Tyrosine kinase 2 inhibitor and its use

Abstract

The present disclosure relates to a compound of formula (I): [Chemical 1] JPEG2025523848000877.jpg59165 or a pharmaceutically acceptable salt thereof, wherein all variable elements in formula (I) are as defined in the present application. The compounds of the present disclosure have the ability to inhibit the activity of tyrosine kinase 2 (TYK2). The present disclosure further provides methods for preparing the compounds of the present disclosure and methods for their therapeutic use.

Description

Technical Field

[0001] Related Applications This application claims priority based on U.S. Provisional Application No. 63 / 389,038, filed on July 14, 2022, and the entire contents of the above application are expressly incorporated herein by reference.

[0002] 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 combination with a pharmaceutically acceptable carrier for the manufacture of pharmaceutical preparations, the use of such pharmaceutical preparations in the treatment of diseases, and methods of treating diseases including administering a TYK2 inhibitor to a warm-blooded animal, particularly a human.

Background Art

[0003] Cytokines are small secreted proteins released by cells and have specific effects on cell-cell interactions and signal transduction. Cytokine pathways mediate a wide range of biological functions, mainly through extracellular signal transduction, including many aspects of inflammation and immunity.

[0004] Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of cytoplasmic protein kinases that associate 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, engagement of a cytokine with its cognate receptor induces activation of the receptor-associated JAKs, which leads to JAK-mediated tyrosine phosphorylation of signal transducer and activator of transcription (STAT) proteins and ultimately to activation of the transcription of specific gene sets (Schindler et al., 2007, J. Biol. Chem. 282:20059-63). Among the numerous cytokines known to activate the JAK family are 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, LlF, CNTF, NNT-1 / BSF-3, G-CSF, CT-1, leptin, IL-12, IL-23), the gammaC family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), the IL-3 family (IL-3, IL-5, GM-CSF), the single-chain family (EPO, GH, PRL, TPO), the receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and the G protein-coupled receptors (AT1).

[0005] TYK2 is important in the signaling of 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 TYK2-deficient humans lack type I interferon, IL-6, IL-10, IL-12, and IL-23 signaling. TYK2 signals in combination with other members of the JAK family: TYK2 / JAK1, TYK2 / JAK2, TYK2 / JAK1 / JAK2.

[0006] Studies have shown that inappropriate JAK activity can result from mutations, overexpression, or inappropriate regulation, dysregulation, or deregulation, and overproduction or underproduction of growth factors or cytokines, and as a result, can cause various biological cellular responses related to cell growth, cell differentiation, cell function, survival, apoptosis, and cell motility. Inappropriate JAK activity has been implicated in many diseases, including but not limited to cancer, cardiovascular disease, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease.

[0007] Small molecule JAK inhibitors have emerged as a major therapeutic advance in the treatment of autoimmune diseases. To date, all known small molecule JAK inhibitors that have progressed into development are active site-specific inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain of the JAK protein (also called the JH1 or “Janus homology 1” domain), which inhibits the catalytic activity of the kinase by blocking ATP and downstream phosphorylation and resulting pathway signaling (Bryan et al., J. Med. Chem. 2018, 61, 9030-9058).

[0008] Throughout the genome, especially within the JAK family, the homology of the ATP active site is high, so it is a major challenge to achieve high selectivity for specific JAK family members while maintaining selectivity within the genome. Therefore, many of the JAK inhibitors developed are either pan-JAK inhibitors or slightly selective for one or more JAK family members. These inhibitors have shown promising results in treating autoimmune diseases, but undesirable side effects resulting in a narrow therapeutic index have been observed, suggesting the need for improved treatment.

[0009] TYK2 has been shown to be important in the differentiation and function of multiple cell types important in inflammatory and autoimmune diseases, including natural killer cells, B cells, and helper T cell subsets. Aberrant TYK2 expression is associated with multiple autoimmune or inflammatory pathologies.

[0010] There continues to be a need for potent compounds that exhibit high selectivity for TYK2 compared to other members of the JAK family as potential therapeutic agents for treating diseases or disorders responsive to TYK2 inhibition. SUMMARY OF THE INVENTION

[0011] The present disclosure provides compounds that are TYK2 inhibitors. In a first aspect, the present disclosure provides a compound having Formula I: [Chemical formula] [wherein, R 1 is H, C 1-6 alkyl, -OR 1a , -NR 1b R 1c , a 3- to 7-membered monocyclic carbocyclyl, or a 4- to 7-membered monocyclic heterocyclyl, and the C 1 alkyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 7-membered monocyclic heterocyclyl represented by R 1-6 are each optionally, one or more R1d is replaced by; R 1a , R 1b and R 1c are each independently H, C 1-4 alkyl, or a 3- to 4-membered monocyclic carbocyclic ring; each R 1d is independently halo, oxo, -CN, -OR 1a , -NR 1b R 1c , C 1-6 alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic ring, or 4- to 7-membered monocyclic heterocyclic ring; R 2 is H, halo, C 1-6 alkyl, C 3-7 cycloalkyl, -OR 2a , -N(R 2b )2, a 4- to 11-membered monocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the C 1-6 alkyl, the C 3-7 cycloalkyl, the 5- to 11-membered monocyclic or bicyclic heterocyclic ring, and the 5- to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R 20 ; R 2a is H, C 1-6 alkyl, C 3-7 cycloalkyl, 5- or 6-membered heteroaryl, and a 4- to 7-membered monocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the C 2a alkyl, the C 1-6 cycloalkyl, the 5- or 6-membered heteroaryl, and the 4- to 7-membered monocyclic heterocyclic ring are optionally substituted with 1 to 3 R 3-7 ; 20 ; each R 2bis, independently, H, C 1-4 alkyl, C 1-3 alkyl-C 1-3 alkoxy, C 1-4 alkoxy, or a 4- to 6-membered monocyclic heterocyclyl; R 20 is, each occurrence, halo, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OR 20c -C(O)R 20b , -C(O)N(R 20b )2, -N(R 20b )2, -SO2R 20b , -P(O)(C 1-3 alkyl)2, phenyl, C 3-7 cycloalkyl, a 5- to 10-membered bicyclic carbocyclic ring, a 4- to 10-membered monocyclic or bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the C 20 alkyl, the phenyl, the C 1-4 alkyl, the phenyl, the C 3-7 cycloalkyl, the 5- to 10-membered bicyclic carbocyclic ring, the 4- to 10-membered monocyclic or bicyclic heterocyclyl, and the 5- to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R 200 ; each R 20b is, independently, H, C 1-4 alkyl or C 1-4 alkoxy; R 20c is H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or a 4- to 6-membered monocyclic heterocyclyl, and the C 1-4 alkyl is optionally substituted with C 1-3 alkoxy; R 200 is, each occurrence, halo, -CN, C 1-4 alkyl, C 1-3 alkyl-C 1-3 alkoxy, C1-4 Haloalkyl, -OH, -N(R 20b )2, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-7 Cycloalkyl, and 1 to 3 C 1-3 Alkyl or C 1-3 5- to 10-membered monocyclic or bicyclic heterocyclyl optionally substituted with 1 to 3 alkyl or C 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 with one or more R B ; Each R B is halo, -CN, -OR Ba , -N(R Bb )2, -C(O)R Bc , -C(O)OR Ba , -SO2R Bc , C 1-6 Alkyl, C 2-6 Alkenyl, 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, each of the C B alkyl, the C 1-6 alkenyl, the phenyl, the 3- to 7-membered monocyclic carbocyclyl, the 4- to 7-membered monocyclic heterocyclyl, and the 5- to 10-membered monocyclic or bicyclic heteroaryl being optionally substituted with one or more R 2-6 ; B1 ; Each R B1 is independently halo, oxo, -CN, -OR Ba , -N(R Bb )2, C 1-4 alkyl, C 1-4 alkyl-R Bd , C 1-4 haloalkyl, -C(O)ORBa selected from phenyl, 5- or 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic, and 4- to 8-membered monocyclic heterocyclic; R Ba is independently H, C 1-4 alkyl, C 3-7 cycloalkyl, or 4- to 8-membered monocyclic or bicyclic heterocyclic, and the C Ba represented by R 1-4 alkyl, the C 3-7 cycloalkyl, and the 4- to 8-membered monocyclic or bicyclic heterocyclic are each optionally substituted with one or two R B0 ; each R B0 is independently halo, -CN, -OH, C 1-4 alkyl or C 1-4 alkoxy; each R Bb is independently H, C 1-4 alkyl, C 1-4 alkoxy or C 3-7 cycloalkyl; R Bc is C 1-6 alkyl or C 3-7 cycloalkyl; R Bd is -C(O)OR Ba 、-N(R Bb )2、-OR Ba 、3- to 7-membered monocyclic carbocyclic, or 4- to 8-membered monocyclic heterocyclic; R N1 and R N2 are each independently H or C 1-4 alkyl) or a pharmaceutically acceptable salt thereof.

[0012] Another aspect of the disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0013] In yet another aspect, the present disclosure provides a method of treating a disease or disorder in a subject that responds to inhibition of TYK2, the method comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof.

[0014] 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 that responds to inhibition of TYK2. Also provided is a compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder that responds to inhibition of TYK2. The present disclosure also includes the use of a compound described herein or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder that responds to inhibition of TYK2. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present disclosure provides compounds and pharmaceutical compositions thereof that may be useful for the treatment of diseases or disorders mediated by TYK2. In some embodiments, the compounds of the present disclosure are TYK2 inhibitors.

[0016] Compounds and Compositions In a first embodiment, the present disclosure provides a compound having Formula I: [Chemical formula] wherein, R 1 is H, C 1-6 alkyl, -OR 1a , -NR 1b R 1c , a 3- to 7-membered monocyclic carbocyclic ring, or a 4- to 7-membered monocyclic heterocyclic ring, and the C 1 alkyl, the 3- to 7-membered monocyclic carbocyclic ring, and the 4- to 7-membered monocyclic heterocyclic ring represented by R 1-6 are each optionally substituted with one or more R 1d ; R 1a , R 1b and R1c is, independently, H, C 1-4 alkyl, or a 3- to 4-membered monocyclic carbocyclyl; each R 1d is independently halo, oxo, -CN, -OR 1a , -NR 1b R 1c , C 1-6 alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, or 4- to 7-membered monocyclic heterocyclyl; R 2 is H, C 1-6 alkyl, C 3-7 cycloalkyl, -OR 2a , -N(R 2b )2, a 4- to 11-membered monocyclic or bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the C 2 alkyl, the C 1-6 cycloalkyl, the 5- to 11-membered monocyclic or bicyclic heterocyclyl, and the 5- to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R 3-7 ; 20 ; R 2a is H, C 1-6 alkyl, C 3-7 cycloalkyl, and a 4- to 7-membered monocyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the C 2a alkyl, the C 1-6 cycloalkyl, and the 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 R 3-7 ; 20 ; each R 2b is independently H, C 1-4 alkyl or C 1-4 alkoxy; R 20 is, each occurrence, halo, -CN, C1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, -N(R 20b )2, phenyl, C 3-7 Cycloalkyl, independently selected from 4- to 10-membered monocyclic or bicyclic heterocyclyl having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and the phenyl, the C 20 represented thereby, the C 3-7 cycloalkyl, the 4- to 10-membered monocyclic or bicyclic heterocyclyl, and the 5- to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R 200 ; Each R 20b is independently H, C 1-4 alkyl or C 1-4 alkoxy; R 200 is, each occurrence, independently halo, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-3 alkoxy, and C 3-7 cycloalkyl; 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 with one or more R B ; Each R B is halo, -CN, -OR Ba , -N(R Bb )2, -C(O)R Bc , -C(O)OR Ba , -SO2R Bc , C 1-6 alkyl, 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, and RB said C represented by 1-6 alkyl, said phenyl, said 3- to 7-membered monocyclic carbocyclyl, said 4- to 7-membered monocyclic heterocyclyl, and said 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with one or more R B1 ; each R B1 is independently halo, oxo, -CN, -OR Ba , -N(R Bb )2, C 1-4 alkyl, C 1-4 alkyl-R Bd , C 1-4 haloalkyl, -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, C 1-4 alkyl or C 3-7 cycloalkyl, and said C Ba alkyl represented by R 1-4 , and said C 3-7 cycloalkyl are each optionally substituted with one or two R B0 ; each R B0 is independently halo, -CN, -OH, C 1-4 alkyl or C 1-4 alkoxy; each R Bb is independently H, C 1-4 alkyl, C 1-4 alkoxy or C 3-7 cycloalkyl; R Bc is C 1-6 alkyl or C 3-7 cycloalkyl; 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; R N1 and R N2is, independently of each other, H or C 1-4 is alkyl〕 and relates to a pharmaceutically acceptable salt thereof.

[0017] In a second embodiment, for the compound 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 1 to 3 R B and the remaining variable elements are as described in the first aspect or the first embodiment.

[0018] In a third embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, R N1 and R N2 are, independently of each other, H or -CH3, and the remaining variable elements are as described in the first aspect or the first aspect or the second embodiment.

[0019] In a fourth embodiment, the compounds of the present disclosure are of formula (II) or (III):

Chemical formula

Chemical formula

[0020] In a fifth embodiment, the compounds of the present disclosure are of formula (IV), (V), (VI) or (VII): [Chemical formula] is represented by, or is a pharmaceutically acceptable salt thereof, and the variable elements in formula (IV), (V), (VI) or (VII) are as defined in the first, second or third embodiment. In another fifth embodiment, the compounds of the present disclosure are of formula (IV), (V), (VI), (VII), (VIII) or (IX): [Chemical formula] is represented by, or is a pharmaceutically acceptable salt thereof, and the variable elements in formula (IV), (V), (VI), (VII), (VIII) or (IX) are as defined in the first, second or third embodiment.

[0021] In a sixth embodiment, for the compounds of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 1 is C 1-4 alkyl or C 3-6 cycloalkyl, and the C 1-4 alkyl is optionally substituted with C 1-3 alkoxy; the remaining variable elements are as described in the first aspect, or the first, second, third, fourth or fifth embodiment. In another sixth embodiment, for the compounds of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 1 is H, C 1-4 alkyl, -OR 1a , -NR 1b R 1c , or C 3-6 cycloalkyl, and the C 1-4 alkyl is optionally substituted with C 1-3 alkoxy; R 1a is C 1-3 alkyl; R 1b and R 1ceach independently is H or C 1-3 is alkyl; the remaining variable elements are as described in the first aspect, or the first, second, third, fourth or fifth embodiments.

[0022] In a seventh embodiment, for a compound of formula (I), (II), (II’), (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; the remaining variable elements are as described in the first aspect, or the first, second, third, fourth or fifth embodiments. In another seventh embodiment, for a compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 1 is selected from H, -CH3, -CH2CH3, -CH2OCH3, -CH2CH2OCH3, -OCH3, -NH2, -NHCH3, and cyclopropyl; the remaining variable elements are as described in the first aspect, or the first, second, third, fourth or fifth embodiments.

[0023] In an eighth embodiment, for a compound 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, C 1-4 alkyl, -OR 2a , and -N(R 2b )2, where the C 2 alkyl represented by R 1-4 is optionally substituted with 1 to 3 R 20 ; R 2a is H, C 1-4 alkyl, C 3-6A cycloalkyl, or a 4- to 6-membered monocyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and R 2a The C represented by 1-4 alkyl, the C 3-6 cycloalkyl, and the 4- to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 R 20 ; R 20 is independently selected from halo, C 1-3 alkyl, C 1-3 alkoxy, -N(R 20b )2, phenyl, C 3-6 cycloalkyl, a 4- to 10-membered monocyclic or bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the phenyl, the C 3-6 cycloalkyl, the 4- to 10-membered monocyclic or bicyclic heterocyclyl, and the 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 R 200 ; R 2b is, each occurrence, independently H or C 1-3 alkyl; R 20b is, each occurrence, independently H or C 1-3 alkyl; R 200 is, each occurrence, independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-2 alkoxy, and C 3-5 cycloalkyl; The remaining variable elements are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, or seventh embodiments.

[0024] In another eighth embodiment, for the compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or pharmaceutically acceptable salts thereof, R 2 is H, halo, C 1-4 alkyl, -OR 2a , and -N(R 2b )2, and is selected from, and the C 2 alkyl represented by R 1-4 is optionally substituted with 1 to 3 R 20 ; R 2a is H, C 1-4 alkyl, C 3-6 cycloalkyl, 5- or 6-membered heteroaryl, or a 4- to 6-membered monocyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the C 2a alkyl, the C 1-4 cycloalkyl, the 5- or 6-membered heteroaryl, and the 4- to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 R 3-6 ; 20 ; R 20 is halo, C 1-4 alkyl, C 1-4 alkoxy, -C(O)R 20b , -C(O)N(R 20b )2, -N(R 20b )2, phenyl, C 3-6 cycloalkyl, a 5- to 10-membered bicyclic carbocyclic ring, a 4- to 10-membered monocyclic or bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and are independently selected, and the C 1-4 alkyl, the phenyl, the C 3-6 cycloalkyl, the 4- to 10-membered monocyclic or bicyclic heterocyclyl, and the 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 R 200 ; R 2b is, each occurrence, independently H or C 1-3 alkyl; R 20b is, each occurrence, independently H or C 1-3is alkyl; R 200 is, independently for each occurrence, halo, C 1-4 alkyl, C 1-3 alkyl-C 1-3 alkoxy, C 1-4 haloalkyl, C 1-2 alkoxy, and C 3-5 cycloalkyl, independently selected.

[0025] In a ninth embodiment, for a compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 2 is H, C 1-4 alkyl, -OR 2a , or -N(R 2b )2, where the C 2 alkyl represented by R 1-4 is optionally substituted with 1 to 3 substituents independently selected from halo, C 1-3 alkoxy and -N(R 20b )2; R 2a is H, or C 1-3 alkyl optionally substituted with 1 to 3 substituents independently selected from halo, C 20b alkoxy and -N(R 1-4 )2; and the remaining variable elements are as described in the eighth embodiment.

[0026] In a tenth embodiment, for a compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 2 is -OR 2a ; R 2a is C 3-6 cycloalkyl, or a 4- to 6-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, where the C 2a cycloalkyl represented by R 3-6 or the 4- to 6-membered monocyclic heterocyclyl is each optionally halo, C1-3 is substituted with 1 to 3 substituents independently selected from alkyl and C 1-3 alkoxy; the remaining variable elements are as described in the eighth embodiment. In another tenth embodiment, for the compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX), R 2 is -OR 2a ; R 2a is C 3-6 cycloalkyl, a 5- or 6-membered heteroaryl, or a 4- to 6-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and the C 2a cycloalkyl represented by R 3-6 , the 5- or 6-membered heteroaryl, and the 4- to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 substituents independently selected from halo, C 1-3 alkyl and C 1-3 alkoxy; the remaining variable elements are as described in the eighth embodiment.

[0027] In the eleventh embodiment, for the compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or pharmaceutically acceptable salts 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, C 1-3 alkyl and C 1-3 alkoxy; the remaining variable elements are as described in the tenth embodiment. In another eleventh embodiment, for the compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX), R 2ais cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl pyrrolidinyl, pyrazinyl, pyridazinyl or pyrazolyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, C 1-3 alkyl and C 1-3 alkoxy; the remaining variable elements are as described in the tenth embodiment.

[0028] In a twelfth embodiment, for a compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 2a is as follows:

Chemical formula

Chemical formula

Chemical formula

[0029] In the 13th embodiment, for the compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 2a is as follows: [Chemical formula] represented by; the remaining variable elements are as described in the 12th embodiment. In another 13th embodiment, for the compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 2a is as follows: [Chemical formula] represented by; the remaining variable elements are as described in the 12th embodiment.

[0030] In the 14th embodiment, for the compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 2 is -OR 2a wherein R 2a is C 20 alkyl substituted with one R 1-4 ; R 20 is phenyl, C 3-6 cycloalkyl, a 4- to 10-membered monocyclic or bicyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the phenyl, the C 3-6 cycloalkyl, the 4- to 10-membered monocyclic or bicyclic heterocyclyl, and the 5- to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R 200is replaced; the remaining variable elements are as described in the eighth embodiment. In another fourteenth 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 -OR 2a wherein R 2a is C 20 alkyl substituted with one R 1-4 ; R 20 is phenyl, C 3-6 cycloalkyl, a 5- to 10-membered bicyclic carbocyclic ring, a 4- to 10-membered monocyclic or bicyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl, the C 3-6 cycloalkyl, the 5- to 10-membered bicyclic carbocyclic ring, the 4- to 10-membered monocyclic or bicyclic heterocyclyl, and the 5- to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R 200 ; the remaining variable elements are as described in the eighth embodiment.

[0031] In the 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 azetidinyl, benzo[d][1,3]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 200is replaced; the remaining variable elements are as described in the 14th embodiment. In another 15th embodiment, for the compounds of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or pharmaceutically acceptable salts thereof, R 20 is independently selected from azetidinyl, benzo[d][1,3]dioxolyl, cyclobutyl, cyclopropyl, spiro[2.2]pentanyl, bicyclo[1.1.1]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, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl and tetrahydrofuranyl, each of which is optionally substituted with 1 to 3 R 200 and the remaining variable elements are as described in the 14th embodiment.

[0032] In the 16th embodiment, for the compounds of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or pharmaceutically acceptable salts thereof, R 20 is independently

Chemical formula

Chem.

Chem.

[0033] In the 17th embodiment, for the compounds of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or pharmaceutically acceptable salts thereof, R 2 is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2OCH3, -CH(CH3)2, -CH2CH2CH2N(CH3)2, cyclopropyl, -CH2OCH3, OH, -OCH3, -OCD3, -OCHF2, -OCH2CH3, -OCD2CH3, -OCD2CD3, -OCH2CHF2, -OCH2CF3, -OCH(CH3)2, -OCH2CH2OCH3, -OCH2CH2OCF2H, -OCH2CH2CH2OCH3, -OCH2CH(CH3)OCH3, -OCH(CH3)CH2OCH3, -OCH2C(CH3)2OCH3, -OCH2CH2OCH2CH3, -OCH2CH2OCH(CH3)2, -OCH2CH2N(CH3)2, -NH2, -N(CH3)2,

Chem.

Chem.

Chem.

Chem.

Chem.

[0034] In the 18th embodiment, for the compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 200 is, independently for each occurrence, selected from F, -CN, -CH3, -CF3, -CH2CH3, -CH(CH3)2, -OCH3, and cyclopropyl; the remaining variable elements are as described in the first aspect, or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth or seventeenth embodiments. In another 18th embodiment, for the compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 200 is, independently for each occurrence, selected from F, -CN, -CH3, -CH2F, -CF3, -CH2CH3, -CH(CH3)2, -CH2OCH3, -OCH3, cyclobutyl and cyclopropyl; the remaining variable elements are as described in the first aspect, or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth or seventeenth embodiments.

[0035] In the 19th embodiment, for the compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 2 is 3-6 cycloalkyl, 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 20is replaced; the remaining variable elements are as described in the first aspect, or in the first, second, third, fourth, fifth, sixth or seventh embodiments.

[0036] In the 20th 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 azetidinyl, cyclopropyl, dioxino[2,3-d]pyridinyl, isoxazolyl, isothiazolyl, morpholinyl, oxaazabicyclo[3.1.1]heptanyl, oxazolyl, pyridazinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl and thiazolyl, each of which is optionally substituted with one or two R 20 is replaced; the remaining variable elements are as described in the first aspect, or in the first, second, third, fourth, fifth, sixth or seventh embodiments. In another 20th embodiment, for the compounds of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 2is azetidinyl, cyclopropyl, tetrahydropyranyl, dioxino[2,3-d]pyridinyl, pyridazinonyl, pyrimidinonyl, pyrazinonyl, isoxazolyl, isothiazolyl, morpholinyl, oxaazabicyclo[3.1.1] heptanyl, oxazolyl, pyridazinyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, pyrimidinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, 6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-8(5H)-onyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazinyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]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[1,2-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, 5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazinyl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazinyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, imidazo[1,2-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-[1,4]dioxino[2,3-b]pyridinyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, and 2,3-dihydroimidazo[2,1-b]oxazolyl, each of which is optionally substituted with 1 to 2 R. 20 ; the remaining variable elements are as described in the first aspect, or in the first, second, third, fourth, fifth, sixth or seventh embodiments.

[0037] In the 21st embodiment, for the compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 2 is

Chemical formula

Chemical formula

Chemical formula

[0038] In the 22nd embodiment, for the compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 20 is, independently for each occurrence, halo, -CN, C 1-3 alkyl, C 1-43 haloalkyl, C 1-3 alkoxy, or C 3-6is cycloalkyl; the remaining variable elements are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, nineteenth, twentieth or twenty - first embodiment. In another 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 is, independently for each occurrence, halo, - CN, C 1-4 alkyl, C 1-4 haloalkyl, OR 20c , - N(R 20b )2, - C(O)C 1-3 alkyl, - SO2C 1-3 alkyl, P(O)(C 1-3 alkyl)2, C 3-6 cycloalkyl, or a 5 - to 10 - membered monocyclic or bicyclic heterocyclyl, wherein the C 20 alkyl represented by R 1-4 is optionally substituted with - CN, OH, - N(R 20b )2, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyl, and optionally a 5 - to 10 - membered monocyclic or bicyclic heterocyclyl substituted with C 1-4 alkyl, and R 20c is H, C 1-4 alkyl, C 1-4 haloalkyl, or a 4 - membered monocyclic heterocyclyl, wherein the C 1-4 alkyl is optionally substituted with C 1-3 alkoxy; the 5 - to 10 - membered monocyclic or bicyclic heterocyclyl represented by R 20 is optionally substituted with C 1-4 alkyl, or C 1-3 alkoxy; each R 20b is independently H, or C 1-3 alkyl optionally substituted with C 1-4is alkyl; and the remaining variable elements are as described in the first aspect, or in the first, second, third, fourth, fifth, sixth, seventh, nineteenth, twentieth or twenty - first embodiments.

[0039] In the twenty - third 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 for each occurrence, selected from F, - Cl, - OCH3, - CH3, - CHF2, cyclopropyl and cyclobutyl; and the remaining variable elements are as described in the twenty - second embodiment. In another twenty - third 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 for each occurrence, - F, - Cl, - Br, - CN, - OH, - OCH3, - OCHF2, - OCH2CH3, - OCH(CH3)2, - OCH2CH2OCH3, - CH3, - CD3, - CHF2, - CH2CH3, - CH(CH3)2, - CF(CH3)2, - C(CH3)3, - CF2CH3, - CHFCH3, - CH2CH2CH3, - CH(CH3)OH, - CH(CH3)OCH3, - CH2CN, - CH2N(CH3)2, - CH(CH3)N(CH3)2, - CH2CH2OCH3, - CH2OCH3, - CH2OCHF2, - CH2N(CH3)2, - CH2C(OH)(CH3)2, - CH2C(OCH3)(CH3)2, - CH2CH2OCH2CH3, - C(CH3)2OH, - C(CH3)2OCH3, - C(CH3)2CN, - C(CH3)2N(CH3)2, - NHCH3, - N(CH3)2, - NHCH(CH3)2, - NHCH2CH2OCH3, - CH2N(CH3)CH2CH2OCH3, - N(CH3)CH2CH2OCH3, - C(O)CH3, SO2CH3, - SO2CH2CH3, P(O)(CH3)2, [Chemical formula] , selected from cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, N-methylpiperazinyl, N-methylmorpholinyl, and morpholinyl; the remaining variable elements are as described in the 22nd embodiment. In some embodiments, R 20 is, independently for each occurrence, selected from F, -CN, -OCH3, -CH3, -CHF2, cyclopropyl and cyclobutyl.

[0040] In the 24th embodiment, for the compounds of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or pharmaceutically acceptable salts thereof, R 3 is H, C 1-4 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, -OR 3a , -N(R 3b )2phenyl, pyridinyl, pyrimidinyl, pyrazoyl, thiazoyl, indazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, and imidazo[1,2-b]pyridazinyl, wherein the phenyl, the pyridinyl, the pyrimidinyl, the pyrazoyl, the thiazoyl, the indazolyl, the [1,2,4]triazolo[1,5-a]pyridinyl, the imidazo[1,2-a]pyridinyl, or the imidazo[1,2-b]pyridazinyl is each optionally substituted with one or two R 3c ; R 3a is H, C 1-3 alkyl, or C 3-6 cycloalkyl, and the C 3a alkyl and the C 1-3 cycloalkyl represented by R 3-6 are each optionally substituted with one or two substituents independently selected from halo, -CN, C 1-2 alkyl, -OH and C 1-2 alkoxy; each R 3b is, independently for each occurrence, H, C 1-3 alkyl, or C3-5 is cycloalkyl; each R 3c is independently halo, oxo, -CN, -OR 3a , -N(R 3b )2, C 1-4 alkyl, C 1-4 alkyl-R 3d , C 1-4 haloalkyl, -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; the remaining variable elements are as described in the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd or 23rd embodiments. In another 24th embodiment, for the compounds of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or pharmaceutically acceptable salts thereof, R 3 is H, halo, C 1-4 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 1-3 alkyl-C 1-3 alkoxy, -OR 3a , -N(R 3b )2, phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, indazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, or imidazo[1,2-b]pyridazinyl, wherein the phenyl, the pyridinyl, the pyrimidinyl, the pyrazolyl, the thiazolyl, the indazolyl, the [1,2,4]triazolo[1,5-a]pyridinyl, the imidazo[1,2-a]pyridinyl, or the imidazo[1,2-b]pyridazinyl are each optionally substituted with one or two R 3c ; R 3a is H, C 1-3Alkyl, 4- to 8-membered monocyclic or bicyclic heterocyclyl, or C 3-6 cycloalkyl, and R 3a is represented by said C 1-3 alkyl and said C 3-6 cycloalkyl are each optionally substituted with one or two substituents independently selected from halo, -CN, C 1-2 alkyl, -OH, and C 1-2 alkoxy; each R 3b is, each occurrence, independently H, C 1-3 alkyl, or C 3-5 cycloalkyl; each R 3c is independently halo, oxo, -CN, -OR 3a , -N(R 3b )2, C 1-4 alkyl, C 1-4 alkyl-R 3d , C 1-4 haloalkyl, -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 variable elements are as described in the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, or 23rd embodiments.

[0041] In the 25th embodiment, for the compounds of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or pharmaceutically acceptable salts thereof, R 3 is H, -CH3, -CH2CH3, -CF2CH3, -CH(CH3)2, cyclopropyl, -OCH3, -OCH2CH2OCH3, -NHCH3,

Chemical formula

Chemical formula

[0042] In the 26th embodiment, for the compounds of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, each R 3c is individually selected from -CN, F, -OCH3, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CHF2, -CH2CF3, -CF3, -CD3, -CH2CH2OCH3, -CH2-cyclopropyl, -CH2CH2-morpholinyl, cyclopropyl, cyclobutyl, -CH2C(O)OH, -C(O)OC(CH3)3, -CH2CH2N(CH3)2, and morpholinyl; the remaining variable elements are as described in the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th or 25th embodiment. In another 26th embodiment, for the compounds of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, each R 3cis, individually, selected from -CN, -F, -Cl, -OCH3, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CHF2, -CH2CF3, -CF3, -CD3, -CH2CH2OCH3, -CH2-cyclopropyl, -CH2CH2-morpholinyl, cyclopropyl, cyclobutyl, -CH2C(O)OH, -C(O)OC(CH3)3, -CH2CH2N(CH3)2, oxetanyl, and morpholinyl; the remaining variable elements are as described in the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th or 25th embodiment.

[0043] In the 27th embodiment, for the compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 4 is C 1-4 haloalkyl, and independently C 1-3 cycloalkyl optionally substituted with 1 to 3 substituents selected from halo and C 3-6 selected; the remaining variable elements are as described in the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th or 26th embodiment. In another 27th embodiment, for the compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 4 is C 1-4 haloalkyl, C 1-3 alkoxy, C 1-3 alkoxy-C 1-3 alkoxy, C 1-3 haloalkoxy, -C 2-4 alkenyl, C 2-4 haloalkenyl, a 5- to 7-membered monocyclic or bicyclic heterocyclyl, and C 3-6Selected from cycloalkyl, said 5- to 7-membered monocyclic or bicyclic heterocyclyl, and said C 3-6 The cycloalkyls are each optionally substituted with 1 to 3 substituents independently selected from halo, C 1-3 haloalkyl, C 1-3 alkyl-C 1-3 alkoxy and C 1-3 alkyl; and the remaining variable elements are as described in the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th or 26th embodiments.

[0044] In the 28th embodiment, for the compounds of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or pharmaceutically acceptable salts thereof, R 4 is -CF2CH3, -CF2CFH2, -CFHCFH2, -CF2CH2CH3, -CF(CH3)2, and

Chemical formula

Chemical formula

[0045] In the 29th embodiment, for the compound of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 5 is H, or a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the 5-membered heteroaryl represented by R 5 is optionally substituted with 1 to 3 R 50 ; the remaining variable elements are as described in the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th or 28th embodiment.

[0046] In the 30th embodiment, for the compound of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 5 is H, or pyrazolyl optionally substituted with 1 to 3 R 50 ; the remaining variable elements are as described in the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th or 29th embodiment.

[0047] In some embodiments, for the compound of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 6 is H, halo, C 1-3 alkoxy; the remaining variable elements are as described in the first aspect or any of the above embodiments. Alternatively, for the compound of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 6is H, -F, or -OCH3; the remaining variable elements are as described in the first aspect or any of the above embodiments.

[0048] In some embodiments, for a compound of formula (I), (II), (II’), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R 7 is H; the remaining variable elements are as described in the first aspect or any of the above embodiments.

[0049] In the 31st embodiment, the compound of the present disclosure has the formula (IV-1) or (V-1):

Chemical formula

[0050] In the 32nd embodiment, for the compound of formula (I), (IV-1) or (V-1), or a pharmaceutically acceptable salt thereof, R 1 Is -CH3; the remaining variable elements are as described in the 31st embodiment.

[0051] In the 33rd embodiment, for the compound of formula (I), (IV-1) or (V-1), or a pharmaceutically acceptable salt thereof, R 2 Is -OCH3, -OCD3, -OCH2CH3, -OCD2CH3, -OCD2CD3, -OCH2CH2OCH3,

Chemical formula

[0052] In the 34th embodiment, for the compound of formula (I), (IV-1) or (V-1), or a pharmaceutically acceptable salt thereof, R 3 Is H, -CH3, -CH2CH3, cyclopropyl, -OCH3, -OCH2CH2OCH3,

Chemical formula

[0053] In the 35th embodiment, for the compound of formula (I), (IV-1) or (V-1), or a pharmaceutically acceptable salt thereof, R 3c is -CH3; R 4 is -CF2CH3, -CF2CFH2, -CFHCFH2, -CF2CH2CH3, -CF(CH3)2; the remaining variable elements are as described in the 31st, 32nd, 33rd or 34th embodiment.

[0054] In the 36th embodiment, the compound of the present disclosure has the formula (III):

Chemical formula

[0055] In the 37th embodiment, for the compound of formula (I) or (III), or a pharmaceutically acceptable salt thereof, R 1 is -CH3; the remaining variable elements are as described in the 36th embodiment.

[0056] In the 38th embodiment, for the compound of formula (I) or (III), or a pharmaceutically acceptable salt thereof, R 2 is -OCH2CH3 or -OCH2CH2OCH3; the remaining variable elements are as described in the 36th or 37th embodiment.

[0057] In the 39th embodiment, for the compound of formula (I) or (III), or a pharmaceutically acceptable salt thereof, R 3 is H or -CH3; the remaining variable elements are as described in the 36th, 37th or 38th embodiment.

[0058] In the 40th embodiment, for the compound of formula (I) or (III), or a pharmaceutically acceptable salt thereof, R 4 is 1-3 haloalkyl, or tetrahydrofuranyl; the remaining variable elements are as described in the 36th, 37th, 38th or 39th embodiment.

[0059] In the 41st embodiment, for the compound of formula (I) or (III), or a pharmaceutically acceptable salt thereof, R 4 is -CF2CH3, or

Chem.

[0060] In the 42nd embodiment, the compound of the present disclosure has the formula (X):

Chem.

[0061] In the 43rd embodiment, for the compound of formula (I) or (X), or a pharmaceutically acceptable salt thereof, A 1 is N; the remaining variable elements are as described in the 42nd embodiment.

[0062] In the 44th embodiment, for the compound of formula (I) or (X), or a pharmaceutically acceptable salt thereof, R 2 is -OCH3, -OCH2CH3, or -OCH2CH2OCH3; the remaining variable elements are as described in the 42nd or 43rd embodiment.

[0063] In the 45th embodiment, for the compound of formula (I) or (X), or a pharmaceutically acceptable salt thereof, R 2is pyrazolyl pyridinyl, pyrimidinyl, or 4,5,6,7 - tetrahydropyrazolo[1,5 - a]pyrazinyl, each of which is optionally substituted with one or two R 20 ; the remaining variable elements are as described in the 42nd or 43rd embodiment.

[0064] In the 46th embodiment, for the compound of formula (I) or (X), or a pharmaceutically acceptable salt thereof, R 2 is

Chemical formula

[0065] In the 47th embodiment, for the compound of formula (I) or (X), or a pharmaceutically acceptable salt thereof, R 2 is

Chemical formula

[0066] In the 48th embodiment, for the compound of formula (I) or (X), or a pharmaceutically acceptable salt thereof, each R 20 is independently -CH3, -CH2CH3, or -CH2N(CH3)2; the remaining variable elements are as described in the 42nd, 43rd, 45th, 46th, or 47th embodiment.

[0067] In the 49th embodiment, for the compound of formula (I) or (X), or a pharmaceutically acceptable salt thereof, R 3 is H, -CH3, -CH2CH3, or -O - cyclopropyl; the remaining variable elements are as described in the 42nd, 43rd, 44th, 45th, 46th, 47th, or 48th embodiment.

[0068] In the 50th embodiment, for the compound of formula (I) or (X), or a pharmaceutically acceptable salt thereof, R 4 is -CF2CH3, or

Chemical formula

[0069] In the 51st embodiment, the present disclosure is N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((4-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((4-(1,1-difluoroethyl)pyrimidin-2-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(difluoromethoxy)pyridin-2-yl)acetamide, N-(5-cyclobutyloxy-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(propan-2-yloxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)propanamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(5-(Cyclopropylmethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((6-Cyclopropyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((6-(1,1-Difluoroethyl)-4-(3-methoxycyclobutyl)oxypyridin-2-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((6-(1,1-Difluoroethyl)-4-(3-methoxycyclobutyl)oxypyridin-2-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(3-methoxycyclobutyl)oxypyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((6-Cyclopropyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methoxypyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(3-methoxycyclobutyl)oxypyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methoxypyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetamide N-(5-(2,2-Difluoroethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(dimethylamino)ethoxy)pyridin-2-yl)acetamide; Formic acid N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)-2-methoxyacetamide N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)-3-methoxypropanamide N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)cyclopropanecarboxamide N-(5-Cyclopropyl-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-phenylmethoxypyridin-2-yl)acetamide N-(5-Ethoxy-4-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide N-(4-((2-(1,1-Difluoroethyl)-6-(2-methoxyethoxy)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((6-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-5-fluoropyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-5-fluoro-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(2-methoxyethoxy)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(5-cyclopropyloxy-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-propan-2-yloxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methoxycyclobutyl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-methylpyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethylpyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-propylpyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-propan-2-ylpyridin-2-yl)acetamide, N-(5-cyclopropyloxy-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(methoxymethyl)pyridin-2-yl)acetamide, N-(5-(methoxymethyl)-4-((6-methoxy-5-(1-methylpyrazol-3-yl)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-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)amino)-5-(1-methylpyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-propan-2-ylpyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(3-hydroxy-3-methylcyclobutyl)oxypyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-methylamino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-vinylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-(trifluoromethyl)cyclopropyl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methylcyclopropyl)methoxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxypropoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(oxetan-3-ylmethoxy)pyridin-2-yl)acetamide, N-(5-(cyclobutylmethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((6-(1,1-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-(1,1-Difluoroethyl)pyridin-2-yl)amino)-5-(2-(dimethylamino)ethoxy)pyridin-2-yl)acetamide, N-(4-((6-Cyclopropyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((6-(1,1-Difluoroethyl)pyrazin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(difluoromethoxy)ethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(3-methoxypropoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-methylpiperazin-1-yl)ethoxy)pyridin-2-yl)acetamide, (R)-N-(5-(2-Methoxyethoxy)-4-((6-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (S)-N-(4-((6-(1,2-Difluoroethyl)pyridin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, (R)-N-(5-((2,2-Difluorocyclopropyl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(1,1-Difluoroethyl)pyrimidin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-isopropoxypyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethoxypyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((4-(1,1-Difluoroethyl)-6-methylpyrimidin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,2-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, (S)-N-(4-((4-(1,2-Difluoroethyl)-6-methylpyrimidin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,2-Difluoropropan-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1-Fluoropropan-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, (R)-N-(5-(1-Cyclopropylethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-((1-Cyanocyclopropyl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(oxetan-2-ylmethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(oxetan-3-yloxy)pyridin-2-yl)acetamide, (4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)methyl carbamate, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)propanamide, (S)-N-(4-((6-(1,2-difluoroethyl)pyrazin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((6-(1-fluorovinyl)pyrazin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, (4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(dimethylamino)ethoxy)pyridin-2-yl)methyl carbamate, N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(trifluoromethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-fluoropyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((6-(2-oxabicyclo[2.1.1]hexan-4-yl)-4-methylpyridin-2-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(pyridin-3-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6-methylpyrazin-2-yl)oxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-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-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyridin-2-ylmethoxy)pyridin-2-yl)acetamide, 2-((6-acetamido-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-3-yl)oxy)-N-methylacetamide, 2-((6-acetamido-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-3-yl)oxy)-N,N-dimethylacetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3,3-difluoropropoxy)pyridin-2-yl)acetamide, N-(5-butoxy-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-methoxypropoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(thiazol-2-ylmethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-ethyloxetan-3-yl)methoxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methylisothiazol-4-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methylthiazol-2-yl)methoxy)pyridin-2-yl)acetamide, N-(5-(2-(tert-Butoxy)ethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-methoxypyridin-4-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methylisothiazol-3-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6-methylpyridin-3-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-methylthiazol-4-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-fluoro-2-methylpropoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-fluoropyridin-4-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methylisoxazol-5-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(oxazol-5-ylmethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4,6-dimethylpyridin-2-yl)methoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-fluoropyridin-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrazin-2-ylmethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methoxypyridin-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methoxypyridin-2-yl)methoxy)pyridin-2-yl)acetamide, N-(5-((4-Cyanopyridin-2-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methylpyridin-2-yl)methoxy)pyridin-2-yl)acetamide, N-(5-((5-Cyanopyridin-2-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6-methoxypyridin-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methylpyridin-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrimidin-2-ylmethoxy)pyridin-2-yl)acetamide, (R)-N-(5-((1,4-Dioxan-2-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((tetrahydro-2H-pyran-3-yl)methoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-methoxybutoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1,5-dimethyl-1H-pyrazol-4-yl)methoxy)pyridin-2-yl)acetamide, (R)-N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((6-(1,1-Difluoroethyl)pyridin-2-yl)amino)-5-(2-hydroxyethoxy)pyridin-2-yl)acetamide, N-(4-((2-(2-oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4’-((2-(2-oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-((difluoromethoxy)methyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(5-cyclopropyl-4-((2-(1,1-difluoroethyl)-5-methoxypyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(5-cyano-4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3’-bipyridin]-6’-yl)acetamide, N-(5-Cyano-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, (S)-N-(4-((6-(1,2-difluoroethyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(difluoromethoxy)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-(dimethylamino)propyl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-methoxypropyl)pyridin-2-yl)acetamide, N-(5-(Cyclopropyldifluoromethyl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1,1-difluoropropyl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-methoxy-2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxy-6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-Difluoroethyl)pyridin-2-yl)amino)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-Difluoroethyl)pyridin-2-yl)amino)-5-(4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-Difluoroethyl)pyridin-2-yl)amino)-5-(1-methyl-2-oxo-1,2-dihydropyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-Difluoroethyl)pyridin-2-yl)amino)-5-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-Difluoroethyl)pyridin-2-yl)amino)-5-(6-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methoxy-2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxy-6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-2-yl)acetamide, N-(4-((6-(Difluoromethoxy)pyridin-2-yl)amino)-5-(pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-Difluoroethyl)pyridin-2-yl)amino)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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)amino)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-Difluoroethyl)pyridin-2-yl)amino)-5-(2-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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)amino)-5-(2-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyridin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-difluoroethyl)pyrazin-2-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((6-(2-fluoropropan-2-yl)pyrazin-2-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-difluoroethyl)-4-methoxypyridin-2-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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)amino)-5-(6-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-difluoroethyl)pyridin-4-yl)amino)-5-(6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(1,1-difluoroethyl)pyrimidin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(1-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-(1,1-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, (R)-N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((6-(1,1-difluoroethyl)-4-methoxypyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-difluoroethyl)-4-(2-methoxyethoxy)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((6-(1,1-difluoroethyl)pyrazin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide-2,2,2-d3, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((6-(2-fluoropropan-2-yl)pyridin-2-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(2-fluoropropan-2-yl)pyridin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyridin-4-yl)amino)-5-(6-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-methylpyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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[1,5-a]pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(7-hydroxy-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(dimethylamino)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(2-ethoxyethyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(2-methoxy-2-methylpropyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(methoxymethyl)thiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(methoxymethyl)thiazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-(methoxymethyl)thiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-morpholinothiazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1,2,4-thiadiazol-5-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(dimethylamino)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-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-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(5-(6-(2-cyanopropan-2-yl)pyrimidin-4-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-isopropoxypyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-ethoxypyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-ethylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-isopropylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(difluoromethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(dimethylamino)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(2-methoxyethoxy)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(2-methoxyethyl)-6-oxo-1,6-dihydropyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methylpyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(dimethylamino)pyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(isopropylamino)pyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-morpholino-1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(dimethylamino)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(2-methoxyethyl)-1H-pyrazol-5-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(2-methoxyethyl)-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(2-methoxyethyl)-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(2-methoxypropan-2-yl)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4’-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-((difluoromethoxy)methyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-((dimethylamino)methyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-morpholino-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(morpholinomethyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(6-(2-methoxyethoxy)pyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(dimethylamino)thiazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methoxypyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(6-((2-methoxyethyl)amino)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(6-((2-methoxyethyl)(methyl)amino)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4’-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(dimethylamino)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4-((2-(1,1-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, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(tetrahydrofuran-2-yl)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(tetrahydrofuran-2-yl)pyridin-2-yl)acetamide, N-(4’-((2-(2-oxabicyclo[2.1.1]hexan-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methyl-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]pyridin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(pyrrolidin-1-ylmethyl)pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(5-(5-Cyanopyridazin-3-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-((dimethylamino)methyl)-1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, 1-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)urea, 1-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)-3-methylurea, 1-(4’-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-fluoro-[2,3’-bipyridin]-6’-yl)-3-methylurea, 1-(4’-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-fluoro-[2,3’-bipyridin]-6’-yl)urea, 1-(5-cyano-4’-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3’-bipyridin]-6’-yl)urea, (S)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-fluoropropoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(5-methoxypyridin-3-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((6-((2-oxaspiro[3.3]heptan-6-yl)oxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, (S)-N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxypropoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((1-methyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((6-(1-Cyclopropyl-1H-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-(1,1-difluoroethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetic acid, N-(4-((2-(1,1-Difluoroethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, 4-(6-((2-Acetamido-5-ethoxypyridin-4-yl)amino)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1H-pyrazole-1-carboxylic acid tert-butyl, N-(4-((2-(1,1-difluoroethyl)-6-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((6-(1-cyclobutyl-1H-pyrazol-4-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(methoxy-d3)pyridin-2-yl)acetamide, N-(5-(2-cyclopropoxyethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-ethylisoxazol-5-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-methyloxazol-5-yl)methoxy)pyridin-2-yl)acetamide, (R)-N-(5-(2-(tert-Butoxy)propoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methyloxazol-5-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methyloxazol-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-(methoxymethyl)cyclopropyl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-ethyloxazol-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(2-fluoropyridin-3-yl)ethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methylthiazol-4-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4,6-dimethylpyrimidin-5-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-ethyl-1,2,4-oxadiazol-5-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1r,3r)-3-fluorocyclobutyl)methoxy)pyridin-2-yl)acetamide, N-(5-((5-cyanofuran-2-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methylthiazol-5-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methylisoxazol-4-yl)methoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-fluorobutoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methoxytetrahydro-2H-pyran-4-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4,5-dimethyloxazol-2-yl)methoxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-fluorobutoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-(fluoromethyl)tetrahydro-2H-pyran-4-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methoxypyrimidin-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6-methoxypyrimidin-4-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1s,4s)-4-methyl-2-oxabicyclo[2.2.2]octan-1-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(pyridin-2-ylmethoxy)pyridin-2-yl)acetamide, N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((3,4-difluorobenzyl)oxy)pyridin-2-yl)acetamide, N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((1r,3r)-3-methoxycyclobutoxy)pyridin-2-yl)acetamide, N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((1s,3s)-3-methoxycyclobutoxy)pyridin-2-yl)acetamide, N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((1r,3r)-3-fluorocyclobutoxy)pyridin-2-yl)acetamide, N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((1s,3s)-3-fluorocyclobutoxy)pyridin-2-yl)acetamide, N-(5-((1-Cyclobutyl-1H-pyrazol-4-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyridin-3-ylmethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methoxypyrazin-2-yl)oxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6-methoxypyrazin-2-yl)oxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6-methoxypyridazin-3-yl)oxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)pyridin-2-yl)acetamide, (4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)methyl carbamate, N-(4-((2-(1,1-difluoroethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(ethoxy-d5)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(ethoxy-d5)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(1-isopropyl-1H-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-(1,1-Difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(pyridin-2-ylmethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(5-methylpyridin-3-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(6-ethylpyridin-3-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(6-methoxypyridin-3-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(5-methoxypyridin-3-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(1-isobutyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((6-Chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(3-fluoropyridin-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((6-(1-Cyclobutyl-1H-pyrazol-4-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((6-(1-Cyclopropyl-1H-pyrazol-4-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((6-(1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(pyridin-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(5-fluoro-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(5-fluoropyridin-2-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(5-fluoro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(2-methylthiazol-5-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(pyridin-3-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(5-methylpyridin-3-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-2'-morpholino-[4,5'-bipyrimidin]-6-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(6-methoxypyridin-3-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(1-isobutyl-1H-pyrazol-4-yl)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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(7-fluoro-2-methyl-2H-indazol-5-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(2,8-dimethyl-[1,2,4]triazolo[1,5-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-(1,1-difluoroethyl)-6-(2,7-dimethyl-2H-indazol-5-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(8-methoxy-2-methylimidazo[1,2-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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, 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-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-fluoroethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(3-fluoropropoxy)pyridin-2-yl)acetamide, N-(4-((2-(2-Fluoropropan-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-fluoroethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-((1r,3r)-3-methoxycyclobutoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-((1s,3s)-3-methoxycyclobutoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-((1r,3r)-3-fluorocyclobutoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-((1s,3s)-3-fluorocyclobutoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1s,3s)-3-fluorocyclobutoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-((1s,3s)-3-fluorocyclobutoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-((1s,3s)-3-fluorocyclobutoxy)pyridin-2-yl)acetamide, N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(methoxy-d3)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-fluorotetrahydro-2H-pyran-3-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((2S,6S)-6-methyltetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6,6-dimethyl-1,4-dioxan-2-yl)methoxy)pyridin-2-yl)acetamide, (S)-N-(5-(2-Cyclobutyl-2-fluoroethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1r,4s)-1-(fluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(spiro[2.2]pentan-1-ylmethoxy)pyridin-2-yl)acetamide, N-(5-(((1r,4r)-7-oxabicyclo[2.2.1]heptan-1-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxybutoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1S,2S)-2-fluorocyclopropyl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1S,2R)-2-fluorocyclopropyl)methoxy)pyridin-2-yl)acetamide, (S)-N-(5-(2-(tert-Butoxy)propoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1R,2S)-2-(fluoromethyl)cyclopropyl)methoxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-fluoro-3-methylbutoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5,5-dimethyl-1,4-dioxan-2-yl)methoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methyltetrahydrofuran-3-yl)methoxy)pyridin-2-yl)acetamide, N-(5-(((1R,3R)-5-oxaspiro[2.4]heptan-1-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, (R)-N-(5-((6-oxaspiro[3.4]octan-7-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-(tetrahydrofuran-2-yl)propoxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-methyltetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-yl)acetamide, 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)amino)-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-methoxyethoxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-methoxy-2-methylpropoxy)pyridin-2-yl)acetamide, N-(4-((4-(2-Fluoropropan-2-yl)-6-methylpyrimidin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((2R,6R)-6-methyltetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-yl)acetamide, (S)-N-(5-((5,8-Dioxaspiro[3.5]nonan-6-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-fluorobutoxy)pyridin-2-yl)acetamide, (S)-N-(5-((1,4-Dioxan-2-yl)methoxy)-4-((6-cyclopropoxy-2-(1,1-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, (4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(dimethylamino)ethoxy)pyridin-2-yl)methyl carbamate, N-(4-((2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(5-Methoxy-4-((6-methyl-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-Methoxy-4-((2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-Methoxy-4-((6-methyl-2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-Methoxy-4-((2-methoxy-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, (S)-N-(5-((1,4-dioxan-2-yl)methoxy)-4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, (R)-N-(5-((1,4-dioxan-2-yl)methoxy)-4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((6-cyclobutoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((6-((1s,3s)-3-cyanocyclobutoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-((1r,3r)-3-fluorocyclobutoxy)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-((1s,3s)-3-fluorocyclobutoxy)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((6-(3,3-difluorocyclobutoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((6-(3,3-difluorocyclobutoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-((1s,3s)-3-fluorocyclobutoxy)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide, N-(4-((6-cyclobutoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-((1s,3s)-3-methylcyclobutoxy)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((6-((1s,3s)-3-cyanocyclobutoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(5-((3,3-difluorocyclobutyl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-fluorobenzyl)oxy)pyridin-2-yl)acetamide, N-(5-((3,4-difluorobenzyl)oxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-methoxybenzyl)oxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-methylpyridin-3-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methylpyridin-3-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methylpyridin-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methoxypyridin-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyridin-4-ylmethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(pyridin-2-yl)ethoxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methylpyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methylpyrrolidin-2-yl)methoxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methylpyrrolidin-3-yl)methoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-isopropoxyethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-fluorooxetan-3-yl)methoxy)pyridin-2-yl)acetamide, N-(5-(Benzo[d][1,3]dioxol-5-ylmethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-(methylamino)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-hydroxypyridin-2-yl)acetamide, N-(5-(Benzyloxy)-4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((6-(Cyclobutylamino)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(ethoxy-d5)pyridin-2-yl)acetamide, N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(ethoxy-d5)pyridin-2-yl)acetamide, N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(5-Ethoxy-4-((6-methoxy-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxy-2-methylpropoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methoxycyclobutyl)methoxy)pyridin-2-yl)acetamide, (S)-N-(5-((1-Cyclopropylpyrrolidin-3-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(isoxazol-3-ylmethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methyl-1H-imidazol-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methylisoxazol-3-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-oxotetrahydrofuran-2-yl)methoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-oxopyrrolidin-2-yl)methoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(1-methylpyrrolidin-2-yl)ethoxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-oxopyrrolidin-2-yl)methoxy)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-isopropylmorpholin-2-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(isoxazol-4-ylmethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(oxazol-4-ylmethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methylazetidin-3-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-ethoxyethoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methyl-1H-pyrazol-4-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-ethyl-1H-pyrazol-4-yl)methoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-isopropyl-5-oxopyrrolidin-3-yl)methoxy)pyridin-2-yl)acetamide, (S)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methyl-5-oxopyrrolidin-3-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methoxy-1-methyl-1H-pyrazol-4-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1R,3S)-3-methoxycyclopentyl)oxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1s,4s)-4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(ethoxy-d5)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoropropyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-5-methoxypyrimidin-4-yl)amino)-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-((1r,3r)-3-methoxycyclobutoxy)-2-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, 1-(5-cyano-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)-3-methylurea, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(4-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((difluoromethoxy)methyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-cyano-4'-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide-2,2,2-d3, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)pyridin-2-yl)acetamide, N-(5-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]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[2,1-c][1,4]oxazin-2-yl)-4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-([1,2,4]Triazolo[4,3-a]pyrazin-6-yl)-4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(2-Fluoropropan-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(imidazo[1,2-a]pyrimidin-7-yl)pyridin-2-yl)acetamide, N-(5-([1,2,4]Triazolo[1,5-a]pyrimidin-5-yl)-4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)pyridin-2-yl)acetamide, N-(5-([1,2,4]Triazolo[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]Triazolo[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)amino)-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(ethylsulfonyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(methylsulfonyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4-((2-(2-oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(methyl-d3)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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)amino)-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5,6-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(2-Methoxyethoxy)pyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(2-Methoxyethoxy)pyrimidin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-Methoxy-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-Methoxypyrimidin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-Methyl-1H-pyrazol-3-yl)-4-((6-methyl-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-Methyl-1H-pyrazol-3-yl)-4-((6-methyl-2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-Methyl-1H-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-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1-Fluorocyclopropyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(2-Methoxyethoxy)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-((1s,4s)-1-(Fluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1-(Methoxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(2-Oxabicyclo[2.1.1]hexan-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(5,5-difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)pyridin-2-yl)acetamide, N-(4’-((2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-ethylpyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(5-(methoxymethyl)-4’-((2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)-[2,3’-bipyridin]-6’-yl)acetamide, N-(5-(methoxymethyl)-4’-((6-methyl-2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((6-ethyl-2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(5-(methoxymethyl)-4’-((6-(methoxymethyl)-2-(tetrahydrofuran-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[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(difluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-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[2.1.1]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-methylpyrimidin-4-yl)amino)-5-(1-methoxyethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((2-(2-Oxabicyclo[2.1.1]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-methylpyrimidin-4-yl)amino)-5-(1-fluoroethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methyloxazol-4-yl)pyridin-2-yl)acetamide, N-(5-(1-Cyclobutyl-1H-pyrazol-4-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methyloxazol-4-yl)pyridin-2-yl)acetamide, N-(4’-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-[2,3’-bipyridin]-6’-yl)acetamide, N-(5-Cyano-4’-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-methyloxazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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’-bipyridin]-6’-yl)acetamide, N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(2-methoxyethyl)-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4’-((6-(Difluoromethoxy)pyrazin-2-yl)amino)-5-(methoxymethyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(1,1-Difluoroethyl)-5-methoxypyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-5-methoxypyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methyloxazol-2-yl)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-methyl-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methylpyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(oxazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-methyl-1H-pyrazol-1-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-fluoropyrazin-2-yl)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-methoxy-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methyloxazol-5-yl)pyridin-2-yl)acetamide, N-(5-(2-Cyano-1-methyl-1H-imidazol-4-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-Cyclopropyl-1H-pyrazol-3-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-isopropyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-Cyclobutyl-1H-pyrazol-4-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(thiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methylthiazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(methoxymethyl)-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-isopropyl-2H-1,2,3-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-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-isopropylthiazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-(Cyclopropylmethyl)-1H-pyrazol-3-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-propyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-fluoro-1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxythiazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1,5-dimethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrazin-2-yl)pyridin-2-yl)acetamide N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methoxy-6-methylpyrimidin-2-yl)pyridin-2-yl)acetamide N-(4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-fluoro-5-methoxy-[2,3’-bipyridin]-6’-yl)acetamide N-(4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-fluoro-[2,3’-bipyridin]-6’-yl)acetamide N-(4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-4-fluoro-[2,3’-bipyridin]-6’-yl)acetamide N-(6’-bromo-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[3,3’-bipyridin]-6-yl)acetamide N-(5-bromo-4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3’-bipyridin]-6’-yl)acetamide N-(4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-4-(dimethylamino)-[2,3’-bipyridin]-6’-yl)acetamide N-(4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-morpholino-[2,3’-bipyridin]-6’-yl)acetamide N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(dimethylamino)pyrimidin-4-yl)pyridin-2-yl)acetamide N-(6-cyano-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide N-(4-cyano-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide N-(5-cyano-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-3-fluoro-[2,3'-bipyridin]-6'-yl)acetamide N-(6-cyano-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-methoxy-[2,3'-bipyridin]-6'-yl)acetamide N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5,6-dimethoxy-[2,3'-bipyridin]-6'-yl)acetamide (S)-N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(1-hydroxyethyl)-[2,3'-bipyridin]-6'-yl)acetamide N-(4'-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(tetrahydrofuran-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, (S)-N-(4'-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(4-methylmorpholin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, (S)-N-(4'-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(4-methylmorpholin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, (R)-N-(4'-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(4-methylmorpholin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, (R)-N-(4'-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methylmorpholin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, (S)-N-(4'-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methylmorpholin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, (R)-N-(4'-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methylmorpholin-3-yl)-[2,3'-bipyridin]-6'-yl)acetamide, (S)-N-(4'-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methylmorpholin-3-yl)-[2,3'-bipyridin]-6'-yl)acetamide, (S)-N-(4'-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(tetrahydro-2H-pyran-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((dimethylamino)methyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(morpholinomethyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(morpholinomethyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methylpiperazin-1-yl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(dimethylamino)-[2,3’-bipyridin]-6’-yl)acetamide, N-(6-(2-cyanopropan-2-yl)-4’-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3’-bipyridin]-6’-yl)acetamide, N-(6-(2-cyanopropan-2-yl)-4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3’-bipyridin]-6’-yl)acetamide, N-(5-(5-cyanopyrimidin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methoxypyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-fluoro-4-methoxypyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(difluoromethoxy)pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(methoxymethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-((difluoromethoxy)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methoxy-5-methylpyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(2-methoxyethyl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(methoxymethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(5-(4-cyclopropylpyrimidin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-(6-cyclopropylpyrazin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(5-(5-Chloropyrimidin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(difluoromethyl)pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methylpyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(methoxymethyl)pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-fluoro-4-methylpyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-morpholinopyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-((dimethylamino)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-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-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5,6-dimethoxypyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2,6-dimethoxypyrimidin-4-yl)pyridin-2-yl)acetamide, N-(5-(6-(Cyanomethyl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(difluoromethoxy)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(oxetan-3-yloxy)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(2-methoxyethoxy)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-((difluoromethoxy)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methylpyrazin-2-yl)pyridin-2-yl)acetamide, N-(5-(5-Cyclopropylpyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-(5-(1,1-Difluoroethyl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(methoxymethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(5-(5-Chloropyrimidin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4’-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-3-fluoro-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-fluoro-4-methoxy-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-4-methyl-[2,3’-bipyridin]-6’-yl)acetamide, N-(5-cyano-4’-((2-(1,1-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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3’-bipyridin]-6’-yl)acetamide, N-(5-((2-oxa-6-azaspiro[3.4]octan-6-yl)methyl)-4’-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3’-bipyridin]-6’-yl)acetamide, N-(5-(1-(Cyclopropylmethyl)-1H-pyrazol-3-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(1-propyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(2-Cyano-1-methyl-1H-imidazol-4-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-isopropyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-ethyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(2-methoxyethyl)-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(methoxymethyl)-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxythiazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(2-fluoropropan-2-yl)thiazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-ethyl-1,3,4-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-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-yl)acetamide, N-(5-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(methoxymethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4’-((5-(2-fluoropropan-2-yl)pyridin-3-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4-((2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-morpholinopyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-methyl-1H-pyrazol-1-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methyl-1H-pyrazol-1-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-methoxy-1H-pyrazol-1-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methoxy-1H-pyrazol-1-yl)pyridin-2-yl)acetamide, N-(5-(4-cyano-1H-pyrazol-1-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-(4-cyano-1H-pyrazol-1-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-2-yl)acetamide, N-(5-(5-(cyanomethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-((dimethylamino)methyl)thiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(pyrrolidin-1-ylmethyl)thiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4’-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-4-((dimethylamino)methyl)-[2,3’-bipyridin]-6’-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(1-(dimethylamino)ethyl)pyrazin-2-yl)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(1-(pyrrolidin-1-yl)ethyl)pyrazin-2-yl)pyridin-2-yl)acetamide, (S)-N-(4’-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-4-(1-(dimethylamino)ethyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(2-methoxyethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4’-((2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-cyano-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)amino)-5-fluoro-[2,3’-bipyridin]-6’-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methoxypyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(2-methoxyethyl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(methoxymethyl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(2-methoxyethyl)thiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(isothiazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-(methoxymethyl)-1,2,4-thiadiazol-5-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(dimethylamino)-1,2,4-thiadiazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-(2-methoxyethyl)-1H-pyrazol-1-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-(methoxymethyl)-1H-pyrazol-1-yl)pyridin-2-yl)acetamide, N-(5-(6-Cyanopyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(difluoromethoxy)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6,7-dihydro-5H-pyrrolo[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[2,1-b]oxazol-6-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-((2-methoxyethyl)(methyl)amino)thiazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-((2-methoxyethyl)(methyl)amino)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(difluoromethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(2-methoxyethoxy)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-(2-methoxyethoxy)pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(2-morpholinoethyl)-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(2-(4-methylpiperazin-1-yl)ethyl)-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(methoxymethyl)thiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-((dimethylamino)methyl)thiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-((4-methylpiperazin-1-yl)methyl)thiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-((dimethylamino)methyl)thiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-((4-methylpiperazin-1-yl)methyl)thiazol-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-((dimethylamino)methyl)thiazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-((4-methylpiperazin-1-yl)methyl)thiazol-4-yl)pyridin-2-yl)acetamide, N-(5-(2-(Azetidin-1-yl)thiazol-4-yl)-4-((2-(1,1-difluoroethyl)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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-(2-Cyanothiazol-4-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(pyrrolidin-1-ylmethyl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-((4-methylpiperazin-1-yl)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(morpholinomethyl)pyrazin-2-yl)pyridin-2-yl)acetamide, 1-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)-3-methylurea, 1-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyridin-2-yl)-3-methylurea, N-(4-((2-(1,1-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-(1,1-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-(1,1-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-(1,1-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)amino)-5-(pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((6-ethyl-2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-5-(pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(2-(dimethylamino)propan-2-yl)-1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-4-(pyrrolidin-1-ylmethyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-4-(morpholinomethyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-((dimethylamino)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-((1R,2S)-2-Cyanocyclopropyl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-fluoro-1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methoxypyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoropyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-fluoropyridin-2-yl)acetamide, N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-fluoropyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-fluoropyridin-2-yl)acetamide, N-(4-((6-(1,1-Difluoroethyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(difluoromethoxy)pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4’-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(difluoromethoxy)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4’-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(difluoromethyl)-[2,3’-bipyridin]-6’-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methoxypyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-methoxypyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methoxypyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((6-Cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-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-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(methoxymethyl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(1,1-difluoroethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(5-(5-Cyanopyrazin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, (R)-N-(5-(5-(1,4-Dioxan-2-yl)pyrimidin-2-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(dimethylamino)pyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(dimethylamino)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(pyrrolidin-1-yl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-morpholinopyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(pyrrolidin-1-yl)pyridazin-3-yl)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(5-Cyanopyrimidin-2-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(difluoromethoxy)pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(difluoromethoxy)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(5-Cyanopyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(difluoromethoxy)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(dimethylamino)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(methylamino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-Difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(difluoromethoxy)pyridazin-3-yl)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(methylamino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(methylamino)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-morpholinopyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(6-(dimethylamino)pyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(6-morpholinopyridazin-3-yl)pyridin-2-yl)acetamide, N-(5-(5-cyanopyrazin-2-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-((2-methoxyethyl)(methyl)amino)pyrazin-2-yl)pyridin-2-yl)acetamide, (R)-N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(3-methoxypyrrolidin-1-yl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(3-methoxy-3-methylazetidin-1-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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-(5-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-(5-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazin-2-yl)-4-((2-(1,1-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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(3-methoxypyrrolidin-1-yl)pyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(3-methoxy-3-methylazetidin-1-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-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridazin-3-yl)-4-((2-(1,1-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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(pyrrolidin-1-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)acetamide, (R)-N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((3-methylmorpholino)methyl)-[2,3'-bipyridin]-6'-yl)acetamide, (S)-N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((3-methoxypyrrolidin-1-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((3-methoxy-3-methylazetidin-1-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(((tetrahydro-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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(5-((1R,5S)-6-Oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)-4-((2-(1,1-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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-((6-Oxa-2-azaspiro[3.4]octan-2-yl)methyl)-4'-((2-(1,1-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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(6-(difluoromethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide, (S)-N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((3-methylmorpholino)methyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(pyrrolidin-1-ylmethyl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(5-(5-(((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-((dimethylamino)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(2-methoxypropan-2-yl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(5-(6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridazin-3-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide, (R)-N-(5-(5-(1,4-dioxan-2-yl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(morpholinomethyl)pyrazin-2-yl)pyridin-2-yl)acetamide, N-(5-(5-(((1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)pyrazin-2-yl)-4-((2-(1,1-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-(((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(pyrrolidin-1-ylmethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-6-(pyrrolidin-1-ylmethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(6-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)pyrimidin-4-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(6-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)pyrimidin-4-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(6-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(morpholinomethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-6-(morpholinomethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-6-((dimethylamino)methyl)-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(((1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)-4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-(((1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)pyrimidin-4-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-(6-(((1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)pyrimidin-4-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide, N-(6-(((1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)-4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(dimethylphosphoryl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(dimethylphosphoryl)pyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide, 1-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(pyrazin-2-yl)pyridin-2-yl)-3-methylurea, 1-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(pyrazin-2-yl)pyridin-2-yl)urea, N-(4-((2-(1,1-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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0070] In a 52nd 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 above embodiments) or a pharmaceutically acceptable salt thereof.

[0071] The compounds and intermediates described herein can be isolated and used as the compounds themselves. Alternatively, if there are sites capable of forming salts, the compounds or intermediates can be isolated and used as their corresponding salts. As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds described herein. The term "salt" includes, in particular, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds described herein and that are generally not undesirable, either biologically or otherwise. In many cases, the compounds of the present disclosure have the ability to form acidic salts and / or basic salts because of the presence of amino groups and / or carboxyl groups, or groups similar thereto.

[0072] Pharmaceutically acceptable acid addition salts can be formed, for example, using inorganic or organic acids such as acetates, aspartates, benzoates, besylates, bromide / hydrobromide salts, bicarbonate / carbonate salts, bisulfate / sulfate salts, camphorsulfonates, chloride / hydrochloride salts, chlortheophyllonate, citrates, ethanedisulfonates, fumarates, gluceptates, gluconates, glucuronates, hippurates, hydroiodide / iodide salts, isethionates, lactates, lactobionates, lauryl sulfates, malates, maleates, malonates, mandelates, mesylates, methyl sulfates, naphthoates, napsylates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, pamoates, phosphate / hydrogen phosphate / dihydrogen phosphate salts, polygalacturonates, propionates, stearates, succinates, sulfates, sulfosalicyclates, tartrates, tosylates and trifluoroacetates.

[0073] Examples of inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0074] Examples of organic acids capable of inducing salts include 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.

[0075] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0076] Examples of inorganic bases capable of inducing salts include ammonium salts and metals in Groups 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, and particularly preferred salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0077] Examples of organic bases capable of inducing salts include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Specific organic amines include isopropylamine, benzathine, cholineate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0078] Salts can be synthesized from compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in their free acid form with a stoichiometric amount of a suitable base (e.g., hydroxides, carbonates, bicarbonates of Na, Ca, Mg or K, etc.) or reacting these compounds in their free base form with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, an organic solvent, or a mixture of the two. Generally, the use of a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is desirable when feasible. A further list of suitable salts can be found, for example, in “Remington’s Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985), and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0079] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art using a suitable isotopically labeled reagent in place of the previously used unlabeled reagent, or by a process similar to those described in the appended examples and preparations. In one embodiment, the present disclosure provides deuterated compounds described herein or pharmaceutically acceptable salts thereof.

[0080] Pharmaceutically acceptable solvates according to the invention include solvates in which the crystallization solvent can be an isotopically substituted solvent, for example, D2O, d6-acetone, d6-DMSO.

[0081] It will be appreciated by those skilled in the art that the compounds of the present invention may contain chiral centers and, therefore, may exist in different stereoisomeric forms. As used herein, the terms "optical isomers" or "stereoisomers" refer to any of the various stereoisomeric arrangements that may exist in a given compound of the present disclosure. It is understood that a substituent may be attached to a chiral center of a carbon atom. Accordingly, the present disclosure encompasses enantiomers, diastereomers, or racemates of the compounds.

[0082] "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 terms "racemic" or "rac" are used to denote a racemic mixture where appropriate. When specifying the stereochemistry of a compound of the present invention, a single stereoisomer for which the relative and absolute configurations of two chiral centers are known is designated using the conventional RS system (e.g., (1S,2S)). "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is defined by the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as either R or S. Optically resolved compounds of unknown absolute configuration may be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) in which they rotate plane-polarized light at the wavelength of the sodium D line. Alternatively, an optically resolved compound can be defined by its respective retention times on chiral HPLC with respect to the corresponding enantiomer / diastereomer.

[0083] Some of the compounds described herein contain one or more asymmetric centers or axes of chirality and, therefore, may give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be designated as (R)- or (S)- by absolute stereochemistry.

[0084] Unless otherwise specified, the compounds of the present disclosure are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, and mixtures of intermediates. The (R)- and (S)-stereoisomers with optical activity can be prepared using a chiral synthon or chiral reagent, or can be resolved using conventional techniques (e.g., separated on a chiral SFC or HPLC chromatography column, such as CHIRALPAK® and CHIRALCEL® available from DAICEL Corp., using an appropriate solvent or solvent mixture for good separation). When the compound contains a double bond, the substituents can be in the E configuration or the Z configuration. When the compound contains a disubstituted cycloalkyl, the substituents of the cycloalkyl can have the cis configuration or the trans configuration. All tautomeric forms are also intended to be included.

[0085] Method of Use The compounds disclosed herein have TYK2 activity. As used herein, "TYK2 inhibitory activity" means the ability of a compound or composition to induce a detectable decrease in TYK2 activity in vivo or in vitro (e.g., at least a 10% decrease in TYK2 activity as measured by a given assay, such as the biological assays described in the Examples and known in the art).

[0086] In certain embodiments, the present disclosure provides a method of treating a disease or disorder responsive to inhibition of TYK2 activity (referred to herein as a "TYK2-mediated disease or disorder" or a "disease or disorder mediated by TYK2") in a subject in need thereof. The method includes administering to the subject a compound described herein (e.g., a compound of formula (I) according to any one of Embodiments 1 to 42), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0087] In certain embodiments, the present disclosure provides for the use of a compound described herein (e.g., a compound of formula (I) according to any one of embodiments 1 to 42) 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 thereof, or the use of a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof.

[0088] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound of formula (I) according to any one of embodiments 1 to 42) 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 subject in need thereof for a TYK2-mediated disorder or disease.

[0089] In some embodiments, the disease or disorder responsive to inhibition of TYK2 activity is inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and myocardial reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain injury, 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 infections, myalgia, endotoxin 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, flushing, eczema, psoriasis, atopic dermatitis, and sunburn.

[0090] In certain embodiments, the present disclosure relates to the aforementioned methods where the subject is a mammal. In certain embodiments, the subject is a primate. In certain embodiments, the subject is a human.

[0091] As used herein, the terms "effective amount" and "therapeutically effective amount" may be used interchangeably. It means an amount effective to treat or reduce the severity of one or more of the diseases, disorders or conditions listed herein. In some embodiments, the effective dosage may be from 10 μg to 500 mg.

[0092] The compounds and compositions according to the methods of the present disclosure can be administered in any amount and by any route of administration effective to treat or reduce the severity of one or more of the diseases, disorders or conditions listed above.

[0093] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the compounds are administered parenterally. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the compounds are administered intramuscularly, intravenously, subcutaneously, orally, intratracheally, rectally, intrathecally, topically or intranasally. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the compounds are administered systemically.

[0094] The compounds of the present invention can be used as pharmaceutical compositions (e.g., the compounds of the present invention and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceutically acceptable carrier" will be understood by those skilled in the art and generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), and the like, as well as combinations thereof (see, e.g., Remington’s Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Any conventional carrier is contemplated for use in therapeutic or pharmaceutical compositions, except where it is incompatible with the active ingredient. For the purposes of the present disclosure, solvates and hydrates are considered to be pharmaceutical compositions comprising the compounds of the present invention and a solvent (i.e., solvate) or water (i.e., hydrate).

[0095] The formulations can be prepared using conventional dissolution and mixing procedures. For example, a bulk active pharmaceutical ingredient (i.e., the compound of the present invention, or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above excipients. The compounds of the present invention are typically formulated into pharmaceutical dosage forms in order to provide an easily controllable dosage of the drug and to give the patient a sophisticated and easily handled product.

[0096] The pharmaceutical composition (or formulation) for administration can be packaged in various ways depending on the method used to administer the drug. Generally, an article for sale includes a container enclosing a pharmaceutical formulation in a suitable form. Suitable containers are well known to those skilled in the art and include, for example, materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container may also include an anti-tampering mechanism to prevent inadvertent access to the contents of the package. In addition, a label describing the contents of the container is placed on the container. The label may also include appropriate cautions.

[0097] The pharmaceutical composition containing the compounds of the present disclosure is typically formulated for use as parenteral administration, oral administration, or as a suppository.

[0098] For example, the oral pharmaceutical composition of the present disclosure can be configured in a solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in a liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical composition can be subjected to conventional pharmaceutical operations such as sterilization, and / or can contain conventional inert diluents, lubricants, or buffering agents, and can also contain excipients such as preservatives, stabilizers, wetting agents, emulsifying agents, and buffering agents.

[0099] Typically, the pharmaceutical composition, together with the active ingredient, a) containing a diluent, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) in the case of tablets, also containing a lubricant, for example, silica, talc, stearic acid, its magnesium salt or calcium salt, and / or polyethylene glycol; c) optionally containing a binder, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, and / or polyvinyl pyrrolidone; d) containing a disintegrant, for example, starch, agar, alginic acid or its sodium salt, or a foaming mixture; and / or e) containing an absorbent, a coloring agent, a flavoring agent and a sweetening agent, which is a tablet or a gelatin capsule.

[0100] The tablets can be film-coated or enteric-coated according to methods known in the art.

[0101] Compositions suitable for oral administration include the compounds of the present disclosure in the form of tablets, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, 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 may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to provide a palatable preparation refined as a drug. Tablets may contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients 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 such as corn starch or alginic acid; binding agents such as starch, gelatin or acacia gum; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be 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, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium such as peanut oil, liquid paraffin or olive oil.

[0102] Parenteral compositions (e.g., intravenous (IV) formulations) are aqueous isotonic solutions or suspensions. Parenteral compositions may be sterilized and / or may contain excipients such as preservatives, stabilizers, wetting or emulsifying agents, solubilizing agents, salts for adjusting osmotic pressure, and / or buffers. In addition, it may also contain other therapeutically valuable substances. The compositions are generally prepared according to conventional mixing, granulating or coating methods respectively, and contain the active ingredient in an amount of about 0.1 to 7.5% or about 1 to 50%.

[0103] The compounds of the present disclosure or pharmaceutical compositions thereof for use in a subject (e.g., a human) are typically administered orally or parenterally at therapeutic doses. When administered intravenously by infusion, the dosage can be determined by the infusion rate at which the IV formulation is administered. In general, the therapeutically effective dosage of a compound, pharmaceutical composition, or combination thereof is determined by the species, body weight, age, and individual physical condition of the subject, the disorder or disease being treated, or the severity thereof. A physician, pharmacist, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient necessary to prevent, treat, or arrest the progression of a disorder or disease.

[0104] The dosage characteristics exemplified above can advantageously be demonstrated in in vitro and in vivo tests using mammals such as mice, rats, dogs, monkeys, or isolated organs, tissues, and preparations thereof. The compounds of the present invention may be applied in vitro in the form of a solution, e.g., an aqueous solution, and may also be applied in vivo enterally or parenterally, preferably intravenously, as, for example, a suspension or an aqueous solution. The dosage in vitro can be in the range between about 10-3 molar concentration and 10-9 molar concentration.

[0105] Definitions As used herein, the terms “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. The term includes mammals, such as humans. Typically, the animal is a mammal. The subject also refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. Preferably, the subject is a human.

[0106] As used herein, the terms “inhibit,” “inhibition,” or “inhibiting” mean the reduction or suppression of a given medical condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0107] As used herein, the terms "treating," "treatment," or "treat" with respect to any disease, condition, or disorder mean the management and care of a patient for the purpose of combating the disease, condition, or disorder, and includes administration of a compound of the invention to obtain the desired pharmacological and / or physiological effect. The effect can be therapeutic and includes, but is not limited to, partially or substantially bringing about one or more of the following results: reducing in part or completely the degree of the disease, condition, or disorder; ameliorating or improving the clinical symptoms, complications, or indicia associated with the disease, condition, or disorder; or delaying, suppressing, or reducing the likelihood of progression of the disease, condition, or disorder; or eliminating the disease, condition, or disorder. In certain embodiments, the effect can be preventing the onset of symptoms or complications of the disease, condition, or disorder.

[0108] As used herein, the term "cancer" has the meaning commonly accepted in the art. In a broad sense, the term can mean abnormal cell growth.

[0109] As used herein, the term "autoimmune disease" has the meaning commonly accepted in the art. In a broad sense, the term can refer to a disease in which the host's immune system targets or attacks the host's normal or healthy tissues.

[0110] As used herein, the term "myelination" has the meaning commonly accepted in the art. In a broad sense, the term can mean the process by which myelin is produced.

[0111] As used herein, the terms "myelin-related disease or disorder," "demyelinating disorder," or "demyelation disorder" have the meaning commonly accepted in the art. In a broad sense, the term can refer to a disease or disorder associated with damage to myelin.

[0112] As used herein, a subject "in need of" treatment is one in which such subject (preferably a human) would biologically, medically or in terms of quality of life benefit from such treatment.

[0113] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". Generally, the term "optionally substituted" means replacing a hydrogen radical with a radical of a designated substituent in a given structure. Specific substituents are described in the definitions and descriptions of the compounds and their examples. Unless otherwise indicated, an optionally substituted group may have substituents at each substitutable position of the group, and if more than one position in any given structure can be substituted with more than one substituent selected from the designated groups, the substituents may be the same or different at all positions. In some embodiments, an optionally substituted group may be substituted with one or more substituents, each of which may be 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 may be the same or different. In some embodiments, the "one or more" substituents can be 1-6, 1-4, 1-3, or 1-2 substituents, each of which may be the same or different. In the case of bicyclic heteroaryl, and bicyclic, fused, spiro or bridged heterocyclyl or carbocyclyl, the optional substituents can be on any or all of the rings. For example, if a bicyclic heteroaryl is illustrated below, the substituent R 3c can be on either the 6-membered or 5-membered ring.

Chemical formula

[0114] As used herein, the term "alkyl" refers to a fully saturated, branched or unbranched hydrocarbon moiety. "C 1-4The term "alkyl" refers to an alkyl having 1 to 4 carbon atoms. "C 1~3 alkyl" and "C 1~2 alkyl" should be interpreted accordingly. "C 1~4 alkyl" representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Similarly, the alkyl moiety of alkoxy (i.e., the alkyl portion) has the same definition as above. When indicated as "optionally substituted", the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (usually 1 to 3 substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0115] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety (i.e., C 1-4 alkyl as defined herein) bonded via an oxygen bridge, -O-C 1-4 alkyl group). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, etc. Preferably, the alkoxy group has about 1 to 4 carbons, more preferably about 1 to 2 carbons. "C 1-2 alkoxy" should be interpreted accordingly.

[0116] As used herein, "C 1-4 alkoxy C 1-4 alkyl" refers to a C 1-4 alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by C 1-4 alkoxy. The C 1-4 alkoxy C 1-4 alkyl group is linked via the alkyl group to the remainder of the molecule described herein.

[0117] The number of carbon atoms in the group is herein indicated by the prefix "C" x-xx ", where x and xx are integers. For example, "C 1-3 alkyl" is an alkyl group having 1 to 3 carbon atoms.

[0118] "Halogen" or "halo" can be fluorine, chlorine, bromine or iodine.

[0119] As used herein, the term "halo-substituted C 1-4 alkyl" or "C 1-4 haloalkyl" refers to a C 1-4 alkyl group as defined herein in which at least one hydrogen atom is replaced by a halo atom. A C 1-4 haloalkyl group can be a monohalo C 1-4 alkyl, a dihalo C 1-4 alkyl, or a polyhalo C 1-4 alkyl including perhalo C 1-4 alkyl. A monohalo C 1-4 alkyl can have one iodine, bromo, chloro or fluoro in the alkyl group. A dihalo C 1-4 alkyl group and a polyhalo C 1-4 alkyl group can have two or more of the same halo atoms or a combination of different halo groups in the alkyl. Typically, a polyhalo C 1-4 alkyl 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 C 1-4 haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhalo C 1-4 alkyl group refers to a C 1-4 alkyl group in which all hydrogen atoms are replaced by halo atoms.

[0120] The term "aryl" refers to a monocyclic or fused bicyclic aromatic carbocyclic ring containing 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0121] The term "heteroaryl" refers to a 5- to 12-membered aromatic radical containing 1 to 4 heteroatoms selected from N, O, and S. Optionally, a nitrogen atom in the heteroaryl may be quaternized. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic". The heteroaryl group may be monocyclic or bicyclic. Examples of monocyclic heteroaryl include, for example, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, furanyl, oxadiazolyl, thiophenyl, and the like. Bicyclic heteroaryl includes groups in which one or more monocyclic heteroaryl rings are fused to one or more aryl rings or heteroaryl rings. Non-limiting examples include pyrazolopyridinyl, pyrazolopyridinyl, benzotriazolyl, imidazopyridinyl, and indolyl.

[0122] The term "carbocyclic ring" or "carboscyclic" refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring, which may exist as a monocyclic, bicyclic ring (including fused, spiro or bridged carbocyclic rings), or a spiro ring. Examples of bicyclic carboscyclic groups include, for example, those in which an unsaturated carbocyclic radical is fused to another unsaturated carbocyclic radical, cycloalkyl or aryl, such as 2,3-dihydroindenyl, decahydronaphthalenyl, and 1,2,3,4-tetrahydronaphthalenyl. Unless otherwise specified, a carbocyclic ring usually contains 4 to 10 ring members.

[0123] "C 3-6 cycloalkyl" refers to a carbocyclic ring that is completely saturated (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0124] The term "heterocyclic ring" 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. The heterocyclyl group can be monocyclic or bicyclic (e.g., bridged, fused, or spirobicyclic rings). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and piperdinyl. Examples of bicyclic heterocyclyl groups include, for example, those in which an unsaturated heterocyclic radical is fused to another unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as tetrahydro-3H-[1,2,3]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 an 8- to 10-membered bicyclic heterocyclyl group. In some embodiments, the heterocyclyl group is an 8- to 10-membered bicyclic saturated heterocyclyl group.

[0125] As used herein, the term "spiro" ring means a bicyclic system in which both rings share one common atom. Examples of spiro rings include 2-oxa-6-azaspiro[3.3]heptanyl and the like.

[0126] The term "fused" ring refers to two ring systems that share two adjacent ring atoms. The fused heterocyclic ring contains ring atoms that are heteroatoms selected from O, N, and S in at least one of the ring systems (e.g., 3-oxabicyclo[3.1.0]hexane).

[0127] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic moiety that is linked by two non-adjacent ring atoms (e.g., 5-oxabicyclo[2.1.1]hexane).

[0128] The term "pharmaceutically acceptable" indicates that the substance, composition or dosage form must be chemically and / or toxicologically compatible with the other components that make up the formulation and / or the mammal to be treated thereby.

[0129] Unless otherwise specified, the term "compounds of the present disclosure" refers to compounds of formula (I), as well as any stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotope-labeled compounds (including deuterium substitution). When there is a moiety capable of forming salts, salts, especially pharmaceutically acceptable salts, are also included.

[0130] As used herein, the terms "a", "an", "the", and similar terms used in the context of the present invention (especially in the context of the claims) should be construed to include both the singular and the plural forms, unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples or exemplary expressions provided herein (e.g., "such as") is merely intended to better illustrate the present invention and does not impose a limitation on the scope of the present invention as otherwise claimed.

[0131] The intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structurally isomeric forms of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) involve interconversion by the movement of protons such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety where a proton can move between two ring nitrogens. Valence tautomers involve interconversion by rearrangement of some of the bonding electrons.

[0132] In one embodiment, the present disclosure relates to the free form of the compounds of formula (I) as defined herein. In another embodiment, the present disclosure relates to the salt form of the compounds of formula (I) as defined herein. In another embodiment, the present disclosure relates to the acid addition salt form of the compounds of formula (I) as defined herein. In a further embodiment, the present disclosure relates to the compounds of formula (I) as defined herein in the form of a pharmaceutically acceptable salt. In yet another further embodiment, the present disclosure relates to the compounds of formula (I) as defined herein in the form of a pharmaceutically acceptable acid addition salt. In yet another further embodiment, the present disclosure relates to the free form of any one of the compounds of the examples. In yet another further embodiment, the present disclosure relates to the salt form of any one of the compounds of the examples. In yet another further embodiment, the present disclosure relates to the acid addition salt form of any one of the compounds of the examples. In yet another further embodiment, the present disclosure relates to the compounds of the examples in the form of a pharmaceutically acceptable salt. In yet another embodiment, the present disclosure relates to the compounds of the examples in the form of a pharmaceutically acceptable acid addition salt.

[0133] The compounds of the present disclosure can be synthesized by synthetic routes that include processes similar to those well known in the chemical art, particularly in view of the descriptions contained herein. Starting materials are generally available from commercial sources such as Sigma-Aldrich or can be readily prepared using methods well known to those skilled in the art (e.g., 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, 4th Aufl. ed. Springer-Verlag, Berlin (also available from the Beilstein online database), including supplements).

[0134] For illustrative purposes, the reaction schemes shown below provide possible routes for synthesizing the compounds and key intermediates of the present disclosure. For a more detailed description of the individual reaction steps, see the Examples section below. Specific starting materials and reagents are shown in the schemes and described below, but it is readily possible to provide various derivatives and / or reaction conditions using other starting materials and reagents instead.

[0135] According to the first process, the compound of formula (I) can be prepared from the compounds of formulas (II’) and (III’) as shown in Scheme 1.

Chemical formula

[0136] The compound of formula (I) can be prepared from the compounds of formulas (II’) and (III’) according to the Buchwald-Hartwig cross-coupling reaction of process step (a). Typical conditions include the reaction of the compound of formula (II’) with the amine of formula (III’) in a suitable solvent at a high temperature in the presence of a suitable palladium catalyst in the presence of a suitable inorganic base and a suitable phosphine ligand. Preferred conditions include reacting the compounds of formulas (II’) and (III’) in a suitable solvent such as dioxane, DMA, DMF or toluene at 80 °C to 120 °C in the presence of a suitable base such as NaOtBu, Cs2CO3, K2CO3 or K3PO4 in the presence of Brettphos Pd G3, MolDalPhos Pd G3, Josiphos Pd G3, [XantPhos Pd(allyl)]Cl, or a combination of Xantphos or BINAP and Pd(OAc)2 or Pd2(dba)3, or a combination of Xantphos and Xantphos Pd G3.

[0137] According to the second process, the compound of formula (I) can be prepared from the compounds of formulas (IV’) and (V’) as shown in Scheme 2. [Chemical] Hal 2 is a halogen, preferably Br, Cl or I.

[0138] The compound of formula (I) can be prepared from the compounds of formulas (IV') and (V') according to the Buchwald reaction of step (a) as described in Scheme 1 above.

[0139] According to a third process, the compound of formula (I) can be prepared from the compounds of formulas (II'), (VI'), (VII'), (VIII'), (IX') and (XV') as shown in Scheme 3. [Chemical] Hal 3 is a halogen, preferably Br or I, Hal 4 is a halogen, preferably Cl.

[0140] The compound of formula (VII') can be prepared from the compounds of formulas (VI') and (II') according to the alkylation reaction of process step (b) in the presence of a suitable inorganic base and a suitable aprotic polar solvent at room temperature to high temperature. Preferred conditions include reacting the compound of formula (VI') with the compound of formula (II') in DMF or THF at room temperature to 35 °C in the presence of Cs2CO3 or K2CO3.

[0141] Alternatively, the compound of formula (VII') can be prepared from the compounds of formulas (VI') and (II') according to the Buchwald reaction of process step (a) as described in Scheme 1 above.

[0142] Here, R 2 is a 4- to 11-membered monocyclic or bicyclic heterocyclic ring, C 1-6 alkyl, or C 3-7is cycloalkyl, and the compound of formula (VIII’) can be prepared from the compound of formula (VII’) and R in accordance with the palladium-catalyzed cross-coupling reaction of process step (c), such as the Suzuki reaction. 2 BPin or R 2 B(OH)2. Typical cross-coupling reaction conditions include a palladium catalyst containing a suitable phosphine ligand in a suitable aqueous solvent from room temperature to the reflux temperature of the reactants in the presence of an inorganic base. Preferred conditions are in the presence of SPhos-Pd-G3, Pd(PCy3)2, Pd(PPh3)4, XPhos Pd(chloroethyl)Cl, Pd(dppf)Cl2, or Pd(OAc)2 and P(Cy)3, and in the presence of a suitable base, such as K3PO4, Na2CO3 or K2CO3, in a suitable solvent at 70 °C to 100 °C, such as an aqueous dioxane solution, DME, EtOH or 2-MeTHF, reacting the compound of formula (VII’) with R 2 BPin.

[0143] Here, R 2 is -OR 2A , or -N(R 2b )2, and the compound of formula (VIII’) can be prepared from the compound of formula (VII’) and HOR 2A or HN(R 2b )2 in accordance with process step (a) or (b) as described in Schemes 1 and 2 above.

[0144] Here, R 2 is a 4- to 11-membered monocyclic or bicyclic heterocyclic ring, C 1-6 alkyl, or C 3-7 cycloalkyl, and the compound of formula (XV’) can be prepared from the compound of formula (VI’) and R 2 BPin or R 2 B(OH)2 in accordance with the palladium-catalyzed cross-coupling reaction of process step (c) as described in Scheme 3. R in the formula 2 is -OR 2A , or -N(R 2b) It is 2, and the compound of formula (XV’) can be prepared from the compound of formula (VI’) and HOR according to process step (a) or (b) as described in the previous Schemes 1 and 2 2A or HN(R 2b )2.

[0145] The compound of formula (VIII’) can be prepared from the compounds of formula (XV’) and (II’) according to process step (a) or (b) described above.

[0146] The compound of formula (I) can be prepared from the compound of formula (VIII’) and R according to the Buchwald reaction of process step (a) as described in the previous Scheme 1 1 C(O)NR N1 and.

[0147] According to the fourth process, the compounds of formula (III’) and (V’) can be prepared from the compounds of formula (IX’), (X’), (XI’), (XII’), (XIII’) and (XIV’) as shown in Scheme 4.

Chemical formula

[0148] The compound of formula (XI’) can be prepared from the compound of formula (X’) and R N2 NHPG according to the Buchwald reaction of process step (a) as described in the previous Scheme 1.

[0149] Alternatively, the compound of formula (XI’) can be prepared from the carboxylic acid of formula (XII’) according to the improved Curtius rearrangement of process step (d). Preferred conditions include reacting the carboxylic acid of formula (XII’) with DPPA in t-BuOH at about 90 °C in the presence of a suitable organic base such as TEA.

[0150] The compound of formula (V') can be prepared from the compounds of formula (X') and (IX') according to the Buchwald reaction of step (a) as described in Scheme 1 above.

[0151] Alternatively, the compound of formula (V') can be prepared from the amine of formula (XIV') and R 1 C(O)LG according to the amide bond formation of process step (f). Preferred conditions include reacting the amine of formula (XIV') and R 1 C(O)LG in a suitable solvent such as pyridine at about room temperature, optionally in the presence of an organic base such as DIPEA.

[0152] The compound of formula (XIII') can be prepared from the compounds of formula (XI') and (IX') according to the Buchwald reaction of step (a) as described in Scheme 1 above.

[0153] Alternatively, the compound of formula (XIII') can be prepared from the compound of formula (V') and R N2 NHPG according to the Buchwald reaction of process step (a) as described in Scheme 1 above.

[0154] The compound of formula (III') can be prepared from the compound of formula (XIII') according to the deprotection reaction of process step (e). Typical conditions include reacting the compound of formula (XIII') with PG as Boc with a suitable acid such as TFA or HCl in DCM or HFIP at room temperature, or reacting with 2,6-lutidine and TMSOTf in DCM. Alternatively, when PG is PMB, typical conditions include cerium ammonium nitrate in an aqueous solution of MeCN at room temperature.

[0155] According to the fifth process, R 2The compound of formula (I) with a 4- to 11-membered monocyclic or bicyclic heterocyclic ring can be prepared from the compounds of formula (II’), (XX’), (XIX’), (XVIII’), (XVII’), (XVI’) and (XXVI’) as shown in Scheme 5. [Chemical formula] W is a boronic ester or boronic acid.

[0156] The compound of formula (XVII’) can be prepared from the compound of formula (XVI’) by the halogenation reaction in process step (h), typically bromination (h). Preferred conditions include reacting the compound of formula (XVI’) with NBS in acetonitrile at 70 °C.

[0157] Alternatively, the compound of formula (XVII’) can be prepared from the compound of formula (XXVI’) by amide formation in process step (o). Preferred conditions include reacting the amine of formula (XXVI’) with R 1 COCl in THF or dioxane at about room temperature in the presence of an organic base such as DIPEA.

[0158] The compound of formula (XVIII’) can be prepared from the compound of formula (XVII’) using process step (e) as described in the previous Scheme 3.

[0159] The compound of formula (XIX’) can be prepared from the compounds of formula (XVIII’) and (II’) using process step (a) as described in the previous Scheme 1.

[0160] The compound of formula (XX’) can be prepared from the compound of formula (XIX’) according to the formation of boronic acid ester in step (i), which is achieved by treating in a suitable non-polar solvent at room temperature to high temperature in the presence of a suitable inorganic base, such as K2CO3 or KOAc, and a suitable catalyst, such as BINAP, Brettphos, Xantphos, XPhos-Pd-G3, Pd(dppf)Cl2, a suitable phosphine ligand, such as Pd2(dba)3, Pd(PPh3)Cl2, or Pd(PPh3)4 having bis(1-adamantyl)butylphosphine, with a suitable boronic acid ester such as (BPin)2.

[0161] The compound of formula (I) can be prepared from the compound of formula (XX’) and R according to the Suzuki-type boronic acid cross-coupling reaction of process step (c) described in Scheme 3 above. 2 Hal 1 and.

[0162] Alternatively, the compound of formula (I) can be prepared from the compound of formula (XX’) and R according to the copper-catalyzed Suzuki cross-coupling reaction of process step (p). 2 Hal 1 and. Preferred conditions include reacting the compound of formula (XX’) and R in MeCN at about 40 °C in the presence of a copper catalyst such as Cu(OAc)2 and DMAP. 2 Hal 1 and.

[0163] Alternatively, the compound of formula (I) can be obtained from the compound of formula (XIX’) by a process in the system of step (j) without isolation of the compound of formula (XX’). Preferred conditions include reacting the compound of formula (XIX’) and R in a suitable solvent such as toluene, MeOH, water at 80 °C to 120 °C in the presence of a suitable phosphane ligand such as bis(1-adamantyl)-butyl-phosphane, a suitable base such as CsF, and bis(pinacolato)diboron (W2) in the presence of Pd(OAc)2. 2 -Hal 1 and.

[0164] According to the 6th process, the compound of formula (XIII’) can be obtained from the compounds of formula (XVII’) and (XXI’) as shown in Scheme 6. [Chemical formula]

[0165] Here, R 2 is a 4- to 11-membered monocyclic or bicyclic heterocycle, and the compound of formula (XIII’) can be prepared from the compound of formula (XVII’) and R 2 Hal 1 according to process step (j) as described in the previous Scheme 5.

[0166] Alternatively, the compound of formula (XXI’) can be prepared according to process step (i) as described in the previous Scheme 5. The compound of formula (XIII’) can be prepared from the compound of formula (XXI’) and R 2 Hal 1 according to process step (c) as described in the previous Scheme 3.

[0167] Alternatively, the compound of formula (XIII’) can be prepared from the compound of formula (XVII’) and R 2 -SnBu3 according to the Still-type cross-coupling reaction of process step (r). Preferred conditions include reacting the compound of formula (XVII’) and R 2 SnBu3 in DMF at about 100 °C in the presence of a suitable catalyst such as PdCl2(PPh3)2.

[0168] Here, R 2 is alkyl or cycloalkyl, and the compound of formula (XIII’) can be obtained from the compound of formula (XVII’) and KR 2 BF3 according to the palladium-catalyzed Suzuki coupling of process step (q). Preferred conditions include reacting the compound of formula (XVII’) and KR 2 BF3 in an aqueous toluene solution at about 90 °C in the presence of the catalyst cataCXium A and KOAc, and a suitable base such as Cs2CO3.

[0169] According to the seventh process, for a compound of formula (XIII’) in which R 2 is a C2-C6 alkyl, it can be obtained from compounds of formula (XVII’), (XXII’) and (XXIII’) as shown in Scheme 7.

Chemical formula

[0170] The compound of formula (XXII’) can be prepared from compounds of formula (XVII’) and (XXIII’) by a Suzuki-type cross-coupling reaction in process step (k). Typical conditions include reacting a compound of formula (XVII’) with an alkyne of formula (XXIII’) in a suitable high-temperature solvent in the presence of a suitable palladium catalyst in the presence of a suitable phosphine ligand, a Cu salt and a base. Preferred conditions include reacting compounds of formula (XVII’) and (XXIII’) in a solvent such as DMF at 80 °C to 120 °C in the presence of Pd(PPh3)2Cl2.DCM, CuI, and a suitable base such as TEA.

[0171] The compound of formula (XIII’) can be prepared from the compound of formula (XXII’) by a hydrogenation reaction in step (l). Typical conditions include reacting the compound of formula (XXII’) in THF at room temperature in the presence of a Pd catalyst and H2.

[0172] According to the eighth process, for a compound of formula (I) in which R 2 is a 4- to 11-membered monocyclic or bicyclic heterocycle, it can be obtained from compounds of formula (XXIV’), (XXV’) and (XIII’) as shown in Scheme 8.

Chemical formula

[0173] ​The compound of formula (I) can be prepared from the compounds of formula (XXIV’) or (XXV’) using standard chemical transformations (m) known to those skilled in the art for converting carboxylic acid esters or other carboxyl derivatives into heterocycles. For example, the methyl ester type of (XXIV’) where X = CO2Me is hydrolyzed with LiOH to the carboxylic acid type of (XXIV’) where X = CO2H, and then treated with N’-hydroxyacetimidamide (acetamidooxime) to obtain 3-methyl-1,2,4-oxadiazole.

[0174] The compound of formula (XIII’) can be obtained from the compound of formula (XXV’) using standard chemical transformations (n) known to those skilled in the art for converting nitriles or other carboxyl derivatives into heterocycles. For example, the nitrile type of (XXV’) where X = CN is reacted with hydroxylamine and then with N’-1,1-dimethoxy-N,N-dimethylethane-1-amine to obtain 5-methyl-1,2,4-oxadiazole.

[0175] According to the ninth process, the compound of formula (I) with R N2 being H can be obtained from the compounds of formula (XXVII’) and (XXVIII’) as shown in Scheme 9.

Chemical formula

[0176] The compound of formula (XXVIII’) can be obtained from the compounds of formula (XXVII’) and (II’) by the alkylation reaction of process step (b) as described in the previous Scheme 3.

[0177] R N2 The compound of formula (I) with R being H can be obtained from the compound of formula (XXVIII’) according to the deprotection reaction of process step (e) as described in the previous Scheme 4.

[0178] R 2According to the tenth process using heteroalkyl or alkyl, the compound of formula (I) can be obtained from the compound of formula (XIX’) as shown in Scheme 10.

Chemical formula

[0179] The compound of formula (I) can be obtained from the compound of formula (XIX’) and R according to the photocatalytic cross-coupling reaction of process step(s). 2 CO2. Preferred conditions include reacting the compound of formula (XIX’) and R 2 CO2H in DMF at room temperature in the presence of Ir[dF(CF3)ppy]2(dtbpy)PF6, NiBr2(dtbbpy), and (2-tert-butyl-1,1,3,3-tetramethyl-guanidine under an LED light source.

[0180] Compounds of formula (II’), (IV’), (VI’), (IX’), (X’), (XII’), (XIV’), (XV’), (XVI’), (XVII’), (XXIII’), (XXIV’), (XXV’), (XXVI’), (XXVII’), R N2 NH-PG, R 2 CO2H, and R 1 C(O)LG can be commercially available or prepared by analogy from methods known in the literature or methods described in the Examples section below.

[0181] Compounds of formula (I), (III’), (IV’), (V’), (VII’), (VIII’), (XI’), (XIII’), (XIV’), (XV’), (XIX’), (XXIV’), (XXVI’) and (XXVII’) can be converted to another compound of formula (I), (III’), (IV’), (V’), (VII’), (VIII’), (XI’), (XIII’), (XIV’), (XV’), (XIX’), (XXIV’), (XXVI’) and (XXVII’) respectively by standard chemical transformations known to those skilled in the art. Examples of these transformations include, but are not limited to, the following: ● Alkylating a heteroatom, such as N or O, using an alkyl halide or aryl halide and a suitable inorganic or organic base. ● Performing reductive amination of an N atom to yield a secondary or tertiary amine. ● Reacting an aryl halide or heteroaryl halide with an alcohol in the presence of an inorganic base to yield an aryl ether or heteroaryl ether. ● Reacting an alkyl halide with a primary or secondary amine or alcohol in the presence of a base to yield a secondary or tertiary amine or ether. ● Reacting a primary alcohol with another alcohol under Mitsunobu conditions to yield an ether ● Fluorinating an aryl chloride with a fluorinating agent such as TBAF to yield an aryl fluoride ● Demethylating an alkylmethoxy group to yield an alkylhydroxy group ● Performing a photocatalytic reaction of an aryl halide or heteroaryl halide with a carboxylic acid (1,3-dioxoisoindolin-2-yl)alkyl, carboxylic acid cycloalkyl, or carboxylic acid heterocyclyl to yield an aryl or heterocycle substituted with an alkyl, cycloalkyl, or heterocyclyl. ● Using a transition metal catalyst, reacting an aromatic halide or heteroaryl halide with ○ A suitable boronic acid or boronic ester under the Suzuki reaction conditions described in step (c), (p), or (q), ○ A suitable alkylzinc compound or heteroaryl zinc compound under Negishi reaction conditions, ○ A suitable alkyltin or heteroaryl tin under Stille reaction conditions ○ An amine or alcohol under Buchwald-type conditions as described in process step (a) to perform a cross-coupling to yield the corresponding substituted aromatic or heteroaromatic group.

[0182] One of ordinary skill in the art will fully understand that it may be necessary to utilize a protecting group strategy suitable for preparing the compounds of formula (I). Typical protecting groups can include carbamates for protection of amines, preferably Boc, benzyl groups for protection of phenolic OH, or TBS groups for protection of alkyl OH.

[0183] Furthermore, it will be fully understood that it may be necessary or desirable to perform the transformations in an order different from that described in the schemes or to modify one or more of the transformations in order to obtain the desired compounds of the invention.

Examples

[0184] Abbreviations: AcOH = acetic acid, Ac2O = acetic anhydride, Aq. = aqueous solution, Bn = benzyl, BnOH = benzyl alcohol, Boc = tert-butoxycarbonyl, 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-butyllithium, ℃ = degrees Celsius, CDCl3 = deuterated chloroform, Cs2CO3 = cesium carbonate, CuI = copper(I) iodide, δ = chemical shift, d = doublet, DAST = diethylaminosulfur trifluoride, dd = doublet of doublets, DCE = 1,2 - dichloroethane, DCM = dichloromethane, DIPEA = N - ethyldiisopropylamine or N,N - diisopropylethylamine, DMAP = 4 - (dimethylamino)pyridine, DME = 1,2 - dimethoxyethane, DMF = N,N - dimethylformamide, DMSO = dimethyl sulfoxide, DMSO - d6 = hexadeuterodimethyl sulfoxide, DPPA = diphenylphosphoryl azide, Et = ethyl, EtOH = ethanol, EtOAc = ethyl acetate, Eq. = equivalent, g = gram, HCl = hydrochloric acid, HCO2H = formic acid, 1 H NMR = proton nuclear magnetic resonance, H2O = water, HPLC = high - performance liquid chromatography, h = hour, IPA = 2 - propanol, Josiphos Pd G3 = {(R)-1 - [(Sp)-2 - (dicyclohexylphosphino)ferrocenyl]ethyldi - tert - butylphosphine}[2 - (2’ - amino - 1,1’ - biphenyl)]palladium(II) methanesulfonate, K2CO3 = potassium carbonate, KF = potassium fluoride, KOH = potassium hydroxide, KOtBu = potassium tert - butoxide, K3PO4 = tripotassium phosphate, L = liter, LCMS = liquid chromatography - mass spectrometry, LiAlH4 = lithium aluminum hydride, m = multiplet, M = molar, m-CPBA = 3-chloroperoxybenzoic acid, Me = methyl, MeCN = acetonitrile, MeI = iodomethane, MeOH = methanol, MeOH-d4 = deuteromethanol, mg = milligram, MgSO4 = magnesium sulfate, MHz = megahertz, mins = minutes, mL = milliliter, mmol = millimole, MorDalPhos Pd G3 = mesyl(2-(di-1-adamantylphosphino)morpholinobenzene)[2-(2’-amino-1,1’-biphenyl)]palladium(II), MS m / z = mass spectrum peak, MTBE = tert-butyl methyl ether, N2 = nitrogen, NaBH4 = sodium borohydride, NaBH3CN = sodium cyanoborohydride, Na2CO3 = sodium carbonate, NaH = sodium hydride, NaHCO3 = sodium bicarbonate, NaOH = sodium hydroxide, NaOMe = sodium methoxide, Na2SO3 = sodium thiosulfate, Na2SO4 = sodium sulfate, NBS = N-bromosuccinimide, NH2Boc = tert-butyl carbamate, NH3 = ammonia, NH4Cl = ammonium chloride, NH4OH = ammonium hydroxide, NMP = 1-methyl-2-pyrrolidone, PE = petroleum ether, Pd(dppf)Cl2 = [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd(OAc)2 = Palladium(II) acetate, Pd2(dba)3 = Tris(dibenzylideneacetone)dipalladium(0), Pd(PPh3)2Cl2 = Bis(triphenylphosphine)palladium(II) dichloride, POCl3 = Phosphorus(V) oxychloride, q = Quartet, rt = Room temperature, RT = Retention time, s = Singlet, sat. = Saturated, soln. = Solution, t = Triplet, TBSCl = tert-Butyldimethylsilyl chloride, TEA = Triethylamine, TFA = Trifluoroacetic acid, THF = Tetrahydrofuran, TLC = Thin layer chromatography, μL = Microliter, μmol = Micromole, Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, Xantphos Pd G3 = [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate.

[0185] General method Preparative HPLC conditions: Method A: Column: YMC-Triart Prep C18 150×40mm×7um; Conditions: Water (NH4HCO3)-MeCN, Gradient time (min): 15; 100%B retention time (min): 3; Flow rate (mL / min): 50; Detection wavelength: 220nm Method B: Column: Welch Xtimate C18 150×25mm×5um; Conditions: Water (10mM of NH4HCO3)-MeCN, Gradient time (min): 11; 100%B retention time (min): 2; Flow rate (mL / min): 25; Detection wavelength: 220nm Method C: Column: Boston Prime C18 150×30mm×5um; Conditions: Water (10mM NH4HCO3)-MeCN, Gradient time (min): 10; Hold time at 100%B (min): 2; Flow rate (mL / min): 25; Detection wavelength: 220nm Method D: Column: Boston Green ODS 150×30mm×5um; Conditions: Water (FA)-MeCN, Gradient time (min): 10; Hold time at 100%B (min): 2; Flow rate (mL / min): 25 Method E: Column: Boston Uni C18 40×150×5um; Conditions: Water (TFA)-MeCN, Gradient time (min): 10; Hold time at 100%B (min): 2; Flow rate (mL / min): 60 Method F: Column: Shapsil-T C18 50×250mm 8um, Conditions: Water (0.1%FA)-MeCN, Gradient: Gradient time: 20 min, Flow rate 80mL / min Method G: Column: Boston Green ODS 150×30mm×5um; Conditions: Water (NH4HCO3)-MeCN, Gradient time (min): 11; Flow rate (mL / min): 25 Method H: Column: Boston Green ODS 150×30mm×5um; Conditions: Water (HCl)-MeCN, Gradient time (min): 10; Hold time at 100%B (min): 2; Flow rate (mL / min): 25 Method I: YMC-Actus Triart C18 150×30mm×5um, Conditions: Water (TFA)-MeCN; Gradient time (min): 10.5; Hold time at 100%B (min): 1.5; Flow rate (mL / min): 40 Method J: Using a Waters Sunfire Prep C18 column, 5 μm, 19mm×100mm, with the mobile phase being H2O and MeCN (adjusted to a final v / v% of 0.2% NH4HCO3), and a flow rate of 30mL / min. Method K: Column: Boston Prime C18 150×30mm×5um; Conditions: Water (NH3·H2O+NH4HCO3)-MeCN, Gradient time (min): 10; Hold time at 100%B (min): 2; Flow rate (ml / min): 25. Method L: Column: Welch Xtimate C18 150×25mm×5um; Conditions: Water (Ammonia hydroxide v / v)-MeCN, Gradient time (min): 11; Hold time at 100%B (min): 2; Flow rate (ml / min): 25; Method M: Column: Boston Prime C18 150×30mm×5um; Conditions: Water (FA)-MeCN, Gradient time (min): 12; Hold time at 100%B (min): 2; Flow rate (ml / min): 25. Method N: Column: Phenomenex C18 150×25mm×10um; Mobile phase: Water (NH4HCO3)-MeCN, Gradient time (min): 10; Hold time at 100%B (min): 2; Flow rate (ml / min): 25. Method O: Column: Phenomenex C18 150×40mm×5um; Conditions: Water (NH3·H2O+NH4HCO3)-MeCN, Gradient time (min): 10; Hold time at 100%B (min): 2; Flow rate (ml / min): 25. Method P: Column: Waters Xbridge BEH C18 100×30mm×10um; Conditions: Water (NH4HCO3)-MeCN, Gradient time (min): 11; Hold time at 100%B (min): 3; Flow rate (ml / min): 25. Method Q: Column: Phenomenex Gemini-NX 150×30mm×5um, Conditions: Water (NH3H2O+NH4HCO3)-MeCN, Gradient time (min): 15; Hold time at 100%B (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; Conditions: Water (NH4HCO3)-MECN, Start B: Gradient time (min): 11; Flow rate (ml / min): 25. Method T: Column: Boston Green ODS 150×30mm, 5mm; MeCN / H2O(TFA). Method U: Column: Waters XSelect CSH C18, 5μm, 30mm×100mm column, mobile phase is H2O (A) and MeCN (B) (modifier is 0.2% NH4OH in final v / v%), flow rate is 60 mL / min). Method V: Column: Waters Sunfire Prep C18 OBD 5um 19×100mm, gradient: MeCN in water, modifier 0.1% TFA, gradient time, 12 minutes. Flow rate: 30 ml / min. Method W: Column: Waters Xbridge BEH C18 100×30mm×10um, conditions: water (HCl)-MeCN; gradient time (minutes): 11; flow rate (ml / min): 50). Method X: Column: Waters Xbridge BEH C18 100×30mm×10um; conditions: water (FA)-MeCN; gradient time (minutes): 11; hold time at 100% B (minutes): 3; flow rate (ml / min): 50. Method Y: Column: Phenomenex luna C18 150×25mm×10um; conditions: water (FA)-MeCN; gradient over 10 minutes, flow rate 25 mL / min. Method Z: Waters Xbridge BEH C18 100×30mm, 10mm, MeCN / H2O (TFA)) Method AA: Column: Agela DuraShell C18 150×25mm×5um; conditions: water (NH3.H2O)-MECN; B%: gradient over 10 minutes.

[0186] Preparation 1 2-Bromo-5-ethoxypyridine 1-oxide

Chemical formula

[0187] Preparation 2 2-Bromo-5-ethoxy-4-nitropyridine 1-oxide

Chemical formula

[0188] Preparation 3 2-Bromo-5-ethoxypyridin-4-amine

Chemical formula

[0189] Preparation 4 (2-Bromo-5-ethoxypyridin-4-yl)(tert-butoxycarbonyl)carbamic acid tert-butyl

Chemical formula

[0190] Preparation 5 (2-Acetamido-5-ethoxypyridin-4-yl)(tert-butoxycarbonyl)carbamic acid tert-butyl

Chemical formula

[0191] Preparation 6 2-Chloro-5-(difluoromethoxy)-4-iodopyridine

Chemical formula

[0192] Preparation 7 2-Chloro-5-cyclobutoxy-4-iodopyridine [Chemical formula] According to the procedure described in Preparation 6, 940 mg of 2-chloro-5-cyclobutoxy-4-iodopyridine was obtained in a yield of 77.6% from 6-chloro-4-iodopyridin-3-ol and bromocyclobutane. LCMS m / z = 309.8 [M+H]+

[0193] Preparation 8 2-Chloro-4-iodo-5-isopropoxypyridine [Chemical formula] According to the procedure described in Preparation 6, 2.2 g of 2-chloro-4-iodo-5-isopropoxypyridine was obtained as a yellow liquid in a yield of 94.4% from 6-chloro-4-iodopyridin-3-ol and 2-iodopropane. 1H NMR (500 MHz, CDCl3) δ ppm: 7.82 (s, 1H), 7.73 (s, 1H), 4.66 - 4.59 (m, 1H), 1.45 - 1.38 (m, 6H).

[0194] Preparation 9 tert-Butyl (2-chloro-5-(difluoromethoxy)pyridin-4-yl)carbamate [Chemical formula] To a solution of 2-chloro-5-(difluoromethoxy)-4-iodopyridine (Preparation 6, 1.1 g, 3.44 mmol) in dioxane (20 mL) were added NH2Boc (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 mixture 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 / 1) to afford tert-butyl (2-chloro-5-(difluoromethoxy)pyridin-4-yl)carbamate (940 mg, yield 93.0%) as a yellow oil. 1 H NMR: (400 MHz, CDCl3) δ: ppm 8.24 (s, 1H), 8.12 (s, 1H), 7.07 (s, 1H), 6.75 - 6.36 (m, 1H), 1.54 (s, 9H).

[0195] Preparation 10 (2-Chloro-5-cyclobutoxypyridin-4-yl)carbamic acid tert-butyl [Chemical formula] To a solution of 2-chloro-5-cyclobutoxypyridin-4-iodine (Preparation 7, 930 mg, 3.0 mmol) and NH2Boc (387.2 mg, 3.31 mmol) in dioxane (15 mL) were 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 mixture 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 × 3). The combined organic phases were washed with brine (50 mL × 3), dried over anhydrous Na2SO4 and concentrated to afford tert-butyl (2-chloro-5-cyclobutoxypyridin-4-yl)carbamate (1.4 g, crude product) as a white solid. LCMS m / z = 299.1 [M + H] +

[0196] Preparation 11 (2-Chloro-5-isopropoxypyridin-4-yl)carbamic acid tert-butyl

Chem.

[0197] Preparation 12 2-Bromo-5-(2-methoxyethoxy)isonicotinic acid

Chem.

[0198] Preparation 13 2-Bromo-5-ethoxyisonicotinic acid

Chem.

[0199] Preparation 14 2-Bromo-5-(2,2,2-trifluoroethoxy)isonicotinic acid

Chemical formula

[0200] Preparation 15 2-Bromo-5-(2,2-difluoroethoxy)isonicotinic acid

Chemical formula

[0201] Preparation 16 2-Bromo-5-(2-(dimethylamino)ethoxy)isonicotinic acid

Chemical formula

[0202] Preparation 17 5-(Benzyloxy)-2-bromoisonicotinic acid

Chemical formula

[0203] Preparation 18 2-Bromo-5-((3-methoxycyclobutyl)methoxy)isonicotinic acid

Chemical formula

[0204] Preparation 19 2-Bromo-5-(cyclopropylmethoxy)isonicotinic acid

Chem.

[0205] Preparation 20 2-Bromo-5-(ethoxy-d5)isonicotinic acid

Chem.

[0206] Preparation 21 (2-Bromo-5-(cyclopropylmethoxy)pyridin-4-yl)carbamic acid tert-butyl

Chemical Structure

[0207] Preparation 22 tert-Butyl (2-bromo-5-(2-methoxyethoxy)pyridin-4-yl)carbamate [Chemical formula] To a solution of 2-bromo-5-(2-methoxyethoxy)isonicotinic acid (Preparation 12, 10.0 g, 36.2 mmol) in t-BuOH (100 mL) were added TEA (7.3 g, 72.4 mmol) and DPPA (9.9 g, 36.2 mmol), and the reaction mixture was stirred at 90 °C for 16 h under N2. The mixture was concentrated under reduced pressure, the residue was diluted with H2O (30 mL), and extracted with EtOAc (35 mL × 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 (from PE / EtOAc 1 / 0 to 5 / 1) to give tert-butyl (2-bromo-5-(2-methoxyethoxy)pyridin-4-yl)carbamate (9.03 g, yield 71.8%) as white crystals. LCMS m / z = 349.1 [M+H] + .

[0208] Preparation 23 tert-Butyl (2-bromo-5-ethoxypyridin-4-yl)carbamate [Chemical formula] Following the procedure described in Preparation 22, 85 g of tert-butyl (2-bromo-5-ethoxypyridin-4-yl)carbamate was obtained as a yellow solid in 73.3% yield from 2-bromo-5-ethoxyisonicotinic acid (Preparation 13) and DPPA. 1H NMR: (400 MHz, DMSO-d6) δ 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).

[0209] Preparations 24 - 29 Following a reaction similar to the reaction described in Preparation 22, the compounds in the following table were obtained from the appropriate 2-bromoisonicotinic acid and DPPA. [Table 1-1] [Table 1-2]

[0210] Preparation 30 (2-Bromo-5-(2-(dimethylamino)ethoxy)pyridin-4-yl)carbamic acid tert-butyl

Chem.

[0211] Preparation 31 (2-Bromo-5-(ethoxy-d5)pyridin-4-yl)carbamic acid tert-butyl

Chem.

[0212] Preparation 32 tert-Butyl (2-acetamido-5-(2-methoxyethoxy)pyridin-4-yl)carbamate

Chemical Structure

[0213] Preparation 33 tert-Butyl (2-acetamido-5-(cyclopropylmethoxy)pyridin-4-yl)carbamate

Chemical Structure

[0214] Preparations 34 - 39 Following a procedure similar to that described in Preparation 33, the compounds in the following table were prepared from the appropriate 2-bromo or 2-chloropyridine and acetamide. [Table 2-1] [Table 2-2]

[0215] Preparation 40 tert-Butyl (2-acetamido-5-(ethoxy-d5)pyridin-4-yl)carbamate [Chemical formula] To (2-bromo-5-(ethoxy-d5)pyridin-4-yl)carbamic acid tert-butyl (Preparation 31, 1.42 g, 4.41 mmol), acetamide (1.30 g, 22.04 mmol), Cs2CO3 (4.31 g, 13.22 mmol) and BrettPhos Pd G3 (300 mg, 330.9 μmol) were added, followed by addition of dioxane (15 mL). The mixture was degassed by bubbling N2 at room temperature for 10 minutes and then heated to 100 °C over 1 hour. The reaction mixture was diluted with EtOAc (25 mL), filtered through Celite® while rinsing with EtOAc (15 mL), and then concentrated to dryness. The crude material was purified by silica gel chromatography (40 g, from heptane to EtOAc) to give (2-acetamido-5-(ethoxy-d5)pyridin-4-yl)carbamic acid tert-butyl (1.26 g, yield 94.9%) as a white solid. LCMS m / z = 301.1 [M+H]+. 1H NMR (DMSO-d6) δ: 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).

[0216] Preparation 41 (2-Acetamido-5-isopropoxypyridin-4-yl)carbamic acid tert-butyl

Chemical formula

[0217] Preparation 42 tert-Butyl (2-acetamido-5-cyclopropoxypyridin-4-yl)carbamate

Chemical formula

[0218] Preparation 43 tert-Butyl (2-acetamido-5-(2,2,2-trifluoroethoxy)pyridin-4-yl)carbamate [Chemistry] According to the procedure described in Preparation 41, 733 mg of tert-butyl (2-acetamido-5-(2,2,2-trifluoroethoxy)pyridin-4-yl)carbamate was obtained as a white solid in 74% yield from tert-butyl (2-bromo-5-(2,2,2-trifluoroethoxy)pyridin-4-yl)carbamate (Preparation 27) and acetamide. 1 1H NMR (400 MHz, CDCl3) δ 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).

[0219] Preparation 44 tert-butyl (2-acetamido-5-((3-methoxycyclobutyl)methoxy)pyridin-4-yl)carbamate [Chemistry] According to the procedure described in Preparation 41, 98 mg of tert-butyl (2-acetamido-5-((3-methoxycyclobutyl)methoxy)pyridin-4-yl)carbamate was obtained as a yellow oil in 43.3% yield from tert-butyl (2-bromo-5-((3-methoxycyclobutyl)methoxy)pyridin-4-yl)carbamate (Preparation 26) and acetamide. 1 1H NMR: (500 MHz, CDCl3) δ 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).

[0220] Preparation 45 tert-butyl (5-ethoxy-2-propionamidopyridin-4-yl)carbamate [Chemical formula] (2-Bromo-5-ethoxypyridin-4-yl)carbamic acid tert-butyl (Preparation 23, 400.0 mg, 1.26 mmol) and propionamide (460.9 mg, 6.31 mmol) were added to a solution of dioxane (5.0 mL), and Cs2CO3 (1.2 g, 3.78 mmol) and BrettPhos Pd G3 (114.3 mg, 0.13 mmol) were added thereto. The reaction mixture was stirred at 100 °C for 1 hour under N2. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (PE / EtOAc = 3 / 1 to 0 / 1) to obtain (5-ethoxy-2-propionamidopyridin-4-yl)carbamic acid tert-butyl (255 mg, yield 65.4%) as a white solid. LCMS m / z = 310.2 [M+H] +

[0221] Preparation 46 (5-Ethoxy-2-(2-methoxyacetamido)pyridin-4-yl)carbamic acid tert-butyl [Chemical formula] According to the procedure described in Preparation 45, 600 mg of (5-ethoxy-2-(2-methoxyacetamido)pyridin-4-yl)carbamic acid tert-butyl was obtained as a yellow solid in a yield of 82.2% from 2-methoxyacetamide and (2-bromo-5-ethoxypyridin-4-yl)carbamic acid tert-butyl (Preparation 23). 1 H NMR (400 MHz, CDCl3) δ: 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).

[0222] Preparation 47 (5-Ethoxy-2-(3-methoxypropanamido)pyridin-4-yl)carbamic acid tert-butyl [Chemistry] Following a procedure similar to that described in Preparation 45, 372 mg of tert-butyl (5-ethoxy-2-(3-methoxypropanamido)pyridin-4-yl)carbamate as a white solid was obtained in 86.9% yield from 3-methoxypropanamide and tert-butyl (2-bromo-5-ethoxypyridin-4-yl)carbamate (Preparation 23). 1 H NMR (500 MHz, CDCl3) δ 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, J = 6.0 Hz, 2H), 3.42 (s, 3H), 2.63 (t, J = 6.0 Hz, 2H), 1.55 (s, 9H), 1.46 (t, J = 7.0 Hz, 3H)

[0223] Preparation 48 tert-Butyl (2-(cyclopropanecarboxamido)-5-ethoxypyridin-4-yl)carbamate [Chemistry] 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 mixture was stirred at 100 °C for 2 h under N2. The cooled reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 0 - 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] +

[0224] Preparation 49 2,4-Dichloro-5-(methoxymethyl)pyridine

Chemical formula

[0225] Preparation 50 N-(4-Chloro-5-(methoxymethyl)pyridin-2-yl)acetamide

Chemical formula

[0226] Preparation 51 N-(4-Chloro-5-methylpyridin-2-yl)acetamide [Chemical formula] To a solution of 4-chloro-5-methylpyridin-2-amine (100 mg, 0.70 mmol) in DCM (2 mL) were 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 × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EtOAc = 1 / 0 - 3 / 1) to give N-(4-chloro-5-methylpyridin-2-yl)acetamide (98 mg, yield 75.7%) as a yellow solid. 1 H NMR: (500 MHz, CDCl3) δ ppm: 9.69 (br s, 1H), 8.38 (s, 1H), 7.97 (s, 1H), 2.30 (s, 3H), 2.11 (s, 3H).

[0227] Preparation 52 (2-Acetamido-5-methylpyridin-4-yl)carbamic acid tert-butyl [Chemical formula] A solution of N-(4-chloro-5-methylpyridin-2-yl)acetamide (Preparation 51, 90 mg, 0.49 mmol) in dioxane (1 mL) was added with NH2Boc (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×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 / 0~0 / 1) to give tert-butyl (2-acetamido-5-methylpyridin-4-yl)carbamate (90 mg, yield 69.6%) as a yellow solid. 1H NMR: (500 MHz, CDCl3) δ 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).

[0228] Preparation 53 tert-Butyl (2-acetamido-5-bromopyridin-4-yl)carbamate [Chemical formula] 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 mixture was stirred at 70 °C for 1 h. The mixture was concentrated in vacuo, and the crude product was purified by column chromatography (PE / EtOAc = 1 / 1~0 / 1) to give tert-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (9.1 g, yield 82.5%) as a white solid. 1 1H NMR (500 MHz, CDCl3) δ 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).

[0229] Preparation 54 (2-Acetamido-5-vinylpyridin-4-yl)carbamic acid tert-butyl

Chem.

[0230] Preparation 55 (2-Acetamido-5-(prop-1-en-2-yl)pyridin-4-yl)carbamic acid tert-butyl

Chem.

[0231] Preparation 56 tert-butyl (2-acetamido-5-(prop-1-yn-1-yl)pyridin-4-yl)carbamate [Chemical formula] 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) were added tributyl(prop-1-yn-1-yl)tin (747.6 mg, 2.27 mmol), NaOAc (62.1 mg, 0.757 mmol), and Pd(PPh3)2Cl2 (53.2 mg, 0.076 mmol), and the reaction mixture was stirred at 100 °C for 3 h under N2. The mixture was poured into H2O (30 mL), extracted with EtOAc (30 mL × 3), the combined organic layers were washed with brine (20 mL × 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-1-yn-1-yl)pyridin-4-yl)carbamate (260.8 mg, 59.5% yield) as a white solid. 11H NMR (400 MHz, CDCl3) δ 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).

[0232] Preparation 57 (2-Acetamido-5-ethylpyridin-4-yl)carbamic acid tert-butyl

Chemical Structure

[0233] Preparation 58 (2-Acetamido-5-isopropylpyridin-4-yl)carbamic acid tert-butyl

Chemical Structure

[0234] Preparation 59 tert-Butyl (2-acetamido-5-propylpyridin-4-yl)carbamate

Chemical Structure

[0235] Preparation 60 (2-Acetamido-5-cyclopropylpyridin-4-yl)carbamic acid tert-butyl [Chemical formula] (2-Acetamido-5-bromopyridin-4-yl)carbamic acid tert-butyl (Preparation 53, 200.0 mg, 0.606 mmol) was added to a solution containing dioxane (5.0 mL) and H2O (0.5 mL), and cyclopropylboronic acid (78.1 mg, 0.909 mmol), K2CO3 (251.2 mg, 1.82 mmol) and Pd(dppf)Cl2 (44.3 mg, 0.061 mmol) were added. The reaction mixture was stirred at 100 °C for 2 hours. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel (PE / EtOAc = 5 / 1 - 0 / 1) to give (2-acetamido-5-cyclopropylpyridin-4-yl)carbamic acid tert-butyl (160 mg, yield 90.7%) as a yellow oil. LCMS m / z = 292.1 [M+H] +

[0236] Preparation 61 N-(4-Amino-5-methoxypyridin-2-yl)acetamide hydrochloride [Chemical formula] 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 4 M HCl / dioxane (200 mL), and the reaction mixture was stirred at 20 °C for 1 h. The mixture was filtered, and the filter cake was dried in vacuo and then lyophilized to give N-(4-amino-5-methoxypyridin-2-yl)acetamide hydrochloride (10.36 g, yield 84.21%) as a yellow solid. LCMS m / z = 182 [M+H] +

[0237] Preparation 62 N-(4-Amino-5-ethoxypyridin-2-yl)acetamide hydrochloride [Chemical formula] 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 4 M HCl / dioxane (5.0 mL), and the reaction mixture 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 pale yellow solid. LCMS m / z = 196.0 [M+H] + .

[0238] Preparation 63 N-(4-Amino-5-(2-methoxyethoxy)pyridin-2-yl)acetamide hydrochloride [Chemical formula] 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 4 M HCl / dioxane (10 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-(2-methoxyethoxy)pyridin-2-yl)acetamide hydrochloride (810 mg, crude) as a brown solid. LCMS m / z = 226.1 [M+H] + 。 1 H NMR: (500 MHz, DMSO-d6) δ 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).

[0239] Preparation 64 N-(4-Amino-5-(cyclopropylmethoxy)pyridin-2-yl)acetamide hydrochloride

Chemical formula

[0240] Preparations 65 - 81 Following a procedure similar to that described in Preparation 64, the compounds in the following table were prepared from the appropriate Boc-protected amines.

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

[0241] Preparation 82 N-(4-Amino-5-(benzyloxy)pyridin-2-yl)acetamide hydrochloride

Chem.

[0242] Preparation 83 N-(4-Amino-5-(ethoxy-d5)pyridin-2-yl)acetamide hydrochloride

Chem.

[0243] Preparation 84 2-(1,1-Difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine [Chemical Structure] To a solution of 4-chloro-2-(1,1-difluoroethyl)pyridine (5.84 g, 32.9 mmol) and (1r,3r)-3-methoxycyclobutan-1-ol (2.8 g, 27.42 mmol) in DMF (50 mL) was added NaH (1.32 g, 32.9 mmol, purity 60%). The reaction mixture was stirred at 60 °C for 16 h, quenched with water (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 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 to 5 / 1) to give 2-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine (5 g, yield 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm: 8.43 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 1.8, 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).

[0244] Preparation 85 2-(1,1-Difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine [Chemical formula] According to the procedure described in Preparation 84, 2-(1,1-difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine was obtained as a colorless oil (3.7 g, yield 91.4%) from 4-chloro-2-(1,1-difluoroethyl)pyridine and (1s,3s)-3-methoxycyclobutan-1-ol. 1H NMR (400 MHz, CDCl3) 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).

[0245] Preparation 86 2-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine 1-oxide

Chemical formula

[0246] Preparation 87 2-(1,1-Difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine 1-oxide

Chemical Structure

[0247] Preparation 88 2-Chloro-6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine [Chemical Structure] To a solution of 2-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine 1-oxide (Preparation 86, 7 g, 27 mmol) was added POCl3 (63.6 mL, 682.72 mmol), and the reaction mixture was stirred at 100 °C for 16 h. The mixture was concentrated, and the residue was dissolved in DCM (20 mL). The solution was poured into water (50 mL), and quenched with saturated NaHCO3 (40 mL) until pH > 8. The aqueous layer was extracted with DCM (80 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EtOAc = 10 / 1) to give 2-chloro-6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine (3.8 g, yield 50.7%) as a yellow oil. LCMS m / z = 278.1 [M + H] +

[0248] Preparation 89 2-Chloro-6-(1,1-difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine [Chemical Structure] Following the procedure described in Preparation 88, 2-chloro-6-(1,1-difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine was obtained as a yellow oil from 2-(1,1-difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine 1-oxide (Preparation 87). LCMS m / z = 278.1 [M+H] +

[0249] Preparation 90 2-(1,1-Difluoroethyl)pyrimidine-4,6-diol

Chem.

[0250] Preparation 91 4,6-Dichloro-2-(1,1-difluoroethyl)pyrimidine

Chem.

[0251] Preparation 92 4-Chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine

Chemical formula

[0252] Preparation 93 2-(1,1-difluoroethyl)-6-methylpyrimidin-4-amine

Chemical formula

[0253] Preparation 94 4-chloro-2-(1,1-difluoroethyl)-6-ethylpyrimidine

Chemical formula

[0254] Preparation 95 4-Chloro-2-(1,1-difluoroethyl)-6-(prop-1-en-2-yl)pyrimidine

Chemical formula

[0255] Preparation 96 4-Chloro-6-cyclopropyl-2-(1,1-difluoroethyl)pyrimidine [Chemical formula] To a solution of 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (Preparation 91, 1.0 g, 4.69 mmol) in dioxane (10.0 mL) and water (1.0 mL) were added cyclopropylboronic acid (483.9 mg, 5.63 mmol), K2CO3 (1.3 g, 9.39 mmol), and Pd(dppf)Cl2 (343.5 mg, 469.5 μmol). The mixture was stirred at 70 °C for 2 hours under N2. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give 4-chloro-6-cyclopropyl-2-(1,1-difluoroethyl)pyrimidine (805.6 mg, yield 78.5%) as a colorless oil. LCMS m / z = 219.1 [M+H] +

[0256] Preparation 97 4-Chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine

Chem.

[0257] Preparation 98 2,4-Dichloro-5-fluoro-6-methylpyrimidine

Chem.

[0258] Preparation 99 4-(Benzyloxy)-2-chloro-5-fluoropyrimidine

Chemical Structure

[0259] Preparation 100 4-(Benzyloxy)-2-chloro-5-fluoro-6-methylpyrimidine

Chemical Structure

[0260] Preparation 101 Methyl 4-(benzyloxy)-5-fluoropyrimidine-2-carboxylate

Chemical Structure

[0261] Preparation 102 Methyl 4-(benzyloxy)-5-fluoro-6-methylpyrimidine-2-carboxylate

Chem.

[0262] Preparation 103 1-(4-(Benzyloxy)-5-fluoropyrimidin-2-yl)ethan-1-one

Chem.

[0263] Preparation 104 1-(4-(Benzyloxy)-5-fluoro-6-methylpyrimidin-2-yl)ethan-1-one

Chemical formula

[0264] Preparation 105 4-(Benzyloxy)-2-(1,1-difluoroethyl)-5-fluoropyrimidine

Chemical formula

[0265] Preparation 106 4-(Benzyloxy)-2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidine

Chemical formula

[0266] Preparation 107 2-(1,1-Difluoroethyl)-5-fluoropyrimidin-4-ol [Chemical formula] A solution of 4-(benzyloxy)-2-(1,1-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 mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1 - 3 / 1) to obtain 2-(1,1-difluoroethyl)-5-fluoropyrimidin-4-ol (3.2 g, yield 72.1%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ ppm: 11.61 (br s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 2.03 (t, J = 18.8 Hz, 3H).

[0267] Preparation 108 2-(1,1-Difluoroethyl)-5-fluoro-6-methylpyrimidin-4-ol [Chemical formula] Following the procedure described in Preparation 107, 2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidin-4-ol was obtained as a colorless oil, 780 mg, 73.5%, from 4-(benzyloxy)-2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidine (Preparation 106). 1 H NMR: (500 MHz, CDCl3) δ ppm: 2.40 (d, J = 3.5 Hz, 3H), 2.02 (t, J = 18.5 Hz, 3H).

[0268] Preparation 109 4-Chloro-2-(1,1-difluoroethyl)-5-fluoropyrimidine [Chemical formula] A solution of 2-(1,1-difluoroethyl)-5-fluoropyrimidin-4-ol (Preparation 107, 3.2 g, 18 mmol) in POCl3 (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 × 60 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over Na2SO4, 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-(1,1-difluoroethyl)-5-fluoropyrimidine (2.3 g, yield 65.1%) as a colorless oil. LCMS m / z = 197.1 [M+H] +

[0269] Preparation 110 4-Chloro-2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidine

Chem.

[0270] Preparation 111 4-Chloro-2-(1,1-difluoroethyl)-6-((1r,3r)-3-methoxycyclobutoxy)pyrimidine

Chem.

[0271] Preparation 112 4-Chloro-2-(1,1-difluoroethyl)-6-(2-methoxyethoxy)pyrimidine

Chemical formula

[0272] Preparation 113 3-(Benzyloxy)-1-methylcyclobutan-1-ol

Chem.

[0273] Preparation 114 (3-(Benzyloxy)-1-methylcyclobutoxy)(tert-butyl)dimethylsilane

Chem.

[0274] Preparation 115 3-((tert-Butyldimethylsilyl)oxy)-3-methylcyclobutan-1-ol

Chemical formula

[0275] Preparation 116 4-(3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutoxy)-6-chloro-2-(1,1-difluoroethyl)pyrimidine

Chem.

[0276] Preparation 117 N-(5-bromo-2-chloropyridin-4-yl)-6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-amine

Chem.

[0277] Preparation 118 N-(5-bromo-2-chloropyridin-4-yl)-2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-amine

Chemical Structure

[0278] Preparation 119 N-(2-Chloro-5-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)-2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-amine [Chemical Structure] Into a vial, add dioxane (3 mL) and water (1 mL) containing N-(5-bromo-2-chloropyridin-4-yl)-2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-amine (Preparation 118, 150 mg, 0.395 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (100 mg, 0.481 mmol), K2CO3 (150 mg, 1.09 mmol), and Pd(dppf)Cl2 (15 mg, 0.0205 mmol). Seal the vial and stir the reaction mixture at 80 °C for 20 h. Remove the reaction from heating and cool to room temperature. Dilute with water (10 mL) and extract with EtOAc (3 × 10 mL). Concentrate the combined organic layers to dryness and then purify by silica gel chromatography (from 100% heptane to 100% EtOAc) to obtain N-(2-chloro-5-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)-2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-amine as a white solid (30 mg, yield 19.9%). LCMS m / z = 381.3 [M+H] + . 1H NMR (DMSO-d6) δ: 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).

[0279] Preparation 120 N-(4-((6-(3-((tert-Butyldimethylsilyl)oxy)-3-methylcyclobutoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide [Chemical formula] To a solution of 4-(3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutoxy)-6-chloro-2-(1,1-difluoroethyl)pyrimidine (Preparation 116, 100 mg, 0.512 mmol) in dioxane (5 mL) were 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 × 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel (from DCM / MeOH 1 / 0 to 10 / 1) to give N-(4-((6-(3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide (225 mg, crude) as a yellow solid. LCMS m / z = 552.3 [M+H] + . 1 H NMR: (400 MHz, CDCl3) δ 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).

[0280] Preparation 121 N-(4-((2-(1,1-Difluoroethyl)-6-(prop-1-en-2-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide [Chemical formula] 4-chloro-2-(1,1-difluoroethyl)-6-(prop-1-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) were placed in a mixture in DMF (4 mL), and BrettPhos Pd G3 (74.6 mg, 0.823 mmol) was added at 20 °C. The reaction mixture was stirred at 70 °C for 2 hours. The mixture was concentrated, and the residue was purified by preparative HPLC (Method C, gradient: 42 - 72%) to obtain N-(4-((2-(1,1-difluoroethyl)-6-(prop-1-en-2-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide (60 mg, yield 20.1%) as a white solid. L...

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