03 (s, 1H), 8.00 (s, 1H), 7.22 (s, 1H), 4.19 (q, J = 7.0 Hz, 2H), 2.95-2.86 (m, 1H), 2.12-2.04 (m, 6H), 1.40 (t, J = 7.0 Hz, 3H), 1.24 (d, J = 6.5 Hz, 6H).

Example 52

N-(4-((2-(l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)am ino)-5-methoxypyri din-2- yl)acetamide To a mixture of N-(4-((2-(l,l-difluoroethyl)-6-(prop-l-en-2-yl)pyrimidin-4-y l)amino)-5- methoxypyridin-2-yl)acetamide (Preparation 121, 50 mg, 0.138 mmol) in MeOH (50 mL) was added Pd/C (43.9 mg, 0.0413 mmol, 10% purity) at 20 °C. The reaction mixture was stirred under H2 (15 psi) at 20 °C for 1 h. The mixture was filtered and concentrated to give a crude, which was purified by prep-HPLC (Method B, Gradient: 32 to 62%) to give N-(4-((2- (l,l-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-metho xypyridin-2-yl)acetamide (25.9 mg, 51.5% yield) as a white solid. LCMS m/z = 366.2 [M+H] ⁺ . 'H NMR: (500 MHz, DMSO-de) 6 ppm: 10.21 (s, 1H), 9.27 (s, 1H), 9.08 (s, 1H), 8.01 (s, 1H), 7.24 (s, 1H), 3.94 (s, 3H), 2.92-2.86 (m, 1H), 2.13-2.04 (m, 6H), 1.23 (d, J= 6.5 Hz, 6H).

Example 53

-((2-(l, 1 -difluoroethyl)-6-(3 -hydroxy-3 -m ethyl cyclobutoxy)pyrimidin-4-yl)amino)-5- ethoxyp yridin-2-yl)acetamide

To a solution of N-(4-((6-(3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobuto xy)-2-(l,l- difhioroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)ace tamide (Preparation 120, 80.0 mg, 0.145 mmol) in DCM (1 mL) was added HCl/dioxane (4 M, 2 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo and the crude product purified by prep-HPLC (Method D, Gradient: 15 to 35%) to give N-(4-((2-(l,l- difluoroethyl)-6-(3 -hydroxy-3 -methyl cyclobutoxy)pyrimidin-4-yl)amino)-5-ethoxypyridin-2- yl)acetamide (22.1 mg, 34.8% yield) as a white solid. LCMS m/z = 438.1 [M+H] ⁺ . 'H NMR: (400 MHz, CDCL) 8 ppm: 9.06 (s, 1H), 7.65 (s, 2H), 6.43 (s, 1H), 4.99-4.91 (m, 1H), 4.18 (q, J=6.8 Hz, 2H), 2.74-2.68 (m, 2H), 2.33-2.25 (m, 2H), 2.25 (s, 3H), 2.08 (t, J=18.8 Hz, 3H), 1.52 (t, J=6.8 Hz, 3H), 1.44 (s, 3H).

Example 54

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)(meth yl)amino)-5-ethoxypyri din-2- yl)acetamide

To a solution of N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 - ethoxypyridin-2-yl)acetamide (Example 10, 60.0 mg, 0.171 mmol) in MeCN (3.0 mL) was added CH3I (48.5 mg, 0.342 mmol) and K2CO3 (70.8 mg, 0.512 mmol) and the reaction was stirred at 70 °C for 4 h. The reaction mixture was concentrated in vacuo and the residue purified by prep-HPLC (Method D, Gradient: 30 to 60%) to give N-(4-((2-(l,l- difluoroethyl)-6-methylpyrimidin-4-yl)(methyl)amino)-5-ethox ypyri din-2 -yl)acetamide (38.4 mg, 61.5% yield) as a white solid. LCMS m/z = 366.1 [M+H] ⁺ . 'H NMR: (400 MHz, CDCh) 8 ppm: 8.14 (s, 1H), 8.02 (s, 1H), 7.85 (s, 1H), 6.13 (s, 1H), 4.07 (q, J=6.8 Hz, 2H), 3.45 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H), 2.00 (t, J=18.8 Hz, 3H), 1.27 (t, J=6.8 Hz, 3H).

Example 55

7V-(4-((2-(l,l-difluoroethyl)-6-vinylpyrimidin-4-yl)amino )-5-(2-methoxyethoxy)pyri din-2- yl)acetamide

To a solution of A-(4-amino-5-(2-methoxyethoxy)pyridin-2-yl)acetamide hydrochloride (Preparation 63, 0.21 g, 0.80 mmol) and 4-chloro-2-(l,l-difluoroethyl)-6-vinylpyrimidine (Preparation 125, 191 mg, 0.93 mmol) in DMF (4 mL) was added BrettPhos Pd G3 (84 mg, 93 pmol) and CS2CO3 (609 mg, 1.87 mmol). The reaction mixture was sparged with N2 for 5 mins then stirred at 70 °C for 2 h under N2. The mixture was diluted with EtOAc, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% MeOH in DCM) and then repurified by silica gel chromatography (0-100% 3: 1 EtOAc-EtOH + 2% NH4OH in heptanes) to give A-(4-((2-( 1,1 -difluoroethyl)-6- vinylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyri din-2 -yl)acetamide (60 mg, 18% yield) as pale yellow solid. LCMS m/z = 394.2 [M+H] ⁺ . 'H NMR (400 MHz, MeOH-t/4) 6 ppm 9.14 (s, 1H), 7.98 (s, 1H), 7.13 (s, 1H), 6.78 (dd, J=17.26, 10.76 Hz, 1H), 6.45 - 6.52 (m, 1H), 5.70 (dd, 7=10.76, 1.25 Hz, 1H), 4.27 - 4.31 (m, 2H), 3.80 - 3.85 (m, 2H), 3.49 (s, 3H),

2.16 (s, 3H), 2.10 (t, 7=18.76 Hz, 3H).

Example 56

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(2-meth oxy ethoxy )pyridin-2-yl)acetamide

To a solution of N-(4-amino-5-(2-methoxyethoxy)pyridin-2-yl)acetamide (Preparation 63, 100 mg, 0.382 mmol, HC1 salt) and 2-bromo-6-(l,l-difluoroethyl)pyridine (84.8 mg, 0.382 mmol) in dioxane (5.0 mL) were added CS2CO3 (373 mg, 1.15 mmol) and BrettPhos Pd G3 (34.6 mg, 38.2 umol) at 25°C. The reaction mixture was stirred at 100°C for 1 h under N2, then concentrated under reduced pressure. The residue was purified by prep-HPLC (Method B, Gradient 25-55%) to give N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(2- methoxyethoxy)pyridin-2-yl)acetamide (31.0 mg, 22.1% yield) as a white solid. LCMS m/z = 367.1 [M+H] ⁺ . 'H NMR: (400 MHz, CDCh) 8 ppm: 9.18 (br s, 1H), 8.35 (br s, 1H), 8.00 (s, 1H), 7.83 (s, 1H), 7.72 (t, 7=8.0 Hz, 1H), 7.27 (d, 7=7.6 Hz, 1H), 6.97 (d, 7=8.4 Hz, 1H), 4.19-4.22 (m, 2H), 3.74-3.77 (m, 2H), 3.50 (s, 3H), 2.21 (s, 3H), 2.17 (t, 7=19.2 Hz, 3H).

Examples 57 to 62

The compounds in the following table were prepared from the corresponding ether substituted pyridines (SM) and 4-chloro-2-(l,l-difluoroethyl)-6-m ethylpyrimidine (Preparation 92) following a similar procedure to that described in Example 56

Examples 63 to 73

The compounds in the following table were prepared from the corresponding ether substituted pyridines (SM) and the appropriate pyridine or pyrimidine (Het) following a similar procedure to that described in Example 56.

Example 74

N-(5-((2,2-difluorocyclopropyl)methoxy)-4-((2-(l,l-difluo roethyl)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide

To a solution of N-(4-amino-5-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl) acetamide (Preparation 253, 200 mg, 0.778 mmol, HC1 salt) in dioxane (5 mL) was added 4-chloro-2- (l,l-difluoroethyl)-6-m ethylpyrimidine (Preparation 92, 165 mg, 0.855 mmol), Xantphos (89.9 mg, 0.155 mmol), CS2CO3 (507 mg, 1.55 mmol) and Pd2(dba)3 (71.2 mg, 77.8 umol). The mixture was stirred at 120°C for 16 h under N2, then concentrated. The crude product was purified by Prep-HPLC (Method C, gradient 28-55%) to give N-(5-((2,2- difhiorocyclopropyl)methoxy)-4-((2-(l,l-difluoroethyl)-6-met hylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide (31 mg, 9.65% yield) as a yellow solid. LCMS m/z = 414.1 [M+H] ⁺ . 'H NMR: (400 MHz, CDCh) 6 ppm: 9.06 (s, 1H), 7.80-7.85 (m, 2H), 7.50 (s, 1H), 6.85 (s, 1H), 4.24-4.28 (m, 1H), 4.08-4.13 (m, 1H), 2.56 (s, 3H), 2.11-2.20 (m, 7H), 1.66- 1.69 (m, 1H), 1.31-1.34 (m, 1H).

Examples 75 to 82 The compounds in the following table were prepared from N-(4-amino-5-(2- methoxyethoxy)pyridin-2-yl)acetamide (Preparation 63) and the appropriate pyridine or pyrimidine (Het) following a similar procedure to that described in Example 74.

Examples 83 to 88

The compounds in the following table were prepared from the corresponding ether substituted pyridines (SM) and the appropriate pyridine or pyrimidine (Het) following a similar procedure to that described in Example 74.

Example 89 and 90,

N-(4-((6-(l,2-difluoroethyl)pyrazin-2-yl)amino)-5-(2-meth oxyethoxy)pyridin-2-yl)acetamide and N-(4-((6-(l-fluorovinyl)pyrazin-2-yl)amino)-5-(2-methoxyetho xy)pyridin-2- yl)acetamide

To a solution of 2-bromo-6-(l,2-difluoroethyl)pyrazine (Preparation 188, 80.0 mg, 0.355 mmol), N-(4-amino-5-(2-methoxyethoxy)pyridin-2-yl)acetamide (Preparation 63, 79.2 mg, 0.355 mmol) and K3PO4 (377 mg, 1.78 mmol) in dioxane (2.0 mL) were added Xantphos (20.6 mg, 35.5 umol) and Pd2(dba)3 (32.6 mg, 35.5 umol). The reaction mixture was stirred at

70°C for 1 h, then purified by prep-HPLC (Method B, Gradient 17-47%) to give N-(4-((6- (l,2-difluoroethyl)pyrazin-2-yl)amino)-5-(2-methoxyethoxy)py ridin-2-yl)acetamide (17.0 mg, 13.0% yield) as a white solid: LCMS m/z = 368.1 [M+H] ⁺ , 'H NMR: (500 MHz, CDCh) 8 ppm: 9.41 (s, 1H), 8.37-8.34 (m, 3H), 7.90-7.98 (m, 2H), 5.81-5.91 (m, 1H), 5.09-5.25 (m, 2H), 4.18-4.22 (m, 2H), 3.75-3.78 (m, 2H), 3.54 (s, 3H), 2.20 (s, 3H), and N-(4-((6-(l- fluorovinyl)pyrazin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2 -yl)acetamide (26.0 mg, 21.1% yield) as a white solid. LCMS m/z = 348.1 [M+H] ⁺ , ^ NMR: (500 MHz, CDCh) 6 ppm: 9.53 (s, 1H), 8.71 (br s, 1H), 8.36-8.39 (m, 2H), 8.24 (s, 1H), 7.87 (s, 1H), 6.34-6.46 (m, 1H), 5.24-5.29 (m, 1H), 4.20-4.22 (m, 2H), 3.76-7.79 (m, 2H), 3.54 (s, 3H), 2.24 (s, 3H).

Example 91

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-methoxypyri din-2- yl)acetamide

To a flask containing N-(4-amino-5-methoxypyridin-2-yl)acetamide hydrochloride (Preparation 61, 20 g, 78.7 mmol) in dioxane (500 mL) were added 4-chloro-6-cyclopropoxy- 2-(l,l-difluoroethyl)pyrimidine (Preparation 163, 20.3 g, 86.6 mmol), CS2CO3 (76.9 g, 236 mmol) and DIPEA (12.2 g, 94.5 mmol). The reaction mixture was degassed, then backfilled with N2, then heated to 95°C. After 10 min, a degassed solution of BINAP (4.90 g, 7.87 mmol) and Pd(OAc)2 (884 mg, 3.94 mmol) in dioxane (100 mL) was heated to 95°C, then transferred via syringe. The reaction mixture was stirred at 95°C for 5 h under N2, then quenched with water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic phases were washed with brine (1000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (15-75 % 3: 1 EtOAc:EtOH in heptane). The desired fractions were concentrated under reduced pressure and the residue azeotroped with EtOH. to afford a sticky yellowwhite foam that was diluted with EtOH. The resulting solid was sonicated in EtOH, the solid filtered and dried to give N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl)am ino)- 5-methoxypyridin-2-yl)acetamide as a white solid, 12.8 g, 42.7%. LCMS m/z = 380.0 [M+H] ⁺ . 'H NMR: (400 MHz, DMSO-t/ ₆ ) 8 ppm: 14.55 (br s, 1H), 7.99-8.05 (m, 2H), 7.68- 7.61 (m, 1H), 7.59-7.66 (m, 3H), 7.48 (s, 1H), 7.39 (d, J= 2.01 Hz, 1H), 6.94 (dd, J= 2.4, 8.8 Hz, 1H), 3.84 (s, 3H).

Example 92 methyl (4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2 - (dimethylamino)ethoxy)pyridin-2-yl)carbamate

A mixture of CS2CO3 (225 mg, 0.691 mmol), methyl (4-amino-5-(2- (dimethylamino)ethoxy)pyridin-2-yl)carbamate hydrochloride (Preparation 265, 75 mg, 0.229 mmol), DIPEA (89.04 mg, 0.689 mmol), 4-chloro-2-(l,l-difluoroethyl)-6-ethyl- pyrimidine (75 mg, 0.363 mmol), Pd(OAc)2 (3 mg, 13.4 umol) and BINAP (10 mg, 16.06 umol) in dioxane (5 mL) was stirred at 90 °C for 2 h. The reaction mixture was cooled to rt, passed through a 0.2 um syringe filter, and rinsed with EtOAc (8 mL). The filtrate was concentrated to dryness and purified via prep-HPLC (Method U, Gradient 5-95%) to give methyl (4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2 - (dimethylamino)ethoxy)pyridin-2-yl)carbamate (44.8 mg, 46.1% yield) . LCMS m/z = 425.2 [M+H] ⁺ . 'H NMR (600 MHz, DMSO-d ₆ ) 8 (ppm) = 9.90 (s, 1H), 9.86 (s, 1H), 8.77 (s, 1H), 8.05 (s, 1H), 6.95 (s, 1H), 4.17 (t, J= 5.5 Hz, 2H), 3.65 (s, 3H), 2.72 (q, J= 7.4 Hz, 2H), 2.60 (t, J= 5.5 Hz, 2H), 2.27 (s, 6H), 2.07 (t, J= 19.1 Hz, 3H), 1.24 (t, J= 7.4 Hz, 3H).

Example 93

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5- (tri fluoromethoxy )pyridin-2-yl)acetamide

A vial containing N-(2-chloro-5-(trifluoromethoxy)pyridin-4-yl)-6-cyclopropoxy -2-(l,l- difhjoroethyl)pyrimidin-4-amine (Preparation 274, 125 mg, 0.302 mmol), acetamide (75 mg, 1.3 mmol), BrettPhos-Pd-G3 (32 mg, 35 umol) and CS2CO3 (308.4 mg, 0.947 mmol) in dioxane (2 mL) was degassed, backfilled with N2 then heated to 95 °C. After 1.5 h, the mixture was cooled to rt then filtered through Celite®, rinsing through with 3 : 1 EtOAc:EtOH then the combined organic layers were concentrated under reduced pressure. The residue was loaded onto a silica gel column and purified with (20-75% EtOAc in heptane.) The product was further purified by HPLC (Method U, Gradient 5-75%) to give N -(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl)ami no)-5- (trifluoromethoxy)pyridin-2-yl)acetamide as a white solid (15 mg, 11 % yield). LCMS m/z = 433.9 [M+ H] ⁺ . 'H NMR (500 MHz, DMSO-d ₆ ) 6 (ppm) = 10.57 (br s, 1H), 9.87 (s, 1H), 9.14 (s, 1H), 8.30 (s, 1H), 6.91 (s, 1H), 4.19 (br s, 1H), 2.09 - 2.00 (m, 6H), 0.84 (br d, J = 5.8 Hz, 2H), 0.81 - 0.77 (m, 2H).

Example 94

A-(4-((2-(l,l-difluoroethyl)-6-fluoropyrimidin-4-yl)amino )-5-ethoxypyridin-2-yl)acetamide trifluoroacetate

TBAF (148 pL, 148 pmol, 1 M in THF) was added to a solution of tert-butyl (2-acetamido-5- ethoxypyridin-4-yl)(6-chloro-2-(l , 1 -difluoroethyl )pyrimidin-4-yl)carbamate (Preparation 277, 35 mg, 74 pmol) in DMF (2.5 mL) and the reaction was heated at 140 °C for 1 h. After cooling to rt, the reaction was diluted with saturated NaHCCh, extracted twice with EtOAc and evaporated to dryness. The residue was purified by reverse phase HPLC (Method V, Gradient 5-45%), to give A-(4-((2-(l,l-difluoroethyl)-6-fluoropyrimidin-4-yl)amino)-5 - ethoxypyridin-2-yl)acetamide trifluoroacetate (4 mg, 11 % yield) as white solid. LCMS m/z = 356.2 [M+H] ⁺ . 'H NMR (600 MHz, DMSO ) 8 ppm 10.35 (br s, 1H), 9.66 (s, 1H), 8.88 (br s, 1H), 8.05 (s, 1H), 6.97 (s, 1H), 4.21 (m, 2H), 2.02 - 2.11 (m, 6H), 1.37 (t, J=6.9 Hz, 3H).

Example 95-

N-(4-((6-(2-oxabicyclo[2.1. l]hexan-4-yl)-4-methylpyridin-2-yl)amino)-5-ethoxypyridin-2- yl)acetamide

To a vial equipped with magnetic stir bar was added NaOAc (359 mg, 4.38 mmol) and placed in a vacuum oven at 75°C overnight. Separately, to another vial was added Cu(TMHD)2 (117.76 mg, 0.274 mmol), l,3-dioxoisoindolin-2-yl 2-oxabicyclo[2.1.1]hexane-4-carboxylate (Preparation 181, 224.4 mg, 0.821 mmol), aminosupersilane (435.8 mg, 1.10 mmol), bis[2- (2-pyridyl)phenyl]iridium(l+);4-tert-butyl-2-(4-tert-butyl-2 - pyridyl)pyridine;hexafluorophosphate (5.0 mg, 5.48 umol), N-(4-((6-bromo-4-methylpyridin- 2-yl)amino)-5-ethoxypyridin-2-yl)acetamide (Preparation 275, 200 mg, 0.548 mmol) and dry acetone (8 mL). The resulting mixture was degassed with N2, then transferred to the initial oven-dried vial containing base. The mixture was purged with N2, sealed, then sonicated for 1 min. The reaction was placed in Integrated Photoreactor (450 nm LEDs) and stirred at rt for 2h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc, washed with water, then brine, dried and concentrated. The crude was purified by HPLC to give the title compound (20 mg, 7% yield) as a TFA salt. ^T H NMR (DMSO-de, 600 MHz) 8 8.8-9.1 (m, 1H), 8.5-8.8 (m, 1H), 7.83 (s, 1H), 7.1-7.2 (m, 1H), 6.91 (s, 1H), 4.57 (t, 1H, J=1.0 Hz), 4.19 (q, 2H, J=7.0 Hz), 3.92 (s, 2H), 2.30 (s, 3H), 22-22 (m, 2H), 2.14 (s, 3H), 1.8-1.9 (m, 2H), 1.43 (t, 3H, ./=7.0 Hz). LCMS m/z = 369 [M+H]+

Example 96

N-(4-((2-(l,l-difluoroethyl)-6-(pyridin-3-yl)pyrimidin-4- yl)amino)-5-ethoxypyri din-2- yl)acetamide

A mixture of tert-butyl (2-acetamido-5-ethoxypyridin-4-yl)(6-chloro-2-(l,l- difhjoroethyl)pyrimidin-4-yl)carbamate (Preparation 277, 50 mg, 0.105 mmol), 3-(4,4,5,5- tetram ethyl- 1, 3, 2-dioxaborolan-2-yl)pyri dine (60 mg, 0.29 mmol), K2CO3 (50 mg, 0.36 mmol), and Pd(dppf)C12 (8 mg, 11 umol) in dioxane (2 mL) and water (1 mL) was stirred at 100 °C for 20 h. The reaction was cooled to rt, diluted with water (3 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layers were concentrated to dryness and purified by silica gel chromatography (heptane to EtOAc with 2% dimethylethylamine) to give N-(4- ((2-(l,l-difluoroethyl)-6-(pyridin-3-yl)pyrimidin-4-yl)amino )-5-ethoxypyri din-2- yl)acetamide as a white solid, (32 mg, 73% yield). LCMS m/z = 415.2 [M+H]+. 1H NMR (600 MHz, DMSO-d ₆ ) 6 (ppm) = 10.26 (s, 1H), 9.29 (s, 1H), 9.26 (dd, J = 0.8, 2.3 Hz, 1H), 9.16 - 8.99 (m, 1H), 8.75 (dd, J = 1.7, 4.8 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.67 - 7.57 (m, 1H), 4.24 (q, J = 6.9 Hz, 2H), 2.16 (t, J = 19.3 Hz, 3H), 2.08 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). Example 97

N-(4-((2-(l,l-difluoroethyl)-6-(l-ethyl-lH-pyrazol-4-yl)p yrimidin-4-yl)amino)-5- methoxypyridin-2-yl)acetamide

A mixture of tert-butyl (2-acetamido-5-methoxypyridin-4-yl)(6-chloro-2-(l,l- difluoroethyl)pyrimidin-4-yl)carbamate (Preparation 278, 27 mg, 60 umol), (1 -ethyl -4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (20 mg, 90 umol), Pd(dppf)C12:DCM (4.9 mg, 6 umol) and CS2CO3 (58 mg, 0.180 mmol) in dioxane (1 mL) and water (0.2 ml) was stirred at 90 °C for 3 h. The reaction was concentrated in vacuo and a solution of TFA (10 uL, 0.120 mmol) and DCM (2 mL) was added to the residue and the mixture stirred for 16 h. The reaction was evaporated and purified by (Method U, Gradient 5-95%) to afford N-(4-((2-(l,l-difhioroethyl)-6-(l-ethyl-lH-pyrazol-4- yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide (3.7 mg, 14 %) as a yellow solid. LCMS m/z = 418 [M+H] ⁺

Example 98

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((6-methylpyrazin-2- yl)oxy)pyridin-2-yl)acetamide

A mixture of N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-hydroxypyri din- 2-yl)acetamide (Preparation 279, 25 mg, 0.077 mmol), 2-chloro-6-methyl-pyrazine (20 mg, 0.155 mmol), DIPEA (20 mg, 0.155 mmol), and MeCN (2.0 mL) was stirred for 72 h at 90 °C. The reaction was cooled to rt, concentrated to dryness, and purified via prep-HPLC (Method U, Gradient 5-95%) to give N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)-5-((6-methylpyrazin-2-yl)oxy)pyridin-2-yl)acetamid e (4.0 mg, 19% yield). LCMS m/z = 416.2 [M+H]+. Examples 99 to 137

To a solution of N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 - hydroxypyridin-2-yl)acetamide (Preparation 279, 25.8 mg, 0.08 mmol) and the appropriate alcohol (0.08 mmol) in toluene (1.00 mL) was added (cyanomethyl ene)tributylphosphorane (77.1 mg, 0.32 mmol) under N2. The reaction mixture was shaken at 50°C for 16 h under N2.

The reaction mixtures were concentrated and the residues were purified by preparative HPLC to give the desired products.

Basic prep. HPLC conditions: Column: Xtimate C18 150*25mm*5pm; Mobile phase: A: NH4OH/H2O = 0.05% v/v; B: CAN; Flow rate: 25 mL/min or 30 mL/min;

Acidic prep. HPLC conditions: Column: Xtimate C18 150*25mm*5pm; Mobile phase: A: FA/H2O = 0.225% v/v; B: CAN; Flow rate: 25 mL/min or 30 mL/min;

Example 138

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-((l,5-dimethyl-lH-pyrazol-4- yl)methoxy)pyridin-2-yl)acetamide

DIAD (28 mg, 0.142 mmol) was added to a solution of (l,5-dimethyl-lH-pyrazol-4- yl)methanol (23 mg, 0.190 mmol), PPhs (37 mg, 0.142 mmol) and N-(4-((2-(l,l- difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-hydroxypyridi n-2-yl)acetamide (Preparation 279, 31 mg, 0.095 mmol) in THF (1 mL) and the reaction was stirred at rt overnight. The reaction was evaporated and purified by HPLC (Method U, Gradient 5-95%) to afford N-(4- ((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((l, 5-dimethyl-lH-pyrazol-4- yl)methoxy)pyridin-2-yl)acetamide (2.9 mg, 7.3 % yield) as tan solid. LCMS m/z = 432 [M+l] ⁺ .

Example 139

N-(4-((6-cyclopropoxy-2-(l,l-difluoroethyl)pyrimidin-4-yl )amino)-5-((tetrahydrofuran-2- yl)methoxy)pyridin-2-yl)acetamide

DEAD (25 mg, 0.144 mmol) was added to a solution of (tetrahydrofuran-2-yl)methanol (10 mg, 0.096 mmol), THF (1 mL), PPhs (37 mg, 0.144 mmol), and N-(4-((6-cyclopropoxy-2- (l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-hydroxypyridin-2- yl)acetamide (Preparation 281, 35 mg, 0.096 mmol) in THF (1 mL) and the reaction was stirred overnight. The reaction was evaporated and purified by HPLC (Method U, Gradient 5-95%) to afford N-(4-((6- cyclopropoxy-2-(l , 1 -difluoroethyl )pyrimidin-4-yl)amino)-5-((tetrahydrofuran-2- yl)methoxy)pyridin-2-yl)acetamide (5.7 mg, 13 % yield) as a white solid. LCMS m/z = 450 [M+H] ⁺

Example 140

N-(4-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(2-hydr oxyethoxy)pyridin-2-yl)acetamide

A solution of 7V-(4-((6-(l, l-difluoroethyl)pyridin-2-yl)amino)-5-(2-methoxyethoxy)pyrid in-2- yl)acetamide (Preparation 56, 32 mg, 0.088 mmol) in DCM (1 mL) was cooled to 0 °C and tribromoborane (88 pL, 1 M in DCM) added slowly. The reaction was sonicated for 30 min to aid dissolution, additional tribromoborane (88 pL, 1 M in DCM) was added and the reaction stirred for 1 h at 0 °C. The reaction was quenched by addition of saturated NaHCCL, extracted with DCM (2x) and evaporated. The residue was purified by silica gel chromatography (0-20% MeOH in DCM) to give A-(4-((6-( 1,1 -difluoroethyl )pyri din-2 - yl)amino)-5-(2-hydroxyethoxy)pyridin-2-yl)acetamide (14 mg, 45% yield) . LCMS m/z = 353.2 [M+H] ⁺ . 'H NMR (400 MHz, CDCh + MeOH-t/ ₄ ) 8 ppm 8.92 (s, 1H), 7.47 - 7.59 (m, 2H), 7.24 - 7.30 (m, 1H), 6.99 - 7.07 (m, 1H), 6.89 - 6.97 (m, 1H), 3.92 - 3.99 (m, 2H), 3.73 - 3.84 (m, 2H), 1.82 - 2.01 (m, 6H).

Example 141

N-(4-((2-(2-oxabicyclo[2.1. l]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(5-methyl- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)a cetamide

A vial containing 4-chloro-6-methyl-2-(l-methyl-2-oxabicyclo[2.1. l]hexan-4-yl)pyrimidine

(Preparation 177, 69 mg, 0.326 mmol), N-(4-amino-5-(5-methyl-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide trifluoroacetate (Preparation

474, 81 mg, 0.203 mmol), Pd2dba3 (20 mg, 22 pmol), DIPEA (0.42 mL, 2.41 mmol) CS2CO3 (211 mg, 0.669 mmol), Xantphos (29 mg, 51 pmol) and Xantphos-Pd-G3 (40 mg, 43 pmol) in dioxane (2 mL) was degassed then backfilled with N2 then heated at 90 °C for 17 h. The mixture was cooled to rt then filtered through Celite®, washing through with EtOAc. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography (20- 100 % 3:1 EtOAc: EtOH in heptane). The product was suspended in EtOH, the heterogenous mixture was heated on the rotovap to 45 °C without vacuum for 20 mins, then filtered and the resulting solid dried to give N-(4-((2-(2-oxabicyclo[2.1.1]hexan-4-yl)-6-m ethyl pyrimidin-4- yl)amino)-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyraz in-2-yl)pyridin-2-yl)acetamide as a white solid. LCMS m/z = 461.2 [M+ H] ⁺ . 'H NMR (500 MHz, DMSO-d ₆ ) 8 (ppm) =

11.38 (s, 1H), 10.37 (s, 1H), 9.53 (s, 1H), 8.59 (s, 1H), 6.79 (s, 1H), 6.70 (s, 1H), 4.55 (s, 1H), 4.31 - 4.27 (m, 2H), 3.98 (s, 2H), 3.66 (s, 2H), 2.91 (t, J = 5.5 Hz, 2H), 2.43 (s, 3H),

2.38 - 2.36 (m, 5H), 2.11 (s, 3H), 1.83 (dd, J = 1.5, 4.3 Hz, 2H).

Example 142

N-(4'-((2-(2-oxabicyclo[2.1. l]hexan-l-yl)-6-methylpyrimidin-4-yl)amino)-5- ((difluoromethoxy)methyl)-[2,3'-bipyridin]-6'-yl)acetamide

A mixture of N-(4'-amino-5-((difluorom ethoxy )methyl)-[2,3'-bipyridin]-6'-yl)acetamide hydrochloride (Preparation 477, 40 mg, 0.116 mmol), XantPhos-Pd-G3 (11 mg, 11.6 pmol) , Xantphos (6.7 mg, 11.6 pmol), K3PO4 (86 mg, 0.406 mmol) in dioxane (2 mL) was degassed with N2, 2-(2-oxabicyclo[2.1.1]hexan-l-yl)-4-chloro-6-methylpyrimidin e (Preparation 176, 37 mg, 0.174 mmol) was then added and the reaction was heated at 100°C for 3h. The cooled reaction mixture was filtered and the filtrate was purified by chromatography on silica gel (10-90%EtOAc-EtOH 3: 1 with 2%NH4OH in heptane) to give N-(4'-((2-(2-oxabicyclo[2.1. l]hexan-l-yl)-6-methylpyrimidin-4-yl)amino)-5- ((difluoromethoxy)methyl)-[2,3'-bipyridin]-6'-yl)acetamide (32 mg, 57% yield). LCMS m/z = 483 [M+H] ⁺ 'H NMR (MeOH-d ₄ , 400 MHz) 8 9.43 (s, 1H), 8.77 (s, 1H), 8.68 (s, 1H), 7.99 (s, 2H), 6.8 (s, 1H), 6.57 (t, 1H, J=74.5 Hz), 5.05 (s, 2H), 4.63 (s, 1H), 4.10 (s, 2H), 2.4-2.5 (m, 5H), 2.21 (s, 3H), 1.96-1.98 (m, 2H).

Example 143 N-(5-cyclopropyl-4-((2-(l,l-difluoroethyl)-5-methoxypyrimidi n-4-yl)amino)pyri din-2- yl)acetamide

N-(5-cyclopropyl-4-((2-(l,l-difluoroethyl)-5-methoxypyrim idin-4-yl)amino)pyridin-2- yl)acetamide was obtained as a white solid, 38 mg, 44%, from N-(4-amino-5- cyclopropylpyridin-2-yl)acetamide (Preparation 371) and 4-chloro-2-(l,l-difluoroethyl)-5- methoxypyrimidine (Preparation 154) following a similar procedure to that described in Example 141. LCMS m/z = 364.1 [M+ H] ⁺ . ^X H NMR (500 MHz, DMSO-d ₆ ) 8 (ppm) = 10.22 (s, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 7.92 (s, 1H), 3.94 (s, 3H), 2.09 - 2.00 (m, 6H), 1.96 - 1.90 (m, 1H), 0.96 - 0.91 (m, 2H), 0.62 - 0.58 (m, 2H).

Example 144

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2,2- dimethyl-2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide trifluoroacetate

A mixture of 2-chloro-5-(2,2-dimethyl-2,3-dihydrobenzo[b][l,4]dioxin-6-yl )pyridin-4-amine (Preparation 496, 50 mg, 0.16 mmol), 4-chloro-2-(l,l-difluoroethyl)pyrimidine (Preparation 148, 34 mg, 0.19 mmol), CS2CO3 (104 mg, 0.32 mmol), Pd2dba3 (3.6 mg, 4.0 umol), and XantPhos (5.5 mg, 9.5 umol) in dioxane (2 m ) was stirred at 90 °C for 20 h. The reaction was removed from heating, cooled to rt, diluted with EtOAc, filtered through a 0.2 um syringe filter, and rinsed with EtOAc. The filtrate was concentrated to dryness. The crude mixture was purified via prep-HPLC (Method V, Gradient: 5-95%) to give N-(4-((2-(l,l- difluoroethyl)pyrimidin-4-yl)amino)-5-(2,2-dimethyl-2,3-dihy dro-[l,4]dioxino[2,3-b]pyridin- 6-yl)pyridin-2-yl)acetamide trifluoroacetate (32 mg, 45% yield). LCMS m/z = 457.2 [M+H]+. 1H NMR (600 MHz, DMSO-d ₆ ) 6 (ppm) = 11.87 (s, 1H), 10.54 (s, 1H), 9.10 - 9.06 (m, 1H), 8.65 (s, 1H), 8.56 (d, J = 5.7 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 5.7 Hz, 1H), 4.23 (s, 2H), 2.12 (s, 3H), 2.11 - 2.02 (m, 3H), 1.36 (s, 6H).

Example 145 to 149 The compounds in the following table were prepared from the appropriate amine and haloheterocycle, following a similar procedure to that described in Example 144.

Example 150

N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-6-(difluoromethoxy)-[2,3'- bipyridin]-6'-yl)acetamide

To a solution of N-(4'-amino-6-(difluoromethoxy)-[2,3'-bipyridin]-6'-yl)aceta mide hydrochloride (Preparation 452, 140.0 mg, 0.476 mmol) and 4-chloro-2-(l,l-difluoroethyl)- 6-methylpyrimidine (Preparation 92, 100.8 mg, 0.523 mmol) in dioxane (10 mL) was added K3PO4 (606.0 mg, 2.85 mmol), Xantphos (27.5 mg, 47.6 umol) and Pd2(dba)3 (43.6 mg, 47.6 umol). The reaction was stirred at 100 °C for 6 h under N2. The cooled mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Method AA, Gradient 32-62%) to give N-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)-6-(difluoromethoxy)-[2,3'-bipyridin]-6'-yl)acetami de (26.3 mg, 12.3% yield) as a white solid. LCMS m/z = 451.1 [M+H] ⁺ 'H NMR (400 MHz, DMSO-t/ ₆ ) 8 ppm 10.61 (s, 1H), 10.21 (s, 1H), 8.82 (s, 1H), 8.58 (s, 1H), 7.96-8.03 (m, 1H), 7.56-7.95 (m, 2H), 7.06 (d,

J=8.0 Hz, 1H), 6.82 (s, 1H), 2.37 (s, 3H), 2.12 (s, 3H), 1.96 (t, J=18.8 Hz, 3H).

Examples 151 to 157 The compounds in the following table were prepared from the appropriate aromatic amine and 4-chloro-2-(l,l-difluoroethyl)-6-methylpyrimidine (Preparation 92), following a similar procedure to that described in Example 150.

Examples 158 to 171 The compounds in the following table were prepared from the appropriate aromatic amine and haloheterocycle, following a similar procedure to that described in Example 150.

Example 172 to 176

The compounds in the following table were prepared from N-(4-amino-5-(2- methylpyrimidin-4-yl)pyridin-2-yl)acetamide hydrochloride (Preparation 459) and the appropriate halide, following a similar procedure to that described in Example 150.

Examples 177 to 181

The compounds in the following table were prepared from N-(4-amino-5-(2- methoxypyrimidin-4-yl)pyridin-2-yl)acetamide hydrochloride (Preparation 457) and the appropriate halide, following a similar procedure to that described in Example 150.

Examples 182 to 192

The compounds in the following table were prepared from N-(4-amino-5-(5-fluoropyrimidin- 2-yl)pyridin-2-yl)acetamide hydrochloride (Preparation 460) and the appropriate halide, following a similar procedure to that described in Example 150.

Example 193 to 196

The compounds in the following table were prepared from N-(4-amino-5-(6- methoxypyrimidin-4-yl)pyridin-2-yl)acetamide hydrochloride (Preparation 458) and the appropriate halide, following a similar procedure to that described in Example 150.

Examples 197 to X

The compounds in the following table were prepared from N-(4-amino-5-(6- methylpyrimidin-4-yl)pyridin-2-yl)acetamide hydrochloride (Preparation 461) and the appropriate halide, following a similar procedure to that described in Example 150.

Examples 202 to 212

The compounds in the following table were prepared from N-(4-amino-5-(l-methyl-lH- pyrazol-3-yl)pyridin-2-yl)acetamide (Preparation 481) and the appropriate halide, following a similar procedure to that described in Example 150.

Example 213

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-methoxypyridazin-3- yl)pyridin-2-yl)acetamide-2,2,2-d3

A vial containing 4-chloro-2-(l,l-difluoroethyl)-6-methylpyrimidine (Preparation 92, 48 mg, 0.249 mmol), N-(4-amino-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide -2,2,2-d3 trifluoroacetate (Preparation 473, 61 mg, 0.162 mmol), K3PO4 (121 mg, 0.572 mmol), Xantphos (33 mg, 57 umol), DIPEA (0.2 mL, 1.15 mmol), and Pd2dba3 (23 mg, 25 umol) in dioxane (2 mL) was degassed then backfilled with N2 then heated at 95 °C for 1.5 h.

The cooled mixture was loaded onto a silica gel column and purified eluting with (25-85 % 3 : 1 EtOAc: EtOH in heptane). The product was further purified by HPLC (Method U, Gradient 5- 60%), to give N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(6- methoxypyridazin-3-yl)pyridin-2-yl)acetamide-2,2,2-d3 (7 mg, 10 % yield) as a white solid. LCMS m/z = 419.1 [M+ H] ⁺ . 'H NMR (500 MHz, DMSO-d ₆ ) 8 (ppm) = 11.54 (br s, 1H), 10.62 (br s, 1H), 9.08 (br s, 1H), 8.68 (br s, 1H), 8.22 (dd, J = 2.3, 9.3 Hz, 1H), 7.40 (br d, J = 8.9 Hz, 1H), 6.95 (br s, 1H), 4.10 (d, J = 2.7 Hz, 3H), 2.42 (br s, 3H), 2.04 (br t, J = 19.2 Hz, 3H).

Example 214

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-me thoxypyridazin-3-yl)pyri din-2- yl)acetamide trifluoroacetate

A mixture of N-(4-amino-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide (Preparation 434, 50 mg, 0.19 mmol), 4-chloro-2-(l,l-difluoroethyl)pyrimidine (Preparation 148, 50 mg, 0.29 mmol), K3PO4 (82 mg, 0.39 mmol), and [XantPhos Pd(allyl)]Cl (7.3 mg, 9.6 mmol) in 2-MeTHF (2 mL) was stirred at 90 °C overnight. The reaction was cooled to rt, diluted with EtOAc (5 mL), filtered through a 0.2 um syringe filter, and rinsed with EtOAc (5 mL). The filtrate was concentrated to dryness and the crude mixture was purified via prep- HPLC (Method V, Gradient 5-95%) to give N-(4-((2-(l,l-difluoroethyl)pyrimidin-4- yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide trifluoroacetate (6.3 mg, 8% yield). LCMS m/z = 402.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ) 8 (ppm) = 11.48 (s, 1H), 10.64 (s, 1H), 9.09 - 8.96 (m, 1H), 8.68 (s, 1H), 8.58 - 8.49 (m, 1H), 8.19 (d, J= 9.5 Hz, 1H), 7.39 (d, J= 9.5 Hz, 1H), 7.10 - 7.07 (m, 1H), 4.10 (s, 3H), 2.14 (s, 3H), 2.04 (s, 3H).

Example 215

N-(4-((6-(2-fluoropropan-2-yl)pyridin-2-yl)amino)-5-(5-fl uoropyrimidin-2-yl)pyridin-2- yl)acetamide

To a solution of 2-bromo-6-(2-fluoropropan-2-yl)pyridine (Preparation 130, 100 mg, 0.459 mmol) in dioxane (10 mL) was added N-(4-amino-5-(5-fluoropyrimidin-2-yl)pyri din-2 - yl)acetamide hydrochloride (Preparation 460, 113.4 mg, 0.459 mmol), CS2CO3 (298.8 mg, 0.917 mmol) and Brettphos Pd G3 (41.6 mg, 45.9 umol). The resulting mixture was stirred at 100 °C for 2 h under N2. The mixture was concentrated and purified by Prep-HPLC (Method B, 40-70%) to give N-(4-((6-(2-fluoropropan-2-yl)pyridin-2-yl)amino)-5-(5-fluor opyrimidin- 2-yl)pyridin-2-yl)acetamide (50.8 mg, 28.8% yield) as a white solid. LCMS m/z = 385.1 [M+H] ⁺ . 'H NMR (400 MHz, CDCh) 6 ppm: 9.33 (s, 2H), 8.71 (s, 2H), 8.36 (br s, 1H), 7.67 (t, ./=7,6 Hz, 1H), 7.18-7.23 (m, 1H), 6.88-6.94 (m, 1H), 2.23 (s, 3H), 1.86 (s, 3H), 1.80 (s, 3H).

Example 216

N-(4-((2-(2-fluoropropan-2-yl)pyridin-4-yl)amino)-5-(5-fl uoropyrimidin-2-yl)pyridin-2- yl)acetamide

N-(4-((2-(2-Fluoropropan-2-yl)pyridin-4-yl)amino)-5-(5-fl uoropyrimidin-2-yl)pyri din-2- yl)acetamide was obtained as a white solid, 10.8 mg, 28% yield, from 4-bromo-2-(2- fluoropropan-2-yl)pyridine and N-(4-amino-5-(5-fluoropyrimidin-2-yl)pyridin-2- yl)acetamide hydrochloride (Preparation 460), following a similar procedure to that described in Example 215. LCMS m/z = 385.1 [M+H] ⁺ . 1HNMR (400 MHz, CDCh) 8 ppm 11.21 (s, 1H), 9.08-9.35 (m, 1H), 8.59 (s, 2H), 8.22-8.43 (m, 3H), 7.17 (dd, J=5.6 Hz, 2.4 Hz, 1H), 7.14 (s, 1H), 2.10 (s, 3H), 1.66 (s, 3H), 1.60 (s, 3H)

Example 217

N-(4-((2-(l,l-difluoroethyl)pyridin-4-yl)amino)-5-(6-meth oxypyrimidin-4-yl)pyri din-2- yl)acetamide

N-(4-((2-(l,l-difluoroethyl)pyridin-4-yl)amino)-5-(6-meth oxypyrimidin-4-yl)pyri din-2- yl)acetamide was obtained as a white solid, 65.7 mg, 64%, from N-(4-amino-5-(6- methoxypyrimidin-4-yl)pyridin-2-yl)acetamide hydrochloride (Preparation 458) and 4- chloro-2-(l,l-difluoroethyl)pyridine, following a similar procedure to that described in Example 215. LCMS m/z = 401.1 [M+H] ^{+ X} HNMR (400 MHz, CDCh) d ppm 11.71 (s, 1H), 8.87 (d, J= 0.8 Hz, 1H), 8.53-8.56 (m, 2H), 8.43 (s, 1H), 8.12 (br s, 1H), 7.48 (d, J= 2.0 Hz, 1H), 7.36 (dd, J= 5.6 Hz, 2.0 Hz, 1H), 7.12 (s, 1H), 4.07 (s, 3H), 2.24 (s, 3H), 2.05 (t, J= 18.8 Hz, 3H) Example 218

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-methyl-lH-pyrazol-3- yl)pyridin-2-yl)acetamide

To a stirring solution of N-(4-amino-5-(l-methyl-lH-pyrazol-3-yl)pyridin-2-yl)acetamid e (Preparation 481, 35 mg, 0.151 mmol) and 4-chloro-2-(l,l-difluoroethyl)-6-methyl- pyrimidine (Preparation 92, 37.9 mg, 0.197 mmol) in dioxane (1 mL) was added CS2CO3 (98.6 mg, 0.303 mmol) and the resulting mixture was degassed using N2 for 15 mins. BrettPhos Pd G3 (27.44 mg, 30.3 umol) and BrettPhos (32.50 mg, 60.5 umol) were added and the reaction mixture was heated under reflux at 100 °C for 16 h. The reaction was filtered through Celite® and the filtrate concentrated in vacuo. The crude was purified by HPLC (Method V, Gradient 5-95%) to give N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin- 4-yl)amino)-5-(l-methyl-lH-pyrazol-3-yl)pyridin-2-yl)acetami de as a white solid, 9.5 mg, 16.2%. LCMS m/z = 388.3 [M+H] ⁺ ; ^X H NMR (600 MHz, DMSO-d ₆ ) 6 11.55 (s, 1H), 10.55 (s, 1H), 9.32 (s, 1H), 8.70 (s, 1H), 7.94 (d, J= 2.4 Hz, 1H), 7.11 (s, 1H), 6.96 (d, J= 2.4 Hz, 1H), 4.07 (s, 3H), 2.23 - 2.11 (m, 6H).

Example 219

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-methylpyridazin-3- yl)pyridin-2-yl)acetamide

A mixture of 4-chloro-2-(l,l-difluoroethyl)-6-methylpyrimidine (Preparation 92) (115 mg, 0.597 mmol), N-(4-amino-5-(6-methylpyridazin-3-yl)pyridin-2-yl)acetamide hydrochloride (Preparation 471, 102 mg, 0.365 mmol), CS2CO3 (333 mg, 1.02 mmol), BINAP (80 mg, 0.129 mmol), DIPEA (1.4 mL, 8.04 mmol) and KO Ac (11 mg, 49 umol) in dioxane (2 mL) was degassed then backfilled with N2, heated to 95 °C and stirred for 8 h. The cooled mixture was purified directly by silica gel chromatography (10-85 % 3: 1 EtOAc: EtOH in heptane) The product was further purified by HPLC (Method U, Gradient 5-55%) to give a white solid as N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-methylpy ridazin-3- yl)pyridin-2-yl)acetamide (8.5 mg, 5% yield). LCMS m/z = 399.9 [M+ H]+. 1H NMR (5OO MHz, DMS0-d6) 8 (ppm) = 11.93 (s, 1H), 10.64 (s, 1H), 9.14 (s, 1H), 8.74 (s, 1H), 8.22 (d, J = 8.9 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H), 6.96 (s, 1H), 2.68 (s, 3H), 2.42 (s, 3H), 2.13 (s, 3H), 2.05 (br t, J = 19.2 Hz, 3H).

Example 220 and 221

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(6-methoxypyridazin-3- yl)pyridin-2-yl)acetamide and N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5- (6-oxo- l,6-dihydropyridazin-3-yl)pyri din-2 -yl)acetamide

To a solution of mixture of N-(4-amino-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide hydrochloride and N-(4-amino-5-(6-oxo-l,6-dihydropyridazin-3-yl)pyridin-2-yl)a cetamide hydrochloride (Preparation 450, 150 mg, 0.51 mmol) in dioxane (5 mL) was added Xantphos (58.7 mg, 0.10 mmol), 4-chloro-2-(l,l-difluoroethyl)-6-ethylpyrimidine (Preparation 94, 104.8 mg, 0.51 mmol), CS2CO3 (331 mg, 1.01 mmol), Pd2(dba)3 (46.45 mg, 0.051 mmol) and the mixture stirred at 100°C for 2 h under N2. The reaction mixture was concentrated and the residue purified by prep-HPLC (Method R, Gradient 35-64%) to afford:

Peak 1, N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5- (6-methoxypyridazin-3- yl)pyridin-2-yl)acetamide (white solid: 35.5 mg, 16%). LCMS m/z = 430.1 [M+H] ⁺ ; 'H NMR (400 MHz, CDCI3) 6 ppm: 12.19 (s, 1H), 9.45 (s, 1H), 8.46 (s, 1H), 7.86-7.88 (m, 2H), 7.17 (d, J=9.2 Hz, 1H), 7.83 (s, 1H), 4.22 (s, 3H), 2.81 (q, J=7.2 Hz, 2H), 2.14-2.25 (m, 6H), 1.34 (t, J=7.2 Hz, 3H).

Peak 2, N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5- (6-oxo-l,6- dihydropyridazin-3-yl)pyridin-2-yl)acetamide (white solid: 30.2 mg, 14%). LCMS m/z = 416.1 [M+H] ⁺ ; 'H NMR (400 MHz, DMSO-d ₆ ) 6 ppm: 10.24 (s, 1H), 8.55 (s, 1H), 8.30-8.33 (m, 2H), 7.85 (br s, 1H), 7.60 (s, 1H), 7.22 (d, J=10.0 Hz, 1H), 2.94 (q, J=7.2 Hz, 2H), 2.00- 2.10 (m, 6H), 1.30 (t, J=7.6 Hz, 3H).

Example 222 N-(5-(5-acetyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl )-4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide trifluoroacetate

A vial containing l-(2-iodo-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)ethan-l -one (Preparation 337, 111 mg, 0.382 mmol), N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyr idin-2-yl)acetamide (Preparation 486, 334 mg, 0.77 mmol), SPhos-Pd-G3 (39 mg, 50 pmol) and K3PO4 (1.5 M aqueous solution, 0.8 mL, 1.2 mmol) in 2-MeTHF (2 mL) was degassed then backfilled with N2 then heated at 75 °C for 3 h. The mixture was cooled to rt and filtered through Celite®, washing through with EtOAc. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (20- 100 % 3:1 EtOAc: EtOH in heptane). The product was further purified by HPLC (Method V: Gradient 5-40%) to give N-(5-(5-acetyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl )-4-((2- (l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-y l)acetamide (TFA Salt) (6 mg, 3% yield) as a white solid. LCMS m/z = 471.2 [M+ H] ⁺ . 'H NMR (500 MHz, DCM-d ₂ ) 8 (ppm) = 12.34 (br d, J = 19.8 Hz, 1H), 12.09 (br d, J = 11.0 Hz, 1H), 9.96 - 9.88 (m, 1H), 8.40 (d, J = 8.2 Hz, 1H), 6.86 (s, 1H), 6.57 (d, J = 3.7 Hz, 1H), 4.93 (s, 1H), 4.85 (s, 1H), 4.44 - 4.34 (m, 2H), 4.18 (br t, J = 5.3 Hz, 1H), 4.03 (br t, J = 5.0 Hz, 1H), 2.60 (s, 3H), 2.31 (s, 3H), 2.27 (d, J = 15.3 Hz, 3H), 2.16 (t, J = 18.9 Hz, 3H).

Example 223

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-oxo-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-oxo-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide was obtained, 3 mg, 2%, from 2-bromo-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (Preparation 344) and N-(4-((2-(l,l- difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4,4,5,5-tetr amethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)acetamide (Preparation 486) following a similar procedure to that described in Example 222. LCMS m/z = 443.1 [M+ H] ⁺ . ^X H NMR (500 MHz, DMSO-d ₆ ) 8 (ppm) = 11.03 (s, 1H), 10.48 (s, 1H), 9.27 (s, 1H), 8.75 (s, 1H), 8.38 (br s, 1H), 7.40 (s, 1H), 7.08 (s, 1H), 4.51 (t, J = 6.1 Hz, 2H), 3.73 - 3.67 (m, 2H), 2.45 (s, 3H), 2.15 - 2.07 (m, 6H).

Example 224

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(7-hydroxy- 5-methyl-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide

A vial containing 2-bromo-7-fluoro-5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]p yrazine (Preparation 350, 100 mg, 0.427 mmol), N-(4-((2-(l,l-difhioroethyl)-6-methylpyrimidin-4- yl)amino)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyr idin-2-yl)acetamide

(Preparation 486, 317 mg, 0.732 mmol), PCy3-Pd-G3 (64 mg, 88 pmol), and KO Ac (1.5 M, 1.50 mmol, 1 mL) in dioxane (4 mL) was degassed then backfilled with N2 then heated at 90 °C for 2.5 h. The cooled mixture was purified directly by silica gel column chromatography (20- 100 % EtOAc with 2% dimethyl ethylamine in heptane then 100% 3 : 1 EtOAc: EtOH.) The product was further purified by HPLC (Method U, Gradient 5-55%) toto give N-(4-((2-(l,l- difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(7-hydroxy-5- methyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide (3 mg, 2 % yield) as a lightyellow solid. LCMS m/z = 459.2 [M+H] ⁺ . 'H NMR (500 MHz, DMSO-d ₆ ) 6 (ppm) = 11.67 (s, 1H), 10.43 (s, 1H), 9.40 (s, 1H), 8.64 (s, 1H), 7.24 (d, J = 6.4 Hz, 1H), 7.12 (s, 1H), 6.72 (s, 1H), 5.76 - 5.70 (m, 1H), 3.72 - 3.57 (m, 2H), 3.04 (br dd, J = 4.0, 12.2 Hz, 1H), 2.74 (br dd, J = 4.9, 12.5 Hz, 1H), 2.46 (s, 3H), 2.41 (s, 3H), 2.19 - 2.08 (m, 6H).

Example 225

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-(dimethylamino)pyrazin-2- yl)pyridin-2-yl)acetamide

A mixture of N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (Preparation 486, 25 mg, 0.058 mmol), Pd(OAc)2 (1.3 mg, 5.8 mmol), PCy3 (3.2 mg, 12 mmol), 5-bromo-N,N-dimethyl- pyrazin-2-amine (23 mg, 0.115 mmol), K2CO3 (16 mg, 0.115 mmol), 2-MeTHF (2.0 mL) and water (1.0 mL) was stirred for 2 h at 90 °C. The reaction was cooled to rt, diluted with water (3 mL) and extracted with 3:1 EtOAc:EtOH (3 x 3 mL). The combined organic layers were concentrated to dryness and purified via prep-HPLC (Method U, Gradient 5-95%) to give N- (4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-( 5-(dimethylamino)pyrazin-2- yl)pyridin-2-yl)acetamide (2.4 mg, 10% yield). LCMS m/z = 429.2 [M+H] ⁺ .

Example 226

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-methyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide

To a solution of (6-acetamido-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)pyri din-3 -yl)boronic acid (Preparation 488, 100 mg, 0.285 mmol) in dioxane (1 mL) and water (0.2 mL) was added 2-bromo-5-methyl-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine (Preparation 331, 123.1 mg, 0.57 mmol), Pd(dppf)C12.DCM (23.26 mg, 28.5 umol), K2CO3 (118.09 mg, 0.854 mmol) and the mixture was stirred at 90 °C for 2 h under N2. The mixture was concentrated and purified by Prep-HPLC (Method R, Gradient 30-60%) to give N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(5-methyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide (65 mg, 51.6% yield) as a white solid. LCMS m/z = 443.3 [M+H] ⁺ . 1HNMR (400 MHz, CDCI3) 6 ppm 11.37 (s, 1H), 9.36 (s, 1H), 8.44 (s, 1H), 7.93 (s, 1H), 6.73 (s, 1H), 6.37 (s, 1H), 4.32 (t, J=5.6 Hz, 2H), 3.71 (s, 2H), 2.97 (t, J=5.6 Hz, 2H), 2.48-2.62 (m, 6H), 2.10-2.28 (m, 6H).

Examples 227 to 254 The compounds in the following table were prepared from (6-acetamido-4-((2-(l,l- difhioroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-3-yl)bor onic acid (Preparation 488) and the appropriate halohetereocycle, following a similar procedure described in Example 226.

Example 255

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-mo rpholino-l,3,4-thiadiazol-2- yl)pyridin-2-yl)acetamide

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-mo rpholino-l,3,4-thiadiazol-2- yl)pyridin-2-yl)acetamide was obtained as a white solid, 35 mg, 25.5%, from (6-acetamido-4- ((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)pyridin-3-yl)bor onic acid (Preparation 487) and 4-(5-bromo-l,3,4-thiadiazol-2-yl)morpholine, following a similar procedure to that described in Example 226. Prep-HPLC (Method R, Gradient 28-58%). LCMS m/z = 463.2 [M+H] ⁺ 'H NMR (400 MHz, DMSO-tL) 8: ppm 11.37 (s, 1H), 10.68 (s, 1H), 9.25 (s, 1H), 8.61 (d, J=3.0 Hz, 1H), 8.51 (s, 1H), 7.17 (s, 1H), 3.75-3.77 (m, 4H), 3.52-3.55 (m, 4H), 2.05-2.15 (m, 6H).

Example 256

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(d imethylamino)pyrimidin-4- yl)pyridin-2-yl)acetamide

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(d imethylamino)pyrimidin-4- yl)pyridin-2-yl)acetamide was obtained as a white solid, 12 mg, 9.8%, from (6-acetamido-4- ((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)pyridin-3-yl)bor onic acid (Preparation 487) and 6-chloro-N,N-dimethylpyrimidin-4-amine, following a similar procedure to that described in Example 226. rep-HPLC (Method R, Gradient 29-59%) (12.0 mg, 9.8% yield) as a white solid. LCMS m/z = 415.1 [M+H] ⁺ 1H NMR (400 MHz, CDCh) 6 ppm: 12.84 (s, 1H), 9.36 (s, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.52 (d, J=5.6 Hz, 1H), 7.93 (s, 1H), 6.87 (d, J=6.0 Hz, 1H), 6.73 (s, 1H), 3.21 (s, 6H), 2.25 (s, 3H), 2.14-2.23 (t, J=18.8 Hz, 3H).

Example 257 and 258

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-(2-methoxyethyl)-lH- pyrazol-3-yl)pyridin-2-yl)acetamide and N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)-5-(l-(2-methoxyethyl)-lH-pyrazol-5-yl)pyridin-2-yl )acetamide

To a solution of (6-acetamido-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)pyri din-3 -yl)boronic acid (Preparation 488, 400 mg, crude) in dioxane (3 mL) and water (0.6 mL) was added Pd(dppf)C12 DCM (23.26 mg, 28.5 umol), K2CO3 (118.09 mg, 0.854 mmol), 3-bromo-l-(2-methoxymethyl)-lH-pyrazole (116.80 mg, 0.57 mmol) and the mixture was stirred at 90 °C for 2 h under N2. The mixture was concentrated and purified by Prep-HPLC (Method R, Gradient 35-65%) to give N-(4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)-5-(l-(2-methoxyethyl)-lH-pyrazol -3-yl)pyridin-2-yl)acetamide (20 mg, 16.3% yield) as a white solid. LCMS m/z = 432.2 [M+H] ⁺ 'H NMR (400 MHz, CDCL) 8: ppm 8.95 (s, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.45 (s, 1H), 6.75 (s, 1H), 6.29 (d, J=1.6 Hz, 1H), 4.09 (t, ./=5,2 Hz, 2H), 3.82 ( s, 2H), 3.31 (s, 3H), 2.51 (s, 3H), 2.25 (s, 3H), 2.08 (t, J=18.4 Hz, 3H). and N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(l-(2-methoxyethyl)-lH- pyrazol-5-yl)pyridin-2-yl)acetamide (18 mg, 14.7% yield) as a grey solid. LCMS m/z = 432.2 [M+H] ^{+ X} H NMR (400 MHz, CDCL) 6: ppm 11.34 (s, 1H), 9.28 (s, 1H), 8.48 (s, 1H), 7.94 ( s, 1H), 7.57 (d, ./=2,4 Hz, 1H), 6.79 (s, 1H), 6.64 (d, J=2.Q Hz, 1H), 4.40 (t, =5.0 Hz, 2H), 3.85 (t, J=5.0 Hz, 2H), 3.38 (s, 3H), 2.55 (s, 3H), 2.06-2.28 (m, 6H).

Example 259 and 260

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-(2-methoxyethyl)-lH- l,2,3-triazol-4-yl)pyridin-2-yl)acetamide and N-(4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)-5-(2-(2-methoxyethyl)-2H-l,2,3-t riazol-4-yl)pyridin-2- yl)acetamide

To a solution of (6-acetamido-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)pyri din-3 -yl)boronic acid (Preparation 488, 150 mg, 0.43 mmol) in dioxane (3 mL) and H2O (0.6 mL) was added a mixture of 4-bromo-2-(2-methoxyethyl)-2H- 1,2, 3 -triazole and 4-bromo-l-(2-methoxyethyl)-lH-l,2,3-triazole (Preparation 290, 105.6 mg, 0.51 mmol), K2CO3 (118 mg, 0.85 mmol), Pd(dppf)C12.DCM (34.9 mg, 0.043 mmol) and the resulting mixture stirred at 100 °C for 3 h under N2. The mixture was evaporated to dryness and the residue purified by prep-HPLC (Method R, Gradient 28-58%) to give the title compounds. The structures were determined by 2D NMR.

Peak 1, Example 259. N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(l-(2- methoxyethyl)-lH-l,2,3-triazol-4-yl)pyridin-2-yl)acetamide as a white solid ,6.6 mg, 3.6%. LCMS m/z = 433.1 [M+H] ⁺ ; 'H NMR (400 MHz, CDCh) 8 ppm: 11.69 (s, 1H), 9.67 (s, 1H), 9.08 (br s, 1H), 8.36 (s, 1H), 8.11 (s, 1H), 6.87 (s, 1H), 4.66 (t, J=4.8 Hz, 2H), 3.83 (t, J=4.8 Hz, 2H), 3.41 (s, 3H), 2.56 (s, 3H), 2.28 (s, 3H), 2.20 (t, J=18.8 Hz, 3H).

Peak 2, Example 260. N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(2-(2- methoxyethyl)-2H- 1,2, 3 -triazol -4-yl)pyri din-2 -yl)acetamide as a white solid, 35 mg, 19%. LCMS m/z = 433.2 [M+H] ⁺ ; 'H NMR (400 MHz, CDCh) 6 ppm: 10.73 (br s, 1H), 9.59 (s, 1H), 8.42 (s, 1H), 7.98 (s, 1H), 6.87 (s, 1H), 4.75 (t, J=4.8 Hz, 2H), 3.98 (t, J=4.8 Hz, 2H), 3.40 (s, 3H), 2.60 (s, 3H), 2.31 (s, 3H), 2.18 (t, J=18.8 Hz, 3H).

Example 261 and 262

N-(4-((2-(l, l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(2-methox yethyl)-2H- 1,2,3- triazol -4-yl)pyridin-2-yl)acetamide and N-(4-((2-(l, l-difluoroethyl)-6-ethylpyrimidin-4- yl)amino)-5-(l-(2-methoxyethyl)-lH-l,2,3-triazol-4-yl)pyridi n-2-yl)acetamide

The title compounds were prepared from (6-acetamido-4-((2-(l,l-difluoroethyl)-6- ethylpyrimidin-4-yl)amino)pyri din-3 -yl)boronic acid (Preparation 490) using an analogous method to that described for Example 259 and 260. The structures were determined by 2D NMR.

Peak 1, Example 261. N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5- (2-(2- methoxyethyl)-2H- 1,2, 3 -triazol -4-yl)pyri din-2 -yl)acetamide LCMS m/z = 447.2 [M+H] ⁺ ; 'H NMR (500 MHz, CDCh) 6 ppm: 10.33 (s, 1H), 9.24 (s, 1H), 8.50 (s, 1H), 7.96 (s, 2H), 6.87 (s, 1H), 4.73 (t, J=5.5 Hz, 2H), 3.98 (t, J=5.5 Hz, 2H), 3.39 (s, 3H), 2.83 (q, J=6.4 Hz, 2H), 2.24 (s, 3H), 2.16 (t, J=19.0 Hz, 3H), 1.35 (t, J=8.0 Hz, 3H).

Peak 2, Example 262. N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5- (l-(2- methoxyethyl)-lH-l,2,3-triazol-4-yl)pyridin-2-yl)acetamide. LCMS m/z = 447.2 [M+H] ⁺ ; 'H NMR (500 MHz, CDCh) 6 ppm: 11.36 (s, 1H), 9.49 (s, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 6.82 (s, 1H), 4.64 (t, J=5.0 Hz, 2H), 3.83 (t, J=5.0 Hz, 2H), 3.41 (s, 3H), 2.81 (q, J=7.5 Hz, 2H), 2.24 (s, 3H), 2.20 (t, J=18.5 Hz, 3H), 1.33 (t, J=7.5 Hz, 3H).

Example 263

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(l-(2-methoxyethyl)-lH- l,2,4-triazol-3-yl)pyridin-2-yl)acetamide

To a solution of (6-acetamido-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)pyri din-3 -yl)boronic acid (Preparation 488, 100 mg, 0.285 mmol) in dioxane (5 mL) and H2O (1 mL) was added 3-bromo-l-(2-methoxyethyl)-lH-l,2,4-triazole (Preparation 291, 117.4 mg, 0.57 mmol), Pd(dppf)Cl ₂ DCM (23.3 mg, 28.5 umol) and K3PO4 (120.9 mg, 0.57 mmol) and the reaction mixture was stirred at 100 °C for 16 h under N2. The mixture was concentrated and was purified by Prep-HPLC (Method M, Gradient 19-39%) to give N- (4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-( l -(2 -methoxy ethyl)- 1H-1, 2,4- triazol-3-yl)pyridin-2-yl)acetamide (18 mg, 14.6% yield) as a yellow solid. LCMS m/z = 433.1 [M+H] ⁺ 'H NMR (400 MHz, CDCh) 8: ppm 11.37 (s, 1H), 9.38 (s, 1H), 9.03 (s, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 6.81 (s, 1H), 4.43 (t, J= 4.8 Hz, 2H), 3.81 (t, J= 4.8 Hz, 2H), 3.38 (s, 3H), 2.55 (s, 3H), 2.15-2.24 (m, 6H).

Example 264

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(6-(2-methoxypropan-2- yl)pyrimidin-4-yl)pyridin-2-yl)acetamide N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(6-(2-methoxypropan-2- yl)pyrimidin-4-yl)pyridin-2-yl)acetamide was obtained as a white solid, 24.1 mg, 9.25%, from (6-acetamido-4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyri din-3 -yl)boronic acid (Preparation 488) and 4-chloro-6-(2-methoxypropan-2-yl)pyrimidine (Example 14, EP3036232B1), following a similar procedure to that described in Example 263. LCMS m/z = 458.1 [M+H] ⁺ 'H NMR (400 MHz, DMSO-r/6) 8 ppm: 11.90 (s, 1H), 10.73 (s, 1H), 9.28 (s, 1H), 9.11 (d, J=4.8 Hz, 1H), 8.86 (s, 1H), 7.99 (s, 1H), 7.05 (s, 1H), 3.12 (s, 3H), 2.42 (s, 3H), 2.14 (s, 3H), 2.02 (t, J=19.6 Hz, 3H), 1.47 (s, 6H).

Example 265 N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((diflu oromethoxy)methyl)-[2,3'- bipyridin]-6'-yl)acetamide

A mixture of N-(4-((2-(l, l-difhioroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (Preparation 486, 125 mg, 0.179 mmol), 2-chloro-5-(difluoromethoxymethyl)pyrazine (Preparation 286, 52 mg, 0.268 mmol), Pd(PCys)2 (11 mg, 17 pmol) and aq. K2CO3 (2 M, 536.7 pmol, 0.268 mL) in dioxane (2 mL) was heated at 100°C for 2h. The cooled mixture was filtered, the filtrate diluted with EtOAc, washed with water and brine. The organic layer was dried and concentrated and the crude product purified by HPLC (Method LT, Gradient 5-95%) to give N-(4'-((2-(l,l- difhjoroethyl)pyrimidin-4-yl)amino)-5-((difluoromethoxy)meth yl)-[2,3'-bipyridin]-6'- yl)acetamide (13 mg, 16% yield). LCMS m/z = 451 [M+H]+

Example 266

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-5-((dimethylamino)methyl)-[2,3'- bipyridin]-6'-yl)acetamide A mixture of N-(4-((2-(l, l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (Preparation 491, 100 mg, 0.224 mmol), l-(6-bromo-3-pyridyl)-N,N-dimethyl-methanamine (68.24 mg, 0.317 mmol), K2CO3 (100 mg, 724 mmol), XPhos Pd(crotyl)Cl (10.00 mg, 14.8 pmol), dioxane (1 mL) and water (1 mL) was sealed and heated to 90 °C for 20 h. The cooled mixture was diluted with water (3 mL) and extracted with EtOAc (3 x 3 mL) and the combined organic extracts concentrated to dryness. The crude was purified by HPLC (Method U, Gradient 5-95%) to give N-(4'-((2- (l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-((dimethy lamino)methyl)-[2,3'- bipyridin]-6'-yl)acetamide (37.7 mg, 37% yield). LCMS m/z = 456.2 [M+H] ⁺ . ^NMR (600 MHz, DMSO-de) 8 (ppm) = 12.86 (s, 1H), 10.54 (s, 1H), 9.24 (s, 1H), 8.80 (s, 1H), 8.72 (d, J = 1.9 Hz, 1H), 8.07 (d, J= 8.4 Hz, 1H), 7.94 - 7.82 (m, 1H), 7.11 (s, 1H), 3.51 (br s, 2H), 2.71 (d, J= 7.6 Hz, 2H), 2.21 (s, 6H), 2.16 - 2.05 (m, 6H), 1.25 (s, 3H).

Example 267

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-5-morpholino-[2,3'-bipyridin]-6'- yl)acetamide

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-5-morpholino-[2,3'-bipyridin]-6'- yl)acetamide was obtained, 120 mg, 89%, from N-(4-((2-(l,l-difluoroethyl)-6- ethylpyrimidin-4-yl)amino)-5-(4,4,5,5-tetramethyl-l,3,2-diox aborolan-2-yl)pyridin-2- yl)acetamide (Preparation 491) and 4-(6-bromo-3-pyridyl)morpholine, following a similar procedure to that described in Example 266. LCMS m/z = 485 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ) 6 (ppm) = 12.93 (s, 1H), 10.48 (s, 1H), 9.23 (s, 1H), 8.72 (s, 1H), 8.50 (d, J= 2.7 Hz, 1H), 7.97 (d, J= 9.2 Hz, 1H), 7.57 (dd, J= 3.1, 9.2 Hz, 1H), 7.05 (s, 1H), 3.84 - 3.77 (m, 4H), 3.31 - 3.25 (m, 4H), 2.71 (q, J= 7.6 Hz, 2H), 2.17 - 2.05 (m, 6H), 1.26 (t, J = 7.6 Hz,

3H).

Example 268

N-(4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino )-5-(morpholinomethyl)-[2,3'- bipyridin]-6'-yl)acetamide

A mixture of 2-chloro-5-(chloromethyl)pyridine (32 mg, 0.20 mmol), K2CO3 (83 mg, 0.60 mmol), 2-MeTHF (2.0 mL), morpholine (26 mg, 0.30 mmol), DMSO (0.25 mL) and DIPEA (26 mg, 0.20 mmol) was stirred for 20 h at 50 °C. The reaction was concentrated to remove solvent, then N-(4-((2-(l, l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (Preparation 491, 45 mg, 0.10 mmol) and XPhos Pd(crotyl)Cl (7 mg, 10 mmol) were added followed by 2-MeTHF (2.0 mL) and water (1.0 mL). The reaction was heated to 90 °C for 20 h, then diluted with water (3 mL) and extracted with 3: 1 EtOAc:EtOH (3 x 3 mL). The combined organic layers were concentrated to dryness and purified via prep-HPLC (Method U, Gradient 5-95%) to give N- (4'-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-( morpholinomethyl)-[2,3'- bipyridin]-6'-yl)acetamide (10 mg, 20.11% yield). LCMS m/z = 498.2 (M+H) ⁺ . 'H NMR (500 MHz, DMSO-d ₆ ) 8 (ppm) = 12.83 (s, 1H), 12.18 - 11.62 (m, 1H), 10.55 (s, 1H), 9.24 (s, 1H), 8.80 (s, 1H), 8.73 (s, 1H), 8.08 (d, J= 8.2 Hz, 1H), 7.91 (dd, J = 2.0, 8.4 Hz, 1H), 7.12 (s, 1H), 3.60 (br t, J = 4.3 Hz, 4H), 3.58 (s, 2H), 2.46 - 2.38 (m, 4H), 2.17 - 2.03 (m, 9H).

Example 269 N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5- (6-(2-methoxyethoxy)pyridazin- 3-yl)pyridin-2-yl)acetamide trifluoroacetate

A mixture of 3,6-dichloropyridazine (65 mg, 0.436 mmol), 2-methoxyethanol (65 mg, 0.854 mmol, 67.36 pL), 2-MeTHF (3 mL) and NaH (35 mg, 0.875 mmol, 60% purity) while stirring at rt. After 10 mins, the mixture was centrifuged, then mother liquor, clear solvent was passed through a syringe filter into another 8 mL vial. To this reaction mixture was added N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5- (4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (Preparation 491, 100 mg, 0.223 mmol), K2CO3 (154.5 mg, 1.12 mmol), XPhos Pd(crotyl)Cl (7 mg, 10.4 pmol) and water (2 mL) . This reaction mixture was sealed and heated to 90 °C overnight, then diluted with 5 mL water and extracted 3 x 10 mL 3 EtOAc. The combined organic layers were concentrated to dryness and purified via prep-HPLC (Method V, Gradient 5-95%) to give N-(4-((2-(l,l- difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(6-(2-methoxye thoxy)pyridazin-3-yl)pyridin- 2-yl)acetamide (69.3 mg, 66% yield). LCMS m/z = 474.2 [M+H] ⁺ . ^X H NMR (600 MHz, DMSO-de) 6 (ppm) = 11.41 (s, 1H), 10.64 (s, 1H), 9.01 (s, 1H), 8.67 (s, 1H), 8.19 (d, J= 9.5 Hz, 1H), 7.41 (d, J= 9.2 Hz, 1H), 6.96 (s, 1H), 4.67 - 4.60 (m, 2H), 3.79 - 3.72 (m, 2H), 3.34 (s, 3H), 2.70 (q, J= 7.6 Hz, 2H), 2.14 (s, 3H), 2.04 (t, J= 19.3 Hz, 3H), 1.23 (t, J= 7.6 Hz, 3H).

Example 270

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(pyrimidin-4-yl)pyri din-2- yl)acetamide

A vial containing N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (Preparation 486, 448 mg, 1.0 mmol), 4-chloropyrimidine hydrochloride (240 mg, 1.6 mmol), PCy3-Pd-G3 (90 mg, 0.123 mmol), and KO Ac (1.5 M, 2.1 mL) in dioxane (5 mL) was degassed then backfilled with N2 then heated at 95 °C 20 h. The cooled mixture was loaded onto a silica gel column and purified eluting with (20-70 % 3: 1 EtOAc:EtOH in heptane) The desired fractions were combined and concentrated under reduced pressure to afford an off-white solid that was suspended in EtOH and heated on the rotovap to 60 °C. After 15 mins, the heterogeneous solution was filtered to afford N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(pyrimidin-4- yl)pyridin-2-yl)acetamide as an off-white solid (53 mg, 13% yield). LCMS m/z = 386.1 [M+ H] ⁺ . 'H NMR (500 MHz, DMSO-d ₆ ) 6 (ppm) = 12.28 (s, 1H), 10.67 (s, 1H), 9.32 (d, J = 1.2 Hz, 1H), 9.25 (s, 1H), 8.90 - 8.86 (m, 2H), 8.16 (dd, J = 1.2, 5.8 Hz, 1H), 7.12 (s, 1H), 2.44 (s, 3H), 2.14 (s, 3H), 2.07 (t, J = 19.2 Hz, 3H).

Example 271 N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(2-(dimethylamino)thiazol-4- yl)pyridin-2-yl)acetamide

To a solution of 4-bromo-N,N-dimethylthiazol-2-amine (Preparation 302, 100 mg, 0.483 mmol) in H2O (0.8 mL), MeOH (4 mL) and toluene (4 mL) was added N-(5-bromo-4-((2-(l,l- difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)ace tamide (Preparation 483, 186.5 mg, 0.483 mmol), (BPin)2 (245.2 mg, 0.967 mmol), CsF (440.1 mg, 2.90 mmol), cataCXium® A (69.3 mg, 0.193 mmol) and Pd(OAc)2 (21.7 mg, 0.096 mmol). The resulting mixture was stirred at 100 °C for 16 h under N2. The mixture was concentrated and purified by Prep-HPLC (Method K, Gradient 63-93%) to give N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)-5-(2-(dimethylamino)thiazol-4-yl)pyridin-2-yl)acet amide (7 mg, 3.3% yield) as a white solid. LCMS m/z = 434.1 [M+H] ⁺ 'H NMR (400 MHz, CDCh) 8 ppm: 12.38 (s, 1H), 9.39 (s, 1H), 8.26 (s, 1H), 6.89 (s, 1H), 6.77 (s, 1H), 3.27 (s, 6H), 2.59 (s, 3H), 2.33 (s, 3H), 2.13 (t, ./= I 8,8 Hz, 3H).

Examples 272 to 275

The compounds in the following table were prepared from N-(5-bromo-4-((2-(l,l- difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)ace tamide (Preparation 483) or N- (5-bromo-4-((2-(l,l -difluoroethyl )pyrimidin-4-yl)amino)pyridin-2-yl)acetamide (Preparation 484) and the appropriate halide, following a similar procedure to that described in Example 270.

Example 276

N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(dim ethylamino)-[2,3'-bipyridin]-6'- yl)acetamide

H2O (0.2 mL), MeOH (0.8 mL) and THF (0.8 mL) were added to a mixture of N-(5-bromo-4- ((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)ace tamide (Preparation 484, 55 mg, 0.15 mmol), (BPin)2 (76 mg, 0.30 mmol), 6-bromo-N,N-dimethylpyridin-3-amine (30 mg, 0.15 mmol), CsF (136 mg, 0.90 mmol), bis(l-adamantyl)-butyl-phosphane (32 mg, 0.090 mmol) and Pd(0Ac)2 (16 mg, 0.075 mmol). The resulting mixture was stirred at 100 °C for 1.5 h. The cooled reaction was diluted with EtOAc, washed with water and concentrated in vacuo. The residue was purified by HPLC to afford N-(4-((2-(l, l-difhioroethyl)-6- methylpyrimidin-4-yl)amino)-5-(l-ethyl-lH-pyrazol-3-yl)pyrid in-2-yl)acetamide (1.6 mg, 2.5% yield) as a white powder. LCMS m/z = 414 [M+H] ⁺ Example 277 N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(5-methyl-4,5,6,7-tetrahydro-

2H-pyrazolo[4,3-c]pyridin-2-yl)pyridin-2-yl)acetamide

5-Methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine (20 mg, 0.146 mmol) was added to a solution of N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (Preparation 486, 69.5 mg, 0.16 mmol), CU(OAC)2 (29.3 mg, 0.160 mmol) and DMAP (35.6 mg, 0.292 mmol) in MeCN (1.1 mL). The reaction mixture was stirred overnight at rt open to air. Additional Cu(OAc)2 (29.13 mg, 0.160 mmol) was added and the reaction mixture was heated at 40°C for 8 h. The cooled reaction mixture was filtered through Celite®, evaporated and purified by HPLC (Method U, Gradient 5-95%) to afford N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(5- methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pyr idin-2-yl)acetamide (3.1 mg, 4.81% yield). LCMS m/z = 443.2 [M+H] ⁺

Examples 278 and 279

(R)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)a mino)-5-(tetrahydrofuran-2- yl)pyridin-2-yl)acetamide and (S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)-5-(tetrahydrofuran-2-yl)pyridin-2-yl)acetamide

A vial containing N-(5-bromo-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide (Preparation 483, 325 mg, 0.842 mmol), tetrahydrofuran-2- carboxylic acid (0.13 mL, 1.35 mmol), Ir[dF(CF3)ppy]2(dtbpy)PFe (19 mg, 17 umol), and NiBr2(dtbbpy) (26 mg, 45 umol) was taken into an inert glovebox, then 2-tert-butyl- 1,1,3,3-tetramethyl-guanidine (0.26 mL, 1.29 mmol) and DMF (8 mL) were added. The vial was capped under a positive pressure of inert gas then sealed with electrical tape. The sealed vial was placed in a photoreactor and vigorously stirred at 23 °C with LED power set to 75%. After 20 h, the mixture was diluted with water and extracted with EtOAc (3 x). The combined organics were dried (NazSCM), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40-100 % EtOAc in heptane) and the product further purified by HPLC (Method U, Gradient 5-60%), to afford a colorless film as N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 - (tetrahydrofuran-2-yl)pyridin-2-yl)acetamide (31 mg, 8 % yield). This was further purified by SFC (Chiralpak IC 30 x 250mm, 5um column eluting with 30% EtOH with 0.1% DEA modifier at 100 mL/min; MB PR 40 psi, column temperature 40°C to afford, the following compounds that were concentrated to dryness then lyophilized:

Peak 1, (R)-N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(tetrahydro furan- 2-yl)pyridin-2-yl)acetamide or (S)-N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)-5-(tetrahydrofuran-2-yl)pyridin-2-yl)acetamide (7 mg, 21% yield). LCMS m/z = 378.1 [M+H] ⁺ . ^X H NMR (400 MHz, DMSO-d ₆ ) 8 (ppm) = 10.44 (s, 1H), 9.17 (s, 1H), 8.60 (s, 1H), 8.22 (s, 1H), 6.92 (s, 1H), 5.06 - 5.00 (m, 1H), 4.09 - 4.03 (m, 1H), 3.84 - 3.77 (m, 1H), 2.39 (s, 3H), 2.31 - 2.24 (m, 1H), 2.07 (s, 3H), 2.04 - 1.94 (m, 5H), 1.74 - 1.64 (m, 1H).

And Peak 2, (S)-N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amin o)-5- (tetrahydrofuran-2-yl)pyri din-2 -yl)acetamide or (R)-N-(4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)-5-(tetrahydrofuran-2-yl)pyridin- 2-yl)acetamide (6 mg, 18 % yield). LCMS m/z = 378.1 (M+H) ⁺ . 'H NMR (400 MHz, DMSO-d ₆ ) 6 (ppm) = 10.44 (s, 1H), 9.17 (s, 1H), 8.60 (s, 1H), 8.22 (s, 1H), 6.92 (s, 1H), 5.05 - 5.00 (m, 1H), 4.09 - 4.03 (m, 1H), 3.84 - 3.78 (m, 1H), 2.39 (s, 3H), 2.31 - 2.23 (m, 1H), 2.07 (s, 3H), 2.05 - 1.93 (m, 5H), 1.72 - 1.65 (m, 1H).

Example 280

N-(4'-((2-(2-oxabicyclo[2.1. l]hexan-l-yl)-6-methylpyrimidin-4-yl)amino)-5- (methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide

A mixture of N-(2-(2-oxabicyclo[2.1. l]hexan-l-yl)-6-methylpyrimidin-4-yl)-6'-chloro-5- (methoxymethyl)-[2,3'-bipyridin]-4'-amine (Preparation 504, 85 mg, 0.2 mmol), acetamide (59.22 mg, 1.0 mmol), CS2CO3 (131 mg, 0.401 mmol) and BrettPhos Pd G3 (18 mg, 20 pmol) in dioxane (2 mL) was heated at 100°C for Ih. The cooled mixture was filtered, the filtrate concentrated and the residue purified by chromatography on silica gel (0- 100%EtOAc-EtOH 3 : 1 with 2%NH ₄ OH in heptane) to give N-(4'-((2-(2- oxabicyclo[2.1. l]hexan-l-yl)-6-methylpyrimidin-4-yl)amino)-5-(methoxymethyl )-[2,3'- bipyridin]-6'-yl)acetamide (58 mg, 64% yield) as a white solid. LCMS m/z = 447 [M+H] ⁺ . 'H NMR (MeOH-d ₄ , 400 MHz) 8 9.3-9.5 (m, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 7.9-8.0 (m, 2H), 6.82 (d, 1H, ./=0,8 Hz), 4.57 (s, 2H), 3.97 (s, 2H), 3.46 (s, 3H), 3.05 (t, 1H, =3.3 Hz), 2.58 (ddd, 2H, J=1.9, 3.1, 4.6 Hz), 2.45 (s, 3H), 2.22 (s, 3H), 1.85 (dd, 2H, J=1.8, 4.8 Hz).

Example 281

N-(4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl)amino) -5-(3-methyl-l,2,4-oxadiazol-5- yl)pyridin-2-yl)acetamide

To a solution of 6-acetamido-4-((2-(l,l-difluoroethyl)-6-ethylpyrimidin-4-yl) amino)nicotinic acid (Preparation 494, 100 mg, 0.274 mmol) in DMF (3 m ) was added HATU (104.1 mg, 0.274 mmol) and TEA (83.1 mg, 0.821 mmol) and the solution stirred at rt for 3 h. (Z)-N'- Hydroxyacetimidamide (60.8 mg, 0.821 mmol) was added and the reaction mixture was stirred at 110 °C for 4 h. The mixture was purified by Prep-HPLC (Method B, 37-67%) to give N-(4-((2-( 1,1 -difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5 -(3 -methyl- 1,2, 4-oxadiazol- 5-yl)pyridin-2-yl)acetamide (46.3 mg, 41.9% yield) as a white solid. LCMS m/z = 404.1 [M+H] ⁺ 1H NMR (500 MHz, CDCh) 6 ppm : 11.02 (s, 1H), 9.56 (s, 1H), 8.93 (s, 1H), 8.11 (s, 1H), 6.80 (s, 1H), 2.86 (q, J=7.0 Hz, 2H), 2.56 (s, 3H), 2.27 (s, 3H), 2.19 (t, J=19.0 Hz, 3H), 1.36 (t, J=7.5 Hz, 3H).

Example 282

N-(4-((2-(l, l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide To a vial containing tert-butyl 2-(6-acetamido-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4 - yl)amino)pyridin-3-yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5( 4H)-carboxylate

(Preparation 514, 100 mg, 0.189 mmol) in DCM (1 mL) was added TFA (0.15 mL, 2 mmol) and the reaction was stirred at 23 °C for 3 days. The reaction mixture was loaded onto a silica gel column and purified eluting with (20-100 % EtOAc with 2% dimethyl ethylamine in heptane then 100% 3 : 1 EtOAc: EtOH). The product was further purified by HPLC (Method U, Gradient 5-50%) to give N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 - (4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl) acetamide as a white solid (46 mg, 54 % yield). LCMS m/z = 429.2 [M+H] ⁺ . 'H NMR (500 MHz, DMSO-d ₆ ) 8 (ppm) = 11.57 (s, 1H), 10.43 (s, 1H), 9.33 (s, 1H), 8.63 (s, 1H), 7.03 (s, 1H), 6.67 (s, 1H), 4.19 (t, J = 5.5 Hz, 2H), 3.97 (s, 2H), 3.19 (t, J = 5.5 Hz, 2H), 2.98 - 2.67 (m, 1H), 2.46 (s, 3H), 2.18 - 2.10 (m, 6H).

Example 283

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-ethyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide

To a suspension of N-(4-((2-(l,l-difhioroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide (Example 282, 40 mg, 0.093 mmol) in MeOH (1 mL) was added acetaldehyde (4.11 mg, 93.4 pmol) followed by NaBHsCN (1 M, 0.187 mmol, 0.187 mL) in THF and the reaction was stirred at rt for 1 h. The mixture was concentrated in vacuo and the residue purified by silica gel chromatography (0-5% MeOH in DCM) to give N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(5-ethyl- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyridin-2-yl)a cetamide as a white solid (22.8 mg, 50.8% yield). LCMS m/z = 457.4 [M+H] ⁺ 1H NMR (500 MHz, CDCh) 6 ppm 11.35 (s, 1H), 9.35 (br s, 1H), 8.45 (s, 1H), 7.86 (s, 1H), 6.74 (s, 1H), 6.39 (s, 1H), 4.32 (t, J=5.5 Hz, 2H), 3.76 (s, 2H), 3.02 (t, J=5.5 Hz, 2H), 2.69 (q, J=7.3 Hz, 2H), 2.55 (s, 3H), 2.16 - 2.27 (m, 6H), 1.22 (t, J=7.2 Hz, 3H).

Example 284

N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-me thyl-5,6-dihydro-4H-pyrrolo[3,4- d]thiazol-2-yl)pyridin-2-yl)acetamide

Step 1 : To a vial was added tert-butyl 2-(6-acetamido-4-((2-(l,l-difluoroethyl)pyrimidin-4- yl)amino)pyridin-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole -5-carboxylate (Preparation 515, 100 mg, 0.193 mmol), DCM (12.39 pL) and TFA (14.80 pL) and the reaction mixture was stirred at rt overnight. The organic layer was dried over Na2SO4 and solvent removed in vacuo to give N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5,6-dih ydro-4H- pyrrolo[3,4-d]thiazol-2-yl)pyridin-2-yl)acetamide.

Step 2: A mixture of N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5,6-dih ydro-4H- pyrrolo[3,4-d]thiazol-2-yl)pyridin-2-yl)acetamide (80 mg, 0.192 mmol), formaldehyde (155.5 mg, 1.92 mmol), MeOH (1.48 mL) and TEA (38.79 mg, 0.383 mmol) was stirred for 30 mins at rt. NaBH(OAc)3 (203.1 mg, 0.958 mmol) and AcOH (34.53 mg, 575 mmol) were added and the reaction mixture was stirred at rt overnight. The organic layer was dried over ISfeSCh and solvent removed in vacuo. The crude product was purified by HPLC (Method U, Gradient 5-95%) to give N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methy l-5,6- dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)pyridin-2-yl)acetamide .

Example 285

N-(5-(5-(cyanomethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]py ridin-2-yl)-4-((2-(l,l- difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyri din-2 -yl)acetamide

To a solution of N-(4-((2-(l,l-difhioroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(4, 5,6,7- tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyridin-2-yl)acetamide hydrochloride (Preparation 519, 50 mg, 0.11 mmol) in MeCN (3 mL) was added K2CO3 (31 mg, 0.22 mmol) and bromoacetonitrile (80.8 mg, 0.67 mmol) and the mixture stirred at 25 °C for 16 h. The reaction was quenched by the addition of saturated aqueous NH4CI solution (20 mL) at 0 °C and evaporated to dryness under reduced pressure. The residue was purified by prep-HPLC (Method R, Gradient 37-67%) to give N-(5-(5-(cyanomethyl)-4,5,6,7-tetrahydrothiazolo[5,4- c]pyridin-2-yl)-4-((2-(l, 1 -difluoroethyl )-6-m ethyl pyrimidin-4-yl)amino)pyridin-2- yl)acetamide as a white solid (12.8 mg, 23%). LCMS m/z = 485.2 [M+H] ⁺ ; ^NMR (500 MHz, CDCh) 6 ppm: 12.32 (s, 1H), 9.56 (s, 1H), 8.53 (s, 1H), 8.38 (br s, 1H), 6.70 (s, 1H), 3.93 (s, 2H), 3.80 (s, 2H), 3.09-3.06 (m, 4H), 2.57 (s, 3H), 2.26 (s, 3H), 2.20 (t, J=19.0 Hz, 3H).

Example 286

N-(5-(5-cyanopyridazin-3-yl)-4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4- yl)amino)pyridin-2-yl)acetamide

Step 1 : To a solution of (6-acetamido-4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4- yl)amino)pyri din-3 -yl)boronic acid (Preparation 488, 200 mg, 0.57 mmol) in dioxane (5 mL) and H2O (1 mL) was added 3,5-dichloropyridazine (170 mg, 1.14 mmol), Pd(dppf)C12.DCM (46.5 mg, 0.057 mmol) and K3PO4 (242 mg, 1.14 mmol) and the mixture stirred at 100 °C for 6 h under N2. The mixture was concentrated and the residue purified by chromatography on silica gel (100% EtOAc) to give N-(5-(5-chloropyridazin-3-yl)-4-((2-(l,l-difluoroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide as a yellow solid (50 mg, 21%). 'H NMR (400 MHz, CDCh) 8 ppm: 12.31 (s, 1H), 9.53 (s, 1H), 9.14 (s, 1H), 8.52 (s, 1H), 8.04 (s, 1H), 8.01 (d, J=2.0 Hz, 1H), 6.81 (s, 1H), 2.54 (s, 3H), 2.14-2.26 (m, 6H).

Step 2. To a solution of N-(5-(5-chloropyridazin-3-yl)-4-((2-(l,l-difhioroethyl)-6- methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide (Step 1, 30 mg, 0.071 mmol) in DMF (1 mL) was added dppf (7.92 mg, 0.014 mmol), Pd2(dba)3 (6.54 mg, 0.072 mmol), Zn (4.67 mg, 0.071 mmol), Zn(CN)2 (25.2 mg, 0.214 mmol) and the mixture stirred in the microwave at 130 °C for 2 h under N2. The reaction mixture was concentrated and the residue purified by prep-HPLC (Method R, Gradient 26-56%) to give N-(5-(5-cyanopyridazin-3-yl)-4-((2-(l,l- difhioroethyl)-6-methylpyrimidin-4-yl)amino)pyri din-2 -yl)acetamide as a yellow solid (15 mg, 51%). LCMS m/z = 411.2 [M+H] ⁺ ; 'H NMR (400 MHz, CDCh) 6 ppm: 12.06 (s, 1H), 9.53 (s, 1H), 9.30 (d, J=1.6 Hz, 1H), 8.55 (s, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 6.83 (s, 1H), 2.55 (s, 3H), 2.27 (s, 3H), 2.18 (t, J=19.2 Hz, 3H).

Example 287

N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino )-5-(5-((dimethylamino)methyl)- 1 -methyl- lH-pyrazol-3-yl)pyridin-2-yl)acetamide

To a solution of N-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(5-formyl-l- methyl-lH-pyrazol-3-yl)pyridin-2-yl)acetamide (Preparation 509, 25 mg, 0.060 mmol) in MeOH (2 mL) was added Me ₂ NH.HCl (5.4 mg, 0.066 mmol) and NaBH ₃ CN (18.9 mg, 0.300 mmol) and the mixture stirred at 70 °C for 16 h. The reaction mixture was concentrated and the residue purified by prep-HPLC (Method D, Gradient 0-30%) to give N-(4-((2-(l,l- difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-((dimethyl amino)methyl)-l-methyl-lH- pyrazol-3-yl)pyridin-2-yl)acetamide as a white solid (10 mg, 37%). LCMS m/z = 445.2 [M+H] ⁺ ; ^X H NMR (500 MHz, DMSO-d ₆ ) 6 ppm: 11.54 (s, 1H), 10.43 (s, 1H), 9.32 (s, 1H), 8.65 (s, 1H), 7.05 (s, 1H), 6.85 (s, 1H), 3.99 (s, 3H), 3.52 (s, 2H), 2.46 (s, 3H), 2.21-2.11 (m, 12H).

Example 288 l-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(l-methyl-lH-pyrazol-3- yl)pyridin-2-yl)urea

To a solution of N-(2-chloro-5-(l-methyl-lH-pyrazol-3-yl)pyridin-4-yl)-2-(l,l - difhioroethyl)-6-methylpyrimidin-4-amine (Preparation 501, 150 mg, 0.411 mmol) in dioxane (5 mL) was added urea (123.5 mg, 2.06 mmol), BrettPhos Pd G ₃ (37.28 mg, 0.041 mmol) and K PO4 (174.6 mg, 0.822 mmol) at 25 °C. The mixture was stirred at 100 °C for 16 h under N2. The mixture was concentrated and purified by /c -HPLC (Column: Phenomenex C18 150*25mm*10pm; Condition: water (NH4HCO ₃ )-ACN; B%: 16%-46%, 10 min) to give l-(4-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5 -(l-methyl-lH- pyrazol-3-yl)pyridin-2-yl)urea (10.7 mg, 6.70% yield) as a white solid. LCMS m/z = 389.2 [M+H] ⁺ 1HNMR (400 MHz, DMSO-d ₆ ) 8 ppm 11.39 (s, 1H), 9.15 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.06 (s, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.59-6.85 (m, 2H), 4.02 (s, 3H), 2.46 (s, 3H), 2.12 (t, J = 19.2 Hz, 3H). Examples 289 to 290

The compounds in the following table were prepared from the appropriate chloride and urea, following a similar procedure to that described in Example 289. Example 291 l-(4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)- 5-fluoro-[2,3'-bipyridin]-6'- yl)urea

To a solution of 6'-chloro-N-(2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)-5 -fluoro-[2,3'- bipyridin]-4'-amine (Preparation 503, 100 mg, 0.263 mmol) in DMF (3 mL) was added urea (79.1 mg, 1.32 mmol), K3PO4 (111.8 mg, 0.527 mmol) and BrettPhos Pd G3 (23.9 mg, 26.3 umol). The mixture was stirred at 90 °C of 1 h under N2 in microwave. The mixture was concentrated and was purified by Prep-HPLC (Method M, Gradient 20-50%) to give l-(4'- ((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-fluo ro-[2,3'-bipyridin]-6'-yl)urea (25 mg, 23.5% yield) as a yellow solid. LCMS m/z = 404.2 [M+H] ⁺ 'H NMR (400 MHz, DMSO-d ₆ ) 8: ppm 11.75 (s, 1H), 9.27 (s, 1H), 8.74 (d, J= 3.2 Hz, 1H), 8.59 (s, 1H), 8.53 (d, J= 4.8 Hz, 1H), 8.02-8.05 (m, 1H), 7.89-7.92 (m, 1H), 7.04 (s, 1H), 6.87 (brs, 2H), 2.41 (s, 3H), 2.06 (t, J= 19.2 Hz, 3H).

Example 292 l-(5-cyano-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl )amino)-[2,3'-bipyridin]-6'- l-(5-Cyano-4'-((2-(l,l-difluoroethyl)-6-methylpyrimidin-4-yl )amino)-[2,3'-bipyridin]-6'- yl)urea was obtained as a yellow solid, 10 mg, 7.9%, from 6'-chloro-4'-((2-(l,l- difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3'-bipyridin e]-5-carbonitrile (Preparation 502) and urea, following the procedure described in Example 292. LCMS m/z = 411.1 [M+H] ⁺ 'H NMR (400 MHz, DMSO-d ₆ ) 8 ppm: 11.86 (s, 1H), 9.36 (s, 1H), 9.15 (s, 1H), 8.72 (s, 1H), 8.60 (s, 1H), 8.40 (dd, J= 8.4 Hz, 2.0 Hz, 1H), 8.16 (d, =8.0 Hz, 1H), 7.07 (s, 1H), 6.86 (brs, 2H), 2.42 (s, 3H), 2.05 (t, J=19.2 Hz, 3H). Examples 293 to 519

The compounds in the table below were made using a similar process to the Examples described above.

Examples 520 to 922

The compounds in the table below were made using a similar process to the Examples described above.

BIOLOGICAL ASSAYS

Compounds of the disclosure were assessed for their ability to inhibit TYK2, JAK1 and JAK2 activity. The inhibitory properties of the compounds of the disclosure described herein can be evidenced by testing in any one of the following protocols.

JH2 biochemical assay

The inhibitory potency of compounds of the disclosure against the kinase activity of recombinantly generated JH2 domain of human Tyk2 was evaluated in a plate-based assay using a TR-FRET assay platform. Briefly, 2 nM of recombinant JH2 domain [lOxHis-tagged TYK2 JH2 domain (amino acid 575-876)] was combined with 2 nM probe ((S)-6-amino-9- (2-carboxy-4-((l-(3-(8-methyl-5-(methylamino)-8H-imidazo[4,5 -d]thiazolo[5,4-b]pyri din-2- yl)phenyl)ethyl)carbamoyl)phenyl)-3-iminio-5-sulfo-3H-xanthe ne-4-sulfonate), 0.1 nM Tb- labeled anti-His antibody, and compounds of disclosure for 60 minutes. Compounds are tested at either 10 pM or 1 pM top concentration, 10 points of 3-fold dilution. The TR-FRET signal inversely correlates to the amount of probe displaced by compounds and signal was calculated by taking the ratio of fluorescence at 520 nm and 495 nm. The data was normalized and the percent activity versus log concentration of compound was fitted with a 4-parameter logistic model to generate IC50 curves. pSTAT4 cell assay

The inhibitory potency of compounds of the disclosure against the Tyk2 kinase activity on STAT4 was evaluated using an MSD-platform plate-based assay format. NK92 cells natively expressing STAT4 and Tyk2 were serum-starved to reduce background phosphorylation levels, then cells were treated compounds for 1 hr with a 10-point four-fold dilution series starting at 10 pM. Cells were then stimulated with 30 ng/mL IL2 for 15 minutes. Cells were lysed and pSTAT5 levels were quantitated using an MSD plate-based assay with anti-STAT4 antibodies. The data were normalized and the percent activity versus log concentration of compound were fitted with a 4-parameter logistic model to generate to generate IC50 curves. pSTAT5 cell assay

Compounds of the disclosure were assessed for their ability to inhibit the JAK2 kinase activity on STAT5 utilizing an MSD-platform plate-based assay format. TF1 cells natively expressing STAT5 and JAK2 were serum-starved to reduce background phosphorylation levels, then cells were treated with compounds of disclosure for 1 hour with a 10-point fourfold dilution series starting at 10 pM. Cells were then stimulated with 30 ng/mL IL-3 for 15 minutes. Cells were then lysed and pSTAT5 levels were quantitated using an MSD platebased assay with anti-STAT5 antibodies. The data were normalized and the percent activity versus log concentration of compound was fitted with a 4-parameter logistic model to generate a curve and an IC50 value. pSTAT3 cell assay

The inhibitory potency of compounds of the disclosure against the JAK1 kinase activity on STAT3 was evaluated using an MSD-platform plate-based assay format. TF1 cells natively expressing STAT3 and JAK1 were serum-starved to reduce background phosphorylation levels, then cells were treated with compounds of the disclosure for 1 hour with a 10-point four-fold dilution series starting at 10 pM. Cells were then stimulated with 30 ng/mL interleukin 6 (IL-6) for 15 minutes. Cells were lysed and pSTAT3 levels were quantitated using an MSD plate-based assay with anti-STAT3 antibodies. The data were normalized and the percent activity versus log concentration of compound was fitted with a 4-parameter logistic model to generate IC50 curves.

DATA FOR EXAMPLES

Table 1 shows the inhibitory activity of selected compounds of this disclosure to assess their ability to inhibit TYK2, JAK1 and JAK2, wherein each compound number corresponds to the compound numbering set forth in Examples 1-923 described herein. The measured IC50 values were scored according to the following hierarchy:

“++++” represents: IC50 < 10 nM

“+++” represents: 10 nM < IC50 < 100 nM

“++” represents: 100 nM < IC50 <1000 nM “+” represents: 1000 nM < IC50

NT means Not Tested

Table 1: Experimental Data