Tyrosine kinase 2 inhibitor and application thereof

Abstract

The present disclosure relates to compounds of formula (I): # imgabs0 # or a pharmaceutically acceptable salt thereof, wherein all the variables in formula (I) are as defined herein. The compounds of the present disclosure are capable of inhibiting the activity of tyrosine kinase 2 (TYK2). The disclosure further provides methods of making the compounds of the disclosure, and methods of therapeutic use thereof.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 389,038, filed July 14, 2022, the entire contents of which are expressly incorporated herein by reference. Technical Field

[0003] This disclosure relates to inhibitors of tyrosine kinase 2 (TYK2) and pharmaceutically acceptable salts thereof, compositions of these compounds, methods of their preparation, their use in treating diseases, their use in combination with pharmaceutically acceptable carriers for the manufacture of pharmaceutical formulations, the use of pharmaceutical formulations in treating diseases, and methods of treating diseases, said methods comprising administering TYK2 inhibitors to warm-blooded animals, particularly humans. Background Art

[0004] Cytokines are small, secreted proteins released by cells and play specific roles in cell-cell interactions and communication. The cytokine pathway mediates a wide range of biological functions, including many aspects of inflammation and immunity, primarily through extracellular signal transduction.

[0005] Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, which are cytokine receptor-associated cytoplasmic protein kinases that play a central role in mediating cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1; and Yamaoka et al., Genome Biology 2004, 5, 253). The JAK family also includes JAK1, JAK2, and JAK3. More specifically, cytokine binding to its homologous receptor triggers activation of JAK-associated receptors, leading to tyrosine phosphorylation of JAK-mediated signal transduction and activation of transcription (STAT) proteins and ultimately transcriptional activation of specific gene sets (Schindler et al., 2007, J. Biol. Chem. 282: 20059-63). Many cytokines known to activate the JAK family include the interferon (IFN) family (IFN-α, IFN-β, IFN-Ω, Limitin, IFN-γ, IL-10, IL-19, IL-20, IL-22), the glycoprotein (gp)130 family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1 / BSF-3, G-CSF, CT-1, leptin, IL-12, IL-23), the γC 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), single-chain families (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and G protein-coupled receptors (AT1).

[0006] TYK2 plays an important role in the signaling of type I interferons (e.g., IFN-α), 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, WT & O'Shea, JJ, 2006, Immunity 25:695-697). Consistent with this, primary cells derived from TYK2-deficient humans are defective in the signaling of type I interferons, IL-6, IL-10, IL-12, and IL-23. TYK2 signals in combination with other members of the JAK family in the following combinations: TYK2 / JAK1, TYK2 / JAK2, and TYK2 / JAK1 / JAK2.

[0007] Studies have shown that inappropriate JAK activity can be caused by mutations, overexpression, inappropriate regulation, abnormal or dysregulated regulation, and excessive or insufficient production of growth factors or cytokines, thereby triggering various biological cellular responses related to cell growth, cell differentiation, cell function, survival, apoptosis, and cell motility. Inappropriate JAK activity is involved 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 diseases such as Alzheimer's disease.

[0008] Small molecule JAK inhibitors have emerged as a significant therapeutic advance in the treatment of autoimmune diseases. To date, all known small molecule JAK inhibitors developed are site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain of the JAK protein (also known as the JH1 or “Janus homology 1” domain), thereby preventing the catalytic activity of the kinase by blocking ATP, downstream phosphorylation, and signal transduction of the resulting pathway (Bryan et al., J. Med. Chem. 2018, 61, 9030-9058).

[0009] Due to the high homology of ATP active sites across the entire kinome, and especially within the JAK family, achieving high selectivity for specific JAK family members while maintaining selectivity within the kinome is a significant challenge. Therefore, many developed JAK inhibitors are pan-JAK inhibitors or exhibit moderate selectivity for one or more JAK family members. While these inhibitors have shown encouraging results in the treatment of autoimmune diseases, undesirable side effects leading to a narrow therapeutic index have been observed, indicating a need for improved treatment.

[0010] TYK2 has been shown to play an important role in the differentiation and function of various important cell types, including natural killer cells, B cells, and T helper cells, in inflammatory and autoimmune diseases. Aberrant TYK2 expression is associated with a variety of autoimmune or inflammatory disorders.

[0011] There is still a need for effective compounds that exhibit higher selectivity for TYK2 compared to other members of the JAK family as potential therapeutic agents for diseases or conditions that respond to TYK2 inhibition. Summary of the Invention

[0012] This disclosure provides compounds as TYK2 inhibitors. In a first aspect, this disclosure relates to compounds having formula I:

[0013]

[0014] or a pharmaceutically acceptable salt thereof, wherein:

[0015] R 1 H, C 1-6 Alkyl, -OR 1a 、-NR 1b R 1c , 3 to 7 member monocyclic carbocyclic groups or 4 to 7 member monocyclic heterocyclic groups, wherein R 1 C represents 1-6 Alkyl groups, 3- to 7-membered monocyclic carbocyclic groups, and 4- to 7-membered monocyclic heterocyclic groups are each optionally surrounded by one or more R groups. 1d replace;

[0016] R 1a 、R 1b and R 1c Each independently represents H and C. 1-4 Alkyl or 3- to 4-membered monocyclic carbocyclic group;

[0017] Each R 1d Independently halogenated, 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 or 4- to 7-membered monocyclic heterocyclic;

[0018] R 2 Selected from H, halogenated group, C 1-6 Alkyl, C 3-7 cycloalkyl, -OR 2a 、-N(R 2b 2. Four to eleven-membered monocyclic or bicyclic heterocyclic groups having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur, and five to six-membered monocyclic heteroaryl groups having one to three heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 2 C represents 1-6 Alkyl, C 3-7 Cycloalkyl, 5 to 11-membered monocyclic or bicyclic heterocyclic groups, and 5 to 6-membered monocyclic heteroaryl groups are each optionally surrounded by 1 to 3 R groups. 20 replace;

[0019] R 2a Selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl groups, and 4- to 7-membered monocyclic heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 2a C represents 1-6 Alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl and 4- to 7-membered monocyclic heterocyclic groups are optionally surrounded by 1 to 3 R groups.20 replace;

[0020] Each R 2b Independently for H and C 1-4 Alkyl, C 1-3 Alkyl-C 1-3 Alkoxy, C 1-4 Alkoxy or 4- to 6-membered monocyclic heterocyclic groups;

[0021] R 20 Each time it appears, it is independently selected from halogenated groups, -CN, and 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 groups, 5- to 10-membered bicyclic carbocyclic groups, 4- to 10-membered monocyclic or bicyclic heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 20 C represents 1-4 Alkyl, phenyl, C 3-7 Cycloalkyl, 5- to 10-membered bicyclic carbocyclic, 4- to 10-membered monocyclic or bicyclic heterocyclic, and 5- to 6-membered monocyclic heteroaryl are each optionally surrounded by 1 to 3 R groups. 200 replace;

[0022] Each R 20b Independently for H and C 1-4 Alkyl or C 1-4 Alkoxy;

[0023] R 20c H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl or 4- to 6-membered monocyclic heterocyclic groups, wherein C 1-4 Alkyl groups are optionally C 1-3 Alkyl substitution;

[0024] R 200 Each time it appears, it is independently selected from halogenated groups, -CN, and C. 1-4 Alkyl, C 1-3 Alkyl-C 1-3 Alkoxy, C 1-4 Haloalkyl, -OH, -N(R) 20b 2. C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C3-7 cycloalkyl groups and optionally 1 to 3 carbon atoms 1-3 Alkyl or C 1-3 Alkoxy-substituted 5- to 10-membered monocyclic or bicyclic heterocyclic groups;

[0025] Ring B is a phenyl group, a 5- to 10-membered monocyclic or bicyclic heteroaryl group, a 3- to 7-membered monocyclic carbocyclic group, or a 4- to 7-membered monocyclic heterocyclic group, wherein each is optionally separated by one or more R groups. B replace;

[0026] Each R B Independently selected from halogenated groups, -CN, and -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 carbocyclic groups, 4- to 7-membered monocyclic or bicyclic heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 10-membered monocyclic or bicyclic heteroaryl groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R B C represents 1-6 Alkyl, C 2-6 Alkenyl, phenyl, 3- to 7-membered monocyclic carbocyclic, 4- to 7-membered monocyclic heterocyclic, and 5- to 10-membered monocyclic or bicyclic heteroaryl groups are each optionally bound by one or more R B1 replace;

[0027] Each R B1 Independently selected from halogenated, oxo, –CN, -OR groups. 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 carbocyclic and 4 to 8-membered monocyclic heterocyclic;

[0028] R Ba Independently for H and C 1-4 Alkyl, C 3-7 Cycloalkyl or 4- to 8-membered monocyclic or bicyclic heterocyclic groups, wherein R Ba C represents 1-4 Alkyl, C 3-7 The cycloalkyl group and the 4- to 8-membered monocyclic or bicyclic heterocyclic group are each optionally surrounded by one or two R groups. B0 replace;

[0029] Each RB0 Independently a halogenated group, -CN, –OH, C 1-4 Alkyl or C 1-4 Alkoxy;

[0030] Each R Bb Independently for H and C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 Cycloalkyl;

[0031] R Bc C 1-6 Alkyl or C 3-7 Cycloalkyl;

[0032] R Bd -C(O)OR Ba 、-N(R Bb )2、-OR Ba , 3 to 7-membered monocyclic carbocyclic groups or 4 to 8-membered monocyclic heterocyclic groups; and

[0033] R N1 and R N2 Each independently is H or C 1-4 alkyl.

[0034] Another aspect of this disclosure relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0035] In another aspect, this disclosure provides a method for treating a disease or condition 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.

[0036] Another aspect of this disclosure relates to the use of at least one of the compounds described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease or condition responsive to inhibition of TYK2. The use of the compounds described herein or a pharmaceutically acceptable salt thereof for treating a disease or condition responsive to inhibition of TYK2 is also provided. This disclosure further includes the use of the compounds described herein or a pharmaceutically acceptable salt thereof for treating a disease or condition responsive to inhibition of TYK2. Detailed Implementation

[0037] This disclosure provides compounds and pharmaceutical compositions thereof that are applicable to the treatment of diseases or conditions via mediating TYK2. In some embodiments, the compounds disclosed herein are TYK2 inhibitors.

[0038] Compounds and Compositions

[0039] In a first embodiment, this disclosure relates to compounds having formula I:

[0040]

[0041] or a pharmaceutically acceptable salt thereof, wherein:

[0042] R 1 H, C 1-6 Alkyl, -OR 1a 、-NR 1b R 1c , 3 to 7 member monocyclic carbocyclic groups or 4 to 7 member monocyclic heterocyclic groups, wherein R 1 C represents 1-6 Alkyl groups, 3- to 7-membered monocyclic carbocyclic groups, and 4- to 7-membered monocyclic heterocyclic groups are each optionally surrounded by one or more R groups. 1d replace;

[0043] R 1a 、R 1b and R 1c Each independently represents H and C. 1-4 Alkyl or 3- to 4-membered monocyclic carbocyclic group;

[0044] Each R 1d Independently halogenated, 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 or 4- to 7-membered monocyclic heterocyclic;

[0045] R 2 Selected from H, C 1-6 Alkyl, C 3-7 cycloalkyl, -OR 2a 、-N(R 2b 2. Four to eleven-membered monocyclic or bicyclic heterocyclic groups having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur, and five to six-membered monocyclic heteroaryl groups having one to three heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 2 C represents 1-6 Alkyl, C 3-7 Cycloalkyl, 5 to 11-membered monocyclic or bicyclic heterocyclic groups, and 5 to 6-membered monocyclic heteroaryl groups are each optionally surrounded by 1 to 3 R groups. 20 replace;

[0046] R 2a Selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl groups and 4- to 7-membered monocyclic heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 2a C represents 1-6 Alkyl, C3-7 Cycloalkyl groups and 4- to 7-membered monocyclic heterocyclic groups are optionally surrounded by 1 to 3 R groups. 20 replace;

[0047] Each R 2b Independently for H and C 1-4 Alkyl or C 1-4 Alkoxy;

[0048] R 20 Each time it appears, it is independently selected from halogenated groups, -CN, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, -N(R) 20b 2. Phenyl, C 3-7 Cycloalkyl groups, 4- to 10-membered monocyclic or bicyclic heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 20 The phenyl group represented by C 3-7 Cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclic groups, and 5- to 6-membered monocyclic heteroaryl groups are each optionally surrounded by 1 to 3 R groups. 200 replace;

[0049] Each R 20b Independently for H and C 1-4 Alkyl or C 1-4 Alkoxy;

[0050] R 200 Each time it appears, it is independently selected from halogenated groups, -CN, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-3 Alkoxy and C 3-7 Cycloalkyl;

[0051] Ring B is a phenyl group, a 5- to 10-membered monocyclic or bicyclic heteroaryl group, a 3- to 7-membered monocyclic carbocyclic group, or a 4- to 7-membered monocyclic heterocyclic group, wherein each is optionally separated by one or more R groups. B replace;

[0052] Each R B Independently selected from halogenated groups, -CN, and -OR Ba 、-N(R Bb )2、-C(O)R Bc 、-C(O)OR Ba 、-SO2R Bc 、C 1-6Alkyl, phenyl, 3- to 7-membered monocyclic carbocyclic groups, 4- to 7-membered monocyclic heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 10-membered monocyclic or bicyclic heteroaryl groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R B C represents 1-6 Alkyl, phenyl, 3- to 7-membered monocyclic carbocyclic, 4- to 7-membered monocyclic heterocyclic, and 5- to 10-membered monocyclic or bicyclic heteroaryl groups are each optionally bound by one or more R B1 replace;

[0053] Each R B1 Independently selected from halogenated, oxo, –CN, -OR groups. 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 carbocyclic and 4 to 8-membered monocyclic heterocyclic;

[0054] R Ba Independently for H and C 1-4 Alkyl or C 3-7 cycloalkyl, wherein R Ba C represents 1-4 Alkyl and C 3-7 Each cycloalkyl group is optionally surrounded by one or two R B0 replace;

[0055] Each R B0 Independently a halogenated group, -CN, –OH, C 1-4 Alkyl or C 1-4 Alkoxy;

[0056] Each R Bb Independently for H and C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 Cycloalkyl;

[0057] R Bc C 1-6 Alkyl or C 3-7 Cycloalkyl;

[0058] R Bd -C(O)OR Ba 、-N(R Bb )2、-OR Ba , 3 to 7-membered monocyclic carbocyclic groups or 4 to 8-membered monocyclic heterocyclic groups; and

[0059] R N1 and RN2 Each independently is H or C 1-4 alkyl.

[0060] In the second embodiment, for compounds of formula (I) or pharmaceutically acceptable salts thereof, ring B is selected from phenyl, pyridyl, pyrimidinyl, and thiazolyl, wherein each is surrounded by one to three R groups. B Replace; and the remaining variables are as described in the first aspect or the first implementation scheme.

[0061] In the third embodiment, for compounds of formula (I) or pharmaceutically acceptable salts thereof, R N1 and R N2 Each is independently H or –CH3; and the remaining variables are as described in the first aspect or the second embodiment.

[0062] In the fourth embodiment, the compounds of this disclosure are represented by formula (II) or (III):

[0063]

[0064] or a pharmaceutically acceptable salt thereof, wherein:

[0065] A 1 N or CR 5 A 2 N or CR 6 And A 3 N or CR 3 The constraint is A 1 、A 2 and A 3 N is defined as having no more than one of the following.

[0066] R 3 Selected from H, -OR 3a 、-N(R 3b 2. C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, phenyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the phenyl and the 5- to 10-membered monocyclic or bicyclic heteroaryl group are each optionally surrounded by 1 to 3 R atoms. 3c replace;

[0067] R 3a H, C 1-4 Alkyl or C 3-7 Cycloalkyl groups, wherein each is optionally surrounded by one or two R groups. 30 replace;

[0068] Each R 30 Independently a halogenated group, -CN, –OH, C1-4 Alkyl or C 1-4 Alkoxy;

[0069] Each R 3b Independently for H and C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 Cycloalkyl;

[0070] Each R 3c Independently selected from halogenated, oxo, –CN, -OR groups. 3a 、-N(R 3b 2. C 1-4 Alkyl, C 1-4 Alkyl-R 3d 、C 1-4 Haloalkyl, -C(O)OR 3a , phenyl, 5 to 6-membered heteroaryl, 3 to 7-membered monocyclic carbocyclic and 4 to 8-membered monocyclic heterocyclic;

[0071] R 3d -C(O)OR 3a 、-N(R 3b )2、-OR 3a 3 to 7-membered monocyclic carbocyclic groups or 4 to 8-membered monocyclic heterocyclic groups;

[0072] R 4 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-4 Alkoxy, -SO2R 4a A 4- to 6-membered monocyclic heterocyclic group having 1 to 2 heteroatoms selected from nitrogen and oxygen, and optionally surrounded by 1 to 3 independently halogenated or C-shaped groups. 1-4 Alkyl substituents substituted C 3-7 Cycloalkyl;

[0073] R 4a C 1-6 alkyl;

[0074] R 5 H, halogenated group, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups or 5- to 6-membered heteroaryl groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 5 The 5 to 6 heteroaryl groups are optionally surrounded by 1 to 3 R groups. 50 Replace; and

[0075] R 50 Each time it appears, it is independently a halogenated group and a C group. 1-4 Alkyl or C 1-4 Halogenated alkyl groups; and

[0076] R 6 H, halogenated group, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-4 Alkyl groups; and the remaining variables are as described in the first aspect or the first, second, or third embodiments. In an alternative fourth embodiment, the compounds of this disclosure are represented by formula (II), (II'), or (III):

[0077]

[0078] or a pharmaceutically acceptable salt thereof, wherein:

[0079] A 1 N or CR 5 A 2 N or CR 6 And A 3 N or CR 3 The constraint is A 1 、A 2 and A 3 N is defined as having no more than one of the following.

[0080] R 3 Selected from H, halogenated group, -OR 3a 、-N(R 3b 2. C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-3 Alkyl-C 1-3 Alkoxy, C2 alkenyl, C 3-7 Cycloalkyl, phenyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the phenyl and the 5- to 10-membered monocyclic or bicyclic heteroaryl group are each optionally surrounded by 1 to 3 R atoms. 3c replace;

[0081] R 3a H, C 1-4 Alkyl, 4- to 8-membered monocyclic or bicyclic heterocyclic groups or C 3-7 Cycloalkyl groups, wherein each is optionally surrounded by one or two R groups. 30 replace;

[0082] Each R 30 Independently a halogenated group, -CN, –OH, C 1-4 Alkyl or C 1-4 Alkoxy;

[0083] Each R 3b Independently for H and C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 Cycloalkyl;

[0084] Each R 3c Independently selected from halogenated, oxo, –CN, -OR groups. 3a 、-N(R 3b 2. C 1-4 Alkyl, C 1-4 Alkyl-R 3d 、C 1-4 Haloalkyl, -C(O)OR 3a , phenyl, 5 to 6-membered heteroaryl, 3 to 7-membered monocyclic carbocyclic and 4 to 8-membered monocyclic heterocyclic;

[0085] R 3d -C(O)OR 3a 、-N(R 3b )2、-OR 3a 3 to 7-membered monocyclic carbocyclic groups or 4 to 8-membered monocyclic heterocyclic groups;

[0086] R 4 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-4 Alkoxy, C 1-3 Alkoxy-C 1-3 Alkoxy, C 1-3 Haloalkoxy, -C2 haloalkenyl, -SO2R 4a 4- to 8-membered monocyclic or bicyclic heterocyclic groups having 1 to 2 heteroatoms selected from nitrogen and oxygen, and C 3-7 Cycloalkyl groups, wherein 4 to 8 membered monocyclic or bicyclic heterocyclic groups and C 3-6 Each cycloalkyl group is optionally surrounded by one to three independently selected from a halogenated group, C... 1-4 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkyl-C 1-3 Substitution of alkoxy groups;

[0087] R 4a C 1-6 alkyl;

[0088] R 5 H, halogenated group, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups or 5- to 6-membered heteroaryl groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 5 The 5 to 6 heteroaryl groups are optionally surrounded by 1 to 3 R groups. 50 Replace; and

[0089] R 50 Each time it appears, it is independently a halogenated group and a C group. 1-4 Alkyl or C 1-4Halogenated alkyl groups; and

[0090] R 6 and R 7 Each is independently H, halogenated group, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-4 Alkoxy groups; and the remaining variables are as described in the first aspect or the first, second or third embodiments.

[0091] In the fifth embodiment, the compounds of this disclosure are represented by formula (IV), (V), (VI), or (VII):

[0092]

[0093] Or a pharmaceutically acceptable salt thereof, wherein the variables in formula (IV), (V), (VI), or (VII) are as defined in the first, second, or third embodiments. In an alternative fifth embodiment, the compounds of this disclosure are represented by formula (IV), (V), (VI), (VII), (VIII), or (IX):

[0094]

[0095] Or a pharmaceutically acceptable salt thereof, wherein the variables in formula (IV), (V), (VI), (VII), (VIII) or (IX) are as defined in the first, second or third embodiments.

[0096] In the sixth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 1 C 1-4 Alkyl or C 3-6 cycloalkyl, wherein C 1-4 Alkyl groups are optionally C 1-3 Alkyl substitution; and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiments. In an alternative sixth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII), or (IX) or their pharmaceutically acceptable salts, R 1 H, C 1-4 Alkyl, -OR 1a 、-NR 1b R 1c Or C 3-6 cycloalkyl, wherein C 1-4 Alkyl groups are optionally C 1-3 Alkoxy substitution; R 1a C1-3 Alkyl; R 1b and R 1c Each independently is H or C 1-3 Alkyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth or fifth embodiments.

[0097] In the seventh embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 1 Selected from -CH3, -CH2CH3, -CH2OCH3, -CH2CH2OCH3 and cyclopropyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth or fifth embodiments. In the alternative seventh embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or pharmaceutically acceptable salts thereof, R 1 The components are selected from H, -CH3, -CH2CH3, -CH2OCH3, -CH2CH2OCH3, -OCH3, -NH2, -NHCH3 and cyclopropyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth or fifth embodiments.

[0098] In the eighth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts;

[0099] R 2 Selected from H, C 1-4 Alkyl, -OR 2a and -N(R 2b )2, where R 2 C represents 1-4 Alkyl groups are optionally surrounded by 1 to 3 R groups. 20 replace;

[0100] R 2a H, C 1-4 Alkyl, C 3-6 Cycloalkyl or 4- to 6-membered monocyclic heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 2a C represents 1-4 Alkyl, C 3-6 The cycloalkyl group and the 4- to 6-membered monocyclic heterocyclic group are each optionally surrounded by 1 to 3 R groups. 20 replace;

[0101] R 20 Independently selected from halogenated groups, C1-3 Alkyl, C 1-3 Alkoxy, -N(R) 20b 2. Phenyl, C 3-6 Cycloalkyl groups, 4- to 10-membered monocyclic or bicyclic heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein phenyl, C 3-6 Cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclic groups, and 5- to 6-membered heteroaryl groups are each optionally surrounded by 1 to 3 R groups. 200 replace;

[0102] R 2b Each time it appears, it is independently either H or C. 1-3 alkyl;

[0103] R 20b Each time it appears, it is independently either H or C. 1-3 Alkyl; and

[0104] R 200 Each time it appears, it is independently selected from halogenated groups and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-2 Alkoxy and C 3-5 Cycloalkyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth or seventh embodiments.

[0105] In the alternative eighth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts;

[0106] R 2 Selected from H, halogenated group, C 1-4 Alkyl, -OR 2a and -N(R 2b )2, where R 2 C represents 1-4 Alkyl groups are optionally surrounded by 1 to 3 R groups. 20 replace;

[0107] R 2a H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered monocyclic heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 2a C represents 1-4 Alkyl, C 3-6 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered monocyclic heterocyclic groups are each optionally surrounded by 1 to 3 R groups. 20replace;

[0108] R 20 Independently selected from halogenated groups, 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, 5- to 10-membered bicyclic carbocyclic rings, 4- to 10-membered monocyclic or bicyclic heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-4 Alkyl, phenyl, C 3-6 Cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclic groups, and 5- to 6-membered heteroaryl groups are each optionally surrounded by 1 to 3 R groups. 200 replace;

[0109] R 2b Each time it appears, it is independently either H or C. 1-3 alkyl;

[0110] R 20b Each time it appears, it is independently either H or C. 1-3 Alkyl; and

[0111] R 200 Each time it appears, it is independently selected from halogenated groups and 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.

[0112] In the ninth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 2 H, C 1-4 Alkyl, -OR 2a or -N(R) 2b )2, where R 2 C represents 1-4 The alkyl group is optionally surrounded by 1 to 3 independently selected from a halogenated group, C... 1-3 Alkoxy and -N(R) 20b Substituents of )2; and R 2a H or optionally 1 to 3 independently selected from halogenated groups, C 1-3 Alkoxy and -N(R) 20b C substituted with a substituent of )21-4 Alkyl groups; and the remaining variables are as described in the eighth embodiment.

[0113] In the tenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 2 For –OR 2a ;R 2a C 3-6 Cycloalkyl or a 4- to 6-membered monocyclic heterocyclic group having 1 to 2 independent heteroatoms selected from nitrogen and oxygen, wherein R 2a C represents 3-6 The cycloalkyl or 4- to 6-membered monocyclic heterocyclic group is optionally composed of 1 to 3 independently selected from halogenated groups, C 1-3 Alkyl and C 1-3 The alkoxy group is substituted; and the remaining variables are as described in the eighth embodiment. In the alternative tenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX), R 2 For –OR 2a ;R 2a C 3-6 Cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, wherein R 2a C represents 3-6 The cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered monocyclic heterocyclic groups are each optionally composed of 1 to 3 independently selected from halogenated groups, C... 1-3 Alkyl and C 1-3 Alkoxy substituents; and the remaining variables are as described in the eighth embodiment.

[0114] In the eleventh embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 2a It is cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, aziridine, tetrahydrofuranyl, or pyrrolidinyl, wherein each is optionally composed of 1 to 3 independently selected from a halogen group, C... 1-3 Alkyl and C 1-3 Alkyl groups are substituted; and the remaining variables are as described in the tenth embodiment. In an alternative eleventh embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX), R 2aThe derivative is cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, aziryl, tetrahydrofuranyl, pyrrolidinyl, pyrazinyl, pyridazinyl, or pyrazolyl, wherein each is optionally composed of 1 to 3 independently selected from a halogenated group, C 1-3 Alkyl and C 1-3 The alkoxy group is substituted; and the remaining variables are as described in the tenth embodiment.

[0115] In the twelfth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 2a It is represented by the following:

[0116] Where p is 0, 1, 2, or 3; and each R 20 Independently halogenated, C 1-3 Alkyl and C 1-3 Alkyl group; and the remaining variables are as described in the tenth embodiment. In the alternative twelfth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 2a It is represented by the following:

[0117] Where p is 0, 1, 2, or 3; and each R 20 Independently halogenated, C 1-3 Alkyl and C 1-3 Alkoxy group; and the remaining variables are as described in the tenth embodiment. In some embodiments, R 2a It is represented by the following:

[0118]

[0119] In the thirteenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 2a It is represented by the following:

[0120]

[0121] And the remaining variables are as described in the twelfth embodiment. In the alternative thirteenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R2a It is represented by the following:

[0122] The remaining variables are as described in the twelfth implementation scheme.

[0123] In the fourteenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 2 For -OR 2a And R 2a For being an R 20 Substituted C 1-4 alkyl; and R 20 For phenyl, C 3-6 Cycloalkyl groups, 4- to 10-membered monocyclic or bicyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and 5- to 6-membered monocyclic heteroaryl groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein phenyl, C 3-6 Cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclic groups, and 5- to 6-membered monocyclic heteroaryl groups are each optionally surrounded by 1 to 3 R groups. 200 Replacement; and the remaining variables are as described in the eighth embodiment. In the alternative fourteenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 2 For -OR 2a And R 2a For being an R 20 Substituted C 1-4 alkyl; and R 20 For phenyl, C 3-6 Cycloalkyl, 5- to 10-membered bicyclic carbocyclic, 4- to 10-membered monocyclic or bicyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and 5- to 6-membered monocyclic heteroaryl groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein phenyl, C 3-6 Cycloalkyl, 5- to 10-membered bicyclic carbocyclic, 4- to 10-membered monocyclic or bicyclic heterocyclic, and 5- to 6-membered monocyclic heteroaryl are each optionally surrounded by 1 to 3 R groups. 200 Replace; and the remaining variables are as described in the eighth implementation scheme.

[0124] In the fifteenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 20Independently selected from aziridine, benzo[d][1,3]dioxacyclopentenyl, cyclobutyl, cyclopropyl, dihydrofuranone, imidazolyl, isoxazolyl, morpholinyl, oxabicyclo[2.2.1]hexyl, oxadiazolyl, aziridine, oxazolyl, phenyl, pyrazolyl, pyridinyl, pyrrolidinyl, and tetrahydrofuranyl, wherein each is optionally separated by 1 to 3 R 200 Replacement; and the remaining variables are as described in the fourteenth embodiment. In the alternative fifteenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 20 Independently selected from aziridine, benzo[d][1,3]dioxacyclopentenyl, cyclobutyl, cyclopropyl, spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, 2-oxabicyclo[2.1.1]hexyl, 5-oxaspiro[2.4]heptyl, 6-oxaspiro[3.4]octyl, dihydrofuranone, 1,3-dioxacyclopentyl, morpholinyl, piperazine, 1,4-dioxacyclohexyl, 5,8-dioxaspiro[3.5]nonyl, tetrahydropyridine 3-oxabicyclo[3.1.1]heptyl, 2-oxabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptyl, imidazolyl, isoxazolyl, morpholinyl, oxabicyclo[2.2.1]hexyl, oxadiazolyl, oxacyclobutyl, oxazolyl, phenyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, and tetrahydrofuranyl, wherein each is optionally surrounded by 1 to 3 R 200 Replace; and the remaining variables are as described in the fourteenth implementation scheme.

[0125] In the sixteenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 20 Selected independently from: Wherein, if the valence permits, m is 0, 1, or 2; and the remaining variables are as described in the fourteenth embodiment. In the alternative sixteenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII), or (IX) or their pharmaceutically acceptable salts, R 20 Selected independently from: Wherein, if the valence allows, m can be 0, 1, or 2; and the remaining variables are as described in the fourteenth implementation scheme.

[0128] In the seventeenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 2 Selected from H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2OCH3, -CH(CH3)2, -CH2CH2CH2N(CH3)2, cyclopropyl, -CH2O CH3, 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, And the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, or seventh embodiments. In the alternative seventeenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII), or (IX), their pharmaceutically acceptable salts, R 2Selected from H, -F, -CH3, -CH2CH3, -CH2CH2CH3, -CF2CH2CH3, -CH2CH2CH2OCH3, -CH(CH3)2, -CH2CH2CH2N(CH3)2, -CF2-cyclopropyl, cyclopropyl, -CH2OCH3, -OH, -OCH3, -OCD3, -OCHF2, -OCH2CH3, -OCD2CH3, -OCD2CD3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CH2F, -OCH2CH2CH(CH3)F, -OCH(CH3)2, -OCH2CF(CH3)2, -OCH2CH2CH2CH3, -OCH2CHFCH(CH3)2, -OCH2CHF-cyclobutyl, -OCH2CH2OH, -OCH2CH(OC H3)CH2CH3, -OCH2CH2OCH3, -OCH2CH2OCF2H, -OCH2CH2OCH2CH3, -OCH2CH2CH2OCH3, -OCH2CH( CH3)OCH3, -OCH2CH(CH3)CH2OCH3, -OCH(CH3)CH2OCH3, -OCH2CH(CH3)OC(CH3)3, -OCH2CH2CH (CH3)OCH3, -OCH2C(CH3)2OCH3, -OCH2CH2OCH2CH3, -OCH2CH2OCH(CH3)2, -OCH2CH2OC(CH3)3 , -OCH2CH2O-cyclopropyl, -OCH2CH2N(CH3)2, -OCH2C(O)NHCH3, -OCH2C(O)N(CH3)2, -NH2, -N(CH3)2, And the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth or seventh implementation schemes.

[0130] In the eighteenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 200Each time it appears, it is independently selected from F, -CN, –CH3, -CF3, -CH2CH3, -CH(CH3)2, –OCH3, and cyclopropyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiments. In the alternative eighteenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII), or (IX) or their pharmaceutically acceptable salts, R 200 Each time it appears, it is independently selected from F, -CN, -CH3, -CH2F, -CF3, -CH2CH3, -CH(CH3)2, -CH2OCH3, –OCH3, cyclobutyl and cyclopropyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth or seventeenth embodiments.

[0131] In the nineteenth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 2 C 3-6 Cycloalkyl, 4- to 6-membered monocyclic heterocyclic, 7- to 10-membered bicyclic heterocyclic, or 5- to 6-membered monocyclic heteroaryl, wherein each is optionally surrounded by 1 to 2 R groups. 20 Replace; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth or seventh implementation scheme.

[0132] In the twentieth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 2 The derivative is selected from aziridine, cyclopropyl, dioxin[2,3-d]pyridinyl, isoxazolyl, isothiazolyl, morpholinyl, oxazabicyclo[3.1.1]heptyl, oxazolyl, pyridazinyl, pyridinyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, and thiazolyl, wherein each is optionally marked by 1 to 2 R 20Replacement; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth or seventh embodiments. In the alternative twentieth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 2 Selected from aziridine, cyclopropyl, tetrahydropyranyl, dioxin[2,3-d]pyridinyl, pyridinoneyl, pyrimidinoneyl, pyrazinoneyl, isoxazolyl, isothiazolyl, morpholinyl, oxazabicyclo[3.1.1]heptyl, oxazolyl, pyridinyl, pyridinyl, pyridinyl, pyrazinyl, pyridinyl, triazinyl, pyrimidinyl, triazolyl, imidazoleyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, 6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-8(5H)-keto, 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]pyridyl, 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-di Hydrogen-5H-cyclopentano[b]pyridin-5-one, furano[3,4-d]pyrimidin-5(7H)-one, 5,7-dihydrofurano[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, wherein each is optionally surrounded by 1 to 2 R 20 Replace; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth or seventh implementation scheme.

[0133] In the twenty-first embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 2 Selected from Where n is 0, 1, or 2; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, or seventh embodiments. In the alternative twenty-first embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII), or (IX) or their pharmaceutically acceptable salts, R 2 Selected from Where n is 0, 1, or 2; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, or seventh implementation scheme.

[0134] In the twenty-second embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 20 Each time it appears, it is independently a halogenated group, -CN, or C. 1-3 Alkyl, C 1-43 Haloalkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, nineteenth, twentieth or twenty-first embodiments. In the alternative twenty-second embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or pharmaceutically acceptable salts thereof, R 20 Each time it appears, it is independently a halogenated group, -CN, or C. 1-4 Alkyl, C 1-4 Halogenated alkyl, 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 5- to 10-membered monocyclic or bicyclic heterocyclic groups, wherein R is a cycloalkyl group or a 5- to 10-membered monocyclic or bicyclic heterocyclic group. 20 C represents 1-4 Alkyl groups may optionally be substituted with: -CN, OH, -N(R)20b 2. C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl and optionally C 1-4 Alkyl-substituted 5- to 10-membered monocyclic or bicyclic heterocyclic groups, R 20c H, C 1-4 Alkyl, C 1-4 Halogenated alkyl or 4-membered monocyclic heterocyclic group, wherein C 1-4 Alkyl groups are optionally C 1-3 Alkoxy substitution; wherein R 20 The 5- to 10-membered monocyclic or bicyclic heterocyclic groups are optionally represented by C 1-4 Alkyl or C 1-3 Alkyl substitution; each R 20b Independently for H or optionally by C 1-3 alkoxy-substituted C 1-4 Alkyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, nineteenth, twentieth or twenty-first embodiments.

[0135] In the twenty-third embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 20 Each time it appears, it is independently selected from F, -CN, -OCH3, –CH3, -CHF2, cyclopropyl, and cyclobutyl; and the remaining variables are as described in the twenty-second embodiment. In the alternative twenty-third embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII), or (IX) or their pharmaceutically acceptable salts, R 20Each time it appears, it is independently selected from -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, -C H2OCHF2, -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, Cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, aziridine, pyrrolidinyl, N-methylpiperazinyl, N-methylmorpholinyl, and morpholinyl; and the remaining variables are as described in the twenty-second embodiment. In some embodiments, R 20 Each time it appears, it is independently selected from F, -CN, -OCH3, –CH3, -CHF2, cyclopropyl, and cyclobutyl.

[0136] In the twenty-fourth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 3 Selected from H, C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, -OR 3a 、-N(R 3b)2phenyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indazole, [1,2,4]triazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, and imidazo[1,2-b]pyridazinyl, wherein phenyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indazole, [1,2,4]triazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, or imidazo[1,2-b]pyridazinyl is each optionally surrounded by 1 or 2 R 3c Replacement; R 3a H, C 1-3 Alkyl or C 3-6 cycloalkyl, wherein R 3a C represents 1-3 Alkyl and C 3-6 Each cycloalkyl group is optionally represented by one or two independently selected from a halogen group, -CN, C. 1-2 Alkyl, -OH and C 1-2 Substituents of alkoxy groups; each R 3b Each time it appears, it is independently H or C. 1-3 Alkyl or C 3-5 cycloalkyl; each R 3c Independently selected from halogenated, oxo, –CN, -OR groups. 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, oxetyl, and morpholino; R 3d -C(O)OR 3a 、-N(R 3b )2、-OR 3a Cyclopropyl or morpholino; and the remaining variables are as described in embodiments four, five, six, seven, eight, nine, ten, eleven, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third. In an alternative twenty-fourth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII), or (IX) or their pharmaceutically acceptable salts, R 3 Selected from H, halogenated group, 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(R3b 2. phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, indazole, [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, or imidazo[1,2-b]pyridazinyl, wherein phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, indazole, [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, or imidazo[1,2-b]pyridazinyl is each optionally surrounded by one or two R... 3c Replacement; R 3a H, C 1-3 Alkyl, 4- to 8-membered monocyclic or bicyclic heterocyclic groups or C 3-6 cycloalkyl, wherein R 3a C represents 1-3 Alkyl and C 3-6 Each cycloalkyl group is optionally represented by one or two independently selected from a halogen group, -CN, C. 1-2 Alkyl, -OH and C 1-2 Substituents of alkoxy groups; each R 3b Each time it appears, it is independently H or C. 1-3 Alkyl or C 3-5 cycloalkyl; each R 3c Independently selected from halogenated, oxo, –CN, -OR groups. 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, oxetyl, or morpholino; R 3d -C(O)OR 3a 、-N(R 3b )2、-OR 3a Cyclopropyl or morpholino; and the remaining variables are as described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second or twenty-third embodiments.

[0137] In the twenty-fifth embodiment, for compounds of formulas (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII), (IX) or pharmaceutically acceptable salts thereof, R 3 Selected from H, -CH3, -CH2CH3, -CF2CH3, -CH(CH3)2, cyclopropyl, -OCH3, -OCH2CH2OCH3, -NHCH3, Where n is 0, 1, or 2; and the remaining variables are as described in the twenty-fourth embodiment. In the alternative twenty-fifth embodiment, for compounds of formula (I), (II'), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) or their pharmaceutically acceptable salts, R 3 Selected from H, -F, -Cl, -CH3, -CH2CH3, -CF2CH3, -CF3, -CH(CH3)2, cyclopropyl, -CH=CH2, -CH2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CH2OCH3, -OCH2CH2CH2OCH3, -NHCH3, Where n is 0, 1, or 2; and the remaining variables are as described in the twenty-fourth implementation scheme.

[0138] In the twenty-sixth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, each R 3c Individually selected from –CN, F, –OCH3, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CHF2, -CH2CF3, -CF3, -CD3, -CH2CH2OCH3, -CH2-cyclopropyl, -CH2CH2-morpholino, cyclopropyl, cyclobutyl, -CH2C(O)OH, -C(O)OC(CH3)3, -CH2CH2N(CH3)2 and morpholino; and the remaining variables are as described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth or twenty-fifth embodiments. In the alternative twenty-sixth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, each R 3cIndividually 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, oxacyclobutyl, and morpholinyl; and the remaining variables are as described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, or twenty-fifth embodiments.

[0139] In the twenty-seventh embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 4 Selected from C 1-4 Halogenated alkyl groups and C 3-6 Cycloalkyl groups, optionally composed of 1 to 3 independently selected from halogenated and C-groups. 1-3 Alkyl substituents; and the remaining variables are as described in embodiments four, five, six, seven, eight, nine, ten, eleven, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-six. In an alternative twenty-seventh embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII), or (IX) or their pharmaceutically acceptable salts, R 4 Selected from C 1-4 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkoxy-C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -C 2-4 Alkenyl, C 2-4 Haloalkenyl, 5- to 7-membered monocyclic or bicyclic heterocyclic groups and C 3-6 Cycloalkyl groups, wherein 5 to 7 membered monocyclic or bicyclic heterocyclic groups and C 3-6 Each cycloalkyl group is optionally surrounded by one to three independently selected from a halogenated group, C... 1-3 Haloalkyl, C 1-3 Alkyl-C 1-3 Alkoxy and C 1-3Alkyl substituents; and the remaining variables are as described in embodiments four, five, six, seven, eight, nine, ten, eleven, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth or twenty-sixth.

[0140] In the twenty-eighth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 4 Selected from -CF2CH3, -CF2CFH2, -CFHCFH2, -CF2CH2CH3, -CF(CH3)2 and And the remaining variables are as described in the twenty-seventh embodiment. In the alternative twenty-seventh embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 4 Selected from -CF2CH3, -CF2CFH2, -CFHCFH2, -CF(CH3)2, -CF(CH3)CFH2, -CH(CH3)CFH2, -CF2CH2CH3, -CF(CH3)2, -OCH3, -OCHF2, -OCH2CH2OCH3, -CF=CH2, And the remaining variables are as described in the twenty-seventh implementation scheme.

[0141] In the twenty-ninth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 5 It is H or a 5-membered heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 5 The 5-membered heteroaryl group is optionally divided by 1 to 3 R groups. 50 Replace; and the remaining variables are as described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh or twenty-eighth implementation scheme.

[0142] In the thirtieth embodiment, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R5 H or optionally 1 to 3 R 50 The substituted pyrazol group; and the remaining variables are as described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, or twenty-ninth embodiments.

[0143] In some embodiments, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 6 H, halogenated group, C 1-3 Alkyl groups, and the remaining variables as described in the first aspect or any of the above embodiments. Alternatively, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 6 It is H, -F, or -OCH3, and the remaining variables are as described in the first aspect or any of the above embodiments.

[0144] In some embodiments, for compounds of formula (I), (II), (II'), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or their pharmaceutically acceptable salts, R 7 H is the variable, and the remaining variables are as described in the first aspect or any of the above embodiments.

[0145] In the thirty-first embodiment, the compounds of this disclosure are represented by formula (IV-1) or (V-1):

[0146]

[0147] or a pharmaceutically acceptable salt thereof, wherein:

[0148] R 1 C 1-3 alkyl;

[0149] R 2 For -OR 2a Or optionally by C 1-3 Alkyl-substituted 5-membered monocyclic heteroaryl groups;

[0150] R 2a For optional use by R 20 Substituted C 1-4 alkyl;

[0151] R20 C 1-3 Alkyl groups or optionally C 1-2 alkoxy-substituted C 3-6 Cycloalkyl;

[0152] R 3 Selected from H, -OR 3a 、C 1-3 Alkyl, C 3-6 Cycloalkyl and pyrazolyl, wherein the pyrazolyl group is optionally surrounded by one or two R groups. 3c replace;

[0153] R 3a For optional use by C 1-3 alkoxy-substituted C 1-3 Alkyl groups, or optionally one or two independently selected from C 1-3 Alkoxy, C 1-3 C substituents of alkyl and -OH groups 3-6 Cycloalkyl;

[0154] R 3c C 1-3 Alkyl; and

[0155] R 4 C 1-3 Halogenated alkyl groups; and the remaining variables are as described in the first aspect or the first embodiment.

[0156] In the thirty-second embodiment, for compounds of formula (I), (IV-1), or (V-1) or their pharmaceutically acceptable salts, R 1 It is –CH3; and the remaining variables are as described in the thirty-first implementation scheme.

[0157] In the thirty-third embodiment, for compounds of formula (I), (IV-1) or (V-1) or their pharmaceutically acceptable salts, R 2 Selected from –OCH3, -OCD3, –OCH2CH3, -OCD2CH3, -OCD2CD3, -OCH2CH2OCH3, And the remaining variables are as described in the thirty-first or thirty-second implementation scheme.

[0158] In the thirty-fourth embodiment, for compounds of formula (I), (IV-1), or (V-1) or their pharmaceutically acceptable salts, R 3 Selected from H, –CH3, -CH2CH3, cyclopropyl, -OCH3, –OCH2CH2OCH3, And the remaining variables are as described in the 31st, 32nd or 33rd implementation schemes.

[0159] In the thirty-fifth embodiment, for compounds of formula (I), (IV-1), or (V-1) or their pharmaceutically acceptable salts, R 3c For –CH3, R 4 The variables are –CF2CH3, -CF2CFH2, -CFHCFH2, -CF2CH2CH3, -CF(CH3)2; and the remaining variables are as described in the 31st, 32nd, 33rd or 34th embodiments.

[0160] In the thirty-sixth embodiment, the compound of this disclosure is represented by formula (III):

[0161]

[0162] or a pharmaceutically acceptable salt thereof, wherein:

[0163] R 1 C 1-6 alkyl;

[0164] R 2 C 1-4 Alkoxy;

[0165] R 3 H or C 1-6 alkyl;

[0166] R 4 C 1-4 Haloalkyl or a 4- to 6-membered monocyclic heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen and oxygen; and

[0167] R N1 and R N2 Each independently is H or C 1-3 Alkyl; and the remaining variables are as described in the first aspect or the first, second or third embodiments.

[0168] In the thirty-seventh embodiment, for compounds of formula (I) or (III) or their pharmaceutically acceptable salts, R 1 It is –CH3; and the remaining variables are as described in the thirty-sixth implementation scheme.

[0169] In the thirty-eighth embodiment, for compounds of formula (I) or (III) or their pharmaceutically acceptable salts, R 2 It is –OCH2CH3 or –OCH2CH2OCH3; and the remaining variables are as described in the thirty-sixth or thirty-seventh implementation scheme.

[0170] In the thirty-ninth embodiment, for compounds of formula (I) or (III) or their pharmaceutically acceptable salts, R 3It is H or -CH3; and the remaining variables are as described in the thirty-sixth, thirty-seventh or thirty-eighth implementation schemes.

[0171] In the fortieth embodiment, for compounds of formula (I) or (III) or their pharmaceutically acceptable salts, R 4 C 1-3 Halogenated alkyl or tetrahydrofuranyl; and the remaining variables are as described in embodiments 36, 37, 38 or 39.

[0172] In the forty-first embodiment, for compounds of formula (I) or (III) or their pharmaceutically acceptable salts, R 4 For –CF2CH3 or And the remaining variables are as described in the fortieth implementation scheme.

[0173] In the forty-second embodiment, the compound of this disclosure is represented by formula (X):

[0174]

[0175] or a pharmaceutically acceptable salt thereof, wherein:

[0176] A 1 For N or CH;

[0177] R 2 For -OR 2a 5 or 6-membered monocyclic heteroaryl or 7 to 10-membered bicyclic heterocyclic group, wherein the 5 or 6-membered monocyclic heteroaryl or 7 to 10-membered bicyclic heterocyclic group is optionally surrounded by one or two R 20 replace;

[0178] R 2a For optional use by C 1-3 alkoxy-substituted C 1-3 alkyl;

[0179] R 20 For optional use by -N(C) 1-3 alkyl)2-substituted C 1-3 alkyl;

[0180] R 3 H, C 1-3 Alkyl or -OR 3a ;

[0181] R 3a C 3-4 Cycloalkyl;

[0182] R 4 C 1-4 Halogenated alkyl or 5- to 7-membered bicyclic heterocyclic groups; and the remaining variables are as described in the first aspect or the first embodiment.

[0183] In the forty-third embodiment, for compounds of formula (I) or (X) or their pharmaceutically acceptable salts, A 1 Let N be the variable; and the remaining variables are as described in the forty-second implementation scheme.

[0184] In the forty-fourth embodiment, for compounds of formula (I) or (X) or their pharmaceutically acceptable salts, R 2 The variable is -OCH3, -OCH2CH3, or -OCH2CH2OCH3; and the remaining variables are as described in the forty-second or forty-third embodiment.

[0185] In the forty-fifth embodiment, for compounds of formula (I) or (X) or their pharmaceutically acceptable salts, R 2 It is pyrazolyl, pyridyl, pyrimidinyl, or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, wherein each is optionally surrounded by one or two R 20 Replace; and the remaining variables are as described in the 42nd or 43rd implementation scheme.

[0186] In the forty-sixth embodiment, for compounds of formula (I) or (X) or their pharmaceutically acceptable salts, R 2 for Where n is 0, 1, or 2; and the remaining variables are as described in the forty-fifth implementation scheme.

[0187] In the forty-seventh embodiment, for compounds of formula (I) or (X) or their pharmaceutically acceptable salts, R 2 for And the remaining variables are as described in the forty-sixth implementation scheme.

[0188] In the forty-eighth embodiment, for compounds of formula (I) or (X) or their pharmaceutically acceptable salts, each R 20 Independently -CH3, -CH2CH3, or -CH2N(CH3)2; and the remaining variables are as described in embodiments 42, 43, 45, 46, or 47.

[0189] In the forty-ninth embodiment, for compounds of formula (I) or (X) or their pharmaceutically acceptable salts, R 3 It is H, -CH3, -CH2CH3 or -O-cyclopropyl; and the remaining variables are as described in embodiments 42, 43, 44, 45, 46, 47 or 48.

[0190] In the fiftieth embodiment, for compounds of formula (I) or (X) or their pharmaceutically acceptable salts, R 4-CF2CH3 or And the remaining variables are as described in implementation schemes 42, 43, 44, 45, 46, 47, 48 or 49.

[0191] In the fifty-first embodiment, this disclosure provides compounds selected from the group consisting of:

[0192] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0193] N-(4-((4-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0194] N-(4-((4-(1,1-difluoroethyl)pyrimidin-2-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0195] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0196] N-(4-((2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0197] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(difluoromethoxy)pyridin-2-yl)acetamide;

[0198] N-(5-cyclobutyloxy-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0199] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-prop-2-yloxypyridin-2-yl)acetamide;

[0200] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)propionamide;

[0201] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0202] N-(5-(cyclopropylmethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0203] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0204] N-(4-((6-cyclopropyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0205] N-(4-((6-(1,1-difluoroethyl)-4-(3-methoxycyclobutyl)oxypyridin-2-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0206] N-(4-((6-(1,1-difluoroethyl)-4-(3-methoxycyclobutyl)oxypyridin-2-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0207] N-(4-((2-(1,1-difluoroethyl)-6-(3-methoxycyclobutyl)oxypyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0208] N-(4-((6-cyclopropyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0209] N-(4-((2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0210] N-(4-((2-(1,1-difluoroethyl)-6-(3-methoxycyclobutyl)oxypyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0211] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0212] N-(4-((2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0213] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0214] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetamide;

[0215] N-(5-(2,2-difluoroethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0216] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(dimethylamino)ethoxy)pyridin-2-yl)acetamide; formic acid;

[0217] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)-2-methoxyacetamide;

[0218] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)-3-methoxypropionamide;

[0219] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)cyclopropaneformamide;

[0220] N-(5-cyclopropyl-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0221] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-phenylmethoxypyridin-2-yl)acetamide;

[0222] N-(5-ethoxy-4-((2-(2-fluoroprop-2-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0223] N-(4-((2-(1,1-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0224] N-(4-((6-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0225] N-(4-((2-(1,1-difluoroethyl)-5-fluoropyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0226] N-(4-((2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0227] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0228] N-(4-((2-(1,1-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0229] N-(5-cyclopropyloxy-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0230] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-prop-2-yloxypyridin-2-yl)acetamide;

[0231] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methoxycyclobutyl)methoxy)pyridin-2-yl)acetamide;

[0232] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-methylpyridin-2-yl)acetamide;

[0233] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethylpyridin-2-yl)acetamide;

[0234] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-propylpyridin-2-yl)acetamide;

[0235] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-propyl-2-ylpyridin-2-yl)acetamide;

[0236] N-(5-cyclopropyloxy-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0237] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0238] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(methoxymethyl)pyridin-2-yl)acetamide;

[0239] N-(5-(methoxymethyl)-4-((6-methoxy-5-(1-methylpyrazol-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide;

[0240] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1,1,2,2,2-pentadeuterethoxy)pyridin-2-yl)acetamide;

[0241] N-(4-((2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)amino)-5-(1-methylpyrazol-3-yl)pyridin-2-yl)acetamide;

[0242] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0243] N-(4-((2-(1,1-difluoroethyl)-6-prop-2-ylpyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0244] N-(4-((2-(1,1-difluoroethyl)-6-(3-hydroxy-3-methylcyclobutyl)oxypyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0245] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-methylamino)-5-ethoxypyridin-2-yl)acetamide;

[0246] N-(4-((2-(1,1-difluoroethyl)-6-vinylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0247] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0248] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-(trifluoromethyl)cyclopropyl)methoxy)pyridin-2-yl)acetamide;

[0249] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methylcyclopropyl)methoxy)pyridin-2-yl)acetamide;

[0250] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methoxypropyl-2-yl)oxy)pyridin-2-yl)acetamide;

[0251] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxypropoxy)pyridin-2-yl)acetamide;

[0252] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(oxetane-3-ylmethoxy)pyridin-2-yl)acetamide;

[0253] N-(5-(cyclobutylmethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0254] N-(4-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0255] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)acetamide;

[0256] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(2-(dimethylamino)ethoxy)pyridin-2-yl)acetamide;

[0257] N-(4-((6-cyclopropyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0258] N-(4-((6-(1,1-difluoroethyl)pyrazin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0259] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(difluoromethoxy)ethoxy)pyridin-2-yl)acetamide;

[0260] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(3-methoxypropoxy)pyridin-2-yl)acetamide;

[0261] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-morpholinylethoxy)pyridin-2-yl)acetamide;

[0262] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-2-yl)acetamide;

[0263] (R)-N-(5-(2-methoxyethoxy)-4-((6-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide;

[0264] (S)-N-(4-((6-(1,2-difluoroethyl)pyridin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0265] (R)-N-(5-((2,2-difluorocyclopropyl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0266] N-(4-((4-(1,1-difluoroethyl)pyrimidin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0267] N-(4-((2-(1,1-difluoroethyl)-6-isopropoxypyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0268] N-(4-((2-(1,1-difluoroethyl)-6-ethoxypyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0269] N-(4-((4-(1,1-difluoroethyl)-6-methylpyrimidin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0270] (S)-N-(4-((2-(1,2-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0271] (S)-N-(4-((4-(1,2-difluoroethyl)-6-methylpyrimidin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0272] (S)-N-(4-((2-(1,2-difluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0273] (S)-N-(4-((2-(1-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0274] (R)-N-(5-(1-cyclopropylethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0275] N-(5-((1-cyanocyclopropyl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0276] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(oxetane-2-ylmethoxy)pyridin-2-yl)acetamide;

[0277] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(oxetane-3-yloxy)pyridin-2-yl)acetamide;

[0278] Methyl (4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)carbamate;

[0279] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)propionamide;

[0280] (S)-N-(4-((6-(1,2-difluoroethyl)pyrazin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0281] N-(4-((6-(1-fluorovinyl)pyrazin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0282] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0283] Methyl (4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(dimethylamino)ethoxy)pyridin-2-yl)carbamate;

[0284] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(trifluoromethoxy)pyridin-2-yl)acetamide;

[0285] N-(4-((2-(1,1-difluoroethyl)-6-fluoropyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0286] N-(4-((6-(2-oxabicyclo[2.1.1]hex-4-yl)-4-methylpyridin-2-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0287] N-(4-((2-(1,1-difluoroethyl)-6-(pyridin-3-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0288] N-(4-((2-(1,1-difluoroethyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0289] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6-methylpyrazin-2-yl)oxy)pyridin-2-yl)acetamide;

[0290] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-fluorocyclopropyl)methoxy)pyridin-2-yl)acetamide;

[0291] N-(5-(bicyclo[1.1.1]pent-1-ylmethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0292] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyridin-2-ylmethoxy)pyridin-2-yl)acetamide;

[0293] 2-((6-acetamido-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-3-yl)oxy)-N-methylacetamide;

[0294] 2-((6-acetamido-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-3-yl)oxy)-N,N-dimethylacetamide;

[0295] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3,3-difluoropropoxy)pyridin-2-yl)acetamide;

[0296] N-(5-Butoxy-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0297] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-2-yl)acetamide;

[0298] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-methoxypropoxy)pyridin-2-yl)acetamide;

[0299] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(thiazolyl-2-ylmethoxy)pyridin-2-yl)acetamide;

[0300] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-ethyloxetane-3-yl)methoxy)pyridin-2-yl)acetamide;

[0301] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)pyridin-2-yl)acetamide;

[0302] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methylisothiazo-4-yl)methoxy)pyridin-2-yl)acetamide;

[0303] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methylthiazo-2-yl)methoxy)pyridin-2-yl)acetamide;

[0304] N-(5-(2-(tert-butoxy)ethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0305] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-methoxypyridin-4-yl)methoxy)pyridin-2-yl)acetamide;

[0306] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methylisothiazo-3-yl)methoxy)pyridin-2-yl)acetamide;

[0307] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6-methylpyridin-3-yl)methoxy)pyridin-2-yl)acetamide;

[0308] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-methylthiazo-4-yl)methoxy)pyridin-2-yl)acetamide;

[0309] 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;

[0310] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-fluoro-2-methylpropoxy)pyridin-2-yl)acetamide;

[0311] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-fluoropyridin-4-yl)methoxy)pyridin-2-yl)acetamide;

[0312] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methylisoxazol-5-yl)methoxy)pyridin-2-yl)acetamide;

[0313] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(oxazol-5-ylmethoxy)pyridin-2-yl)acetamide;

[0314] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4,6-dimethylpyridin-2-yl)methoxy)pyridin-2-yl)acetamide;

[0315] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)pyridin-2-yl)acetamide;

[0316] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-fluoropyridin-2-yl)methoxy)pyridin-2-yl)acetamide;

[0317] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrazin-2-ylmethoxy)pyridin-2-yl)acetamide;

[0318] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methoxypyridin-2-yl)methoxy)pyridin-2-yl)acetamide;

[0319] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methoxypyridin-2-yl)methoxy)pyridin-2-yl)acetamide;

[0320] N-(5-((4-cyanopyridin-2-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0321] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methylpyridin-2-yl)methoxy)pyridin-2-yl)acetamide;

[0322] N-(5-((5-cyanopyridin-2-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0323] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6-methoxypyridin-2-yl)methoxy)pyridin-2-yl)acetamide;

[0324] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methylpyridin-2-yl)methoxy)pyridin-2-yl)acetamide;

[0325] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrimidin-2-ylmethoxy)pyridin-2-yl)acetamide;

[0326] (R)-N-(5-((1,4-dioxane-2-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0327] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((tetrahydro-2H-pyran-3-yl)methoxy)pyridin-2-yl)acetamide;

[0328] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-methoxybutoxy)pyridin-2-yl)acetamide;

[0329] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1,5-dimethyl-1H-pyrazol-4-yl)methoxy)pyridin-2-yl)acetamide;

[0330] (R)-N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)acetamide;

[0331] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(2-hydroxyethoxy)pyridin-2-yl)acetamide;

[0332] N-(4-((2-(2-oxabicyclo[2.1.1]hex-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;

[0333] N-(4'-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-((difluoromethoxy)methyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0334] N-(5-cyclopropyl-4-((2-(1,1-difluoroethyl)-5-methoxypyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0335] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide;

[0336] N-(5-cyano-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0337] N-(5-cyano-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0338] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0339] 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;

[0340] (S)-N-(4-((6-(1,2-difluoroethyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0341] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(difluoromethoxy)-[2,3'-bipyridine]-6'-yl)acetamide;

[0342] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-(dimethylamino)propyl)pyridin-2-yl)acetamide;

[0343] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-methoxypropyl)pyridin-2-yl)acetamide;

[0344] N-(5-(cyclopropyldifluoromethyl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0345] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1,1-difluoropropyl)pyridin-2-yl)acetamide;

[0346] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-methoxy-2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0347] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxy-6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0348] 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;

[0349] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-2-yl)acetamide;

[0350] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl)acetamide;

[0351] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(1-methyl-2-oxo-1,2-dihydropyrimidin-4-yl)pyridin-2-yl)acetamide;

[0352] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)pyridin-2-yl)acetamide;

[0353] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(6-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0354] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methoxy-2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0355] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxy-6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0356] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)acetamide;

[0357] 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;

[0358] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide;

[0359] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)acetamide;

[0360] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-yl)acetamide;

[0361] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-2-yl)acetamide;

[0362] N-(4-((6-(difluoromethoxy)pyridin-2-yl)amino)-5-(pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0363] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0364] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0365] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0366] N-(4-((2-(2-fluoroprop-2-yl)pyrimidin-4-yl)amino)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0367] N-(4-((2-(2-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0368] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(2-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0369] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0370] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0371] N-(4-((2-(2-fluoroprop-2-yl)pyrimidin-4-yl)amino)-5-(2-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0372] N-(4-((2-(2-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0373] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0374] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0375] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0376] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0377] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0378] N-(4-((2-(1,1-difluoroethyl)pyridin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0379] N-(4-((6-(1,1-difluoroethyl)pyrazin-2-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0380] N-(4-((6-(2-fluoroprop-2-yl)pyrazin-2-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0381] N-(4-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0382] N-(4-((6-(1,1-difluoroethyl)-4-methoxypyridin-2-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0383] N-(4-((2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0384] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0385] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0386] N-(4-((2-(2-fluoroprop-2-yl)pyrimidin-4-yl)amino)-5-(6-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0387] N-(4-((2-(2-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0388] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0389] N-(4-((2-(2-fluoroprop-2-yl)pyrimidin-4-yl)amino)-5-(6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0390] N-(4-((2-(1,1-difluoroethyl)pyridin-4-yl)amino)-5-(6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0391] N-(4-((2-(2-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0392] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0393] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0394] N-(4-((4-(1,1-difluoroethyl)pyrimidin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0395] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0396] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0397] N-(4-((6-cyclopropyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0398] N-(4-((2-(1,1-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0399] (R)-N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide;

[0400] N-(4-((6-(1,1-difluoroethyl)-4-methoxypyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0401] N-(4-((6-(1,1-difluoroethyl)-4-(2-methoxyethoxy)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0402] 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;

[0403] N-(4-((6-(1,1-difluoroethyl)pyrazin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0404] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-methoxypyridazine-3-yl)pyridin-2-yl)acetamide-2,2,2-d3;

[0405] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methoxypyridazine-3-yl)pyridin-2-yl)acetamide;

[0406] N-(4-((6-(2-fluoroprop-2-yl)pyridin-2-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0407] N-(4-((2-(2-fluoroprop-2-yl)pyridin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0408] N-(4-((2-(1,1-difluoroethyl)pyridin-4-yl)amino)-5-(6-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0409] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0410] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-methylpyridazin-3-yl)pyridin-2-yl)acetamide;

[0411] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(6-methoxypyridazine-3-yl)pyridin-2-yl)acetamide;

[0412] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(6-oxo-1,6-dihydropyridazin-3-yl)pyridin-2-yl)acetamide;

[0413] 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;

[0414] 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;

[0415] (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;

[0416] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(dimethylamino)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0417] 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;

[0418] 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;

[0419] 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;

[0420] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(2-ethoxyethyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0421] 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;

[0422] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(methoxymethyl)thiazo-2-yl)pyridin-2-yl)acetamide;

[0423] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(methoxymethyl)thiazolyl-4-yl)pyridin-2-yl)acetamide;

[0424] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-(methoxymethyl)thiazo-2-yl)pyridin-2-yl)acetamide;

[0425] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-morpholinylthiazo-4-yl)pyridin-2-yl)acetamide;

[0426] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1,2,4-thiadiazol-5-yl)pyridin-2-yl)acetamide;

[0427] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(dimethylamino)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide;

[0428] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[4,5-c]pyridin-2-yl)pyridin-2-yl)acetamide;

[0429] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)pyridin-2-yl)acetamide;

[0430] 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;

[0431] 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;

[0432] N-(5-(6-(2-cyanopropyl-2-yl)pyrimidin-4-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0433] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-isopropoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0434] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-ethoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0435] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-ethylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0436] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-isopropylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0437] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(difluoromethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0438] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(dimethylamino)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0439] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0440] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(2-methoxyethoxy)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0441] 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;

[0442] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide;

[0443] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methylpyridazin-3-yl)pyridin-2-yl)acetamide;

[0444] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(dimethylamino)pyridazin-3-yl)pyridin-2-yl)acetamide;

[0445] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(isopropylamino)pyridazin-3-yl)pyridin-2-yl)acetamide;

[0446] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-morpholino-1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide;

[0447] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(dimethylamino)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0448] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0449] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(2-methoxyethyl)-1H-pyrazol-5-yl)pyridin-2-yl)acetamide;

[0450] 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;

[0451] 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;

[0452] 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;

[0453] 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;

[0454] 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;

[0455] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(2-methoxypropyl-2-yl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0456] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((difluoromethoxy)methyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0457] N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-((dimethylamino)methyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0458] N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-morpholino-[2,3'-bipyridine]-6'-yl)acetamide;

[0459] N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(morpholinylmethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0460] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(6-(2-methoxyethoxy)pyridazin-3-yl)pyridin-2-yl)acetamide;

[0461] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0462] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(dimethylamino)thiazo-4-yl)pyridin-2-yl)acetamide;

[0463] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(2-hydroxypropyl-2-yl)-1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0464] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methoxypyrazin-2-yl)pyridin-2-yl)acetamide;

[0465] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-((2-methoxyethyl)amino)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0466] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-((2-methoxyethyl)(methyl)amino)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0467] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(dimethylamino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0468] 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;

[0469] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(tetrahydrofuran-2-yl)pyridin-2-yl)acetamide;

[0470] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(tetrahydrofuran-2-yl)pyridin-2-yl)acetamide;

[0471] N-(4'-((2-(2-oxabicyclo[2.1.1]hex-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0472] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl)acetamide;

[0473] 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;

[0474] 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;

[0475] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazo-2-yl)pyridin-2-yl)acetamide;

[0476] N-(5-(5-(cyanomethyl)-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0477] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(pyrrolidin-1-ylmethyl)pyrimidin-2-yl)pyridin-2-yl)acetamide;

[0478] N-(5-(5-cyanopyridazin-3-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0479] 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;

[0480] 1-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)urea;

[0481] 1-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)-3-methylurea;

[0482] 1-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridine]-6'-yl)-3-methylurea;

[0483] 1-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridine]-6'-yl)urea;

[0484] 1-(5-cyano-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)urea;

[0485] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)acetamide;

[0486] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)acetamide;

[0487] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-fluoropropoxy)pyridin-2-yl)acetamide;

[0488] N-(4-((2-(1,1-difluoroethyl)-6-(5-methoxypyridin-3-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0489] N-(4-((6-((2-oxaspiro[3.3]hept-6-yl)oxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0490] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0491] (S)-N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxypropoxy)pyridin-2-yl)acetamide;

[0492] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0493] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((1-methyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)acetamide;

[0494] N-(4-((2-(1,1-difluoroethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0495] N-(4-((2-(1,1-difluoroethyl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0496] N-(4-((6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0497] 2-(4-(6-((2-acetamido-5-ethoxypyridin-4-yl)amino)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetic acid;

[0498] N-(4-((2-(1,1-difluoroethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0499] 4-(6-((2-acetamido-5-ethoxypyridin-4-yl)amino)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester;

[0500] N-(4-((2-(1,1-difluoroethyl)-6-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0501] 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;

[0502] N-(4-((2-(1,1-difluoroethyl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0503] N-(4-((2-(1,1-difluoroethyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0504] N-(4-((6-(1-cyclobutyl-1H-pyrazol-4-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0505] N-(4-((2-(1,1-difluoroethyl)-6-(1-(2-morpholinylethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0506] N-(4-((2-(1,1-difluoroethyl)-6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0507] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(methoxy-d3)pyridin-2-yl)acetamide;

[0508] N-(5-(2-cyclopropoxyethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0509] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methyltetrahydro-2H-pyran-4-yl)methoxy)pyridin-2-yl)acetamide;

[0510] (S)-N-(5-(2-(tert-butoxy)propoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0511] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-ethylisoxazol-5-yl)methoxy)pyridin-2-yl)acetamide;

[0512] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-methyloxazol-5-yl)methoxy)pyridin-2-yl)acetamide;

[0513] (R)-N-(5-(2-(tert-butoxy)propoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0514] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methoxyisoxazol-5-yl)methoxy)pyridin-2-yl)acetamide;

[0515] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(isothiazo-3-ylmethoxy)pyridin-2-yl)acetamide;

[0516] N-(5-((3-oxabicyclo[3.1.1]hept-1-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0517] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methyloxazol-2-yl)methoxy)pyridin-2-yl)acetamide;

[0518] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-(methoxymethyl)cyclopropyl)methoxy)pyridin-2-yl)acetamide;

[0519] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-ethyloxazol-2-yl)methoxy)pyridin-2-yl)acetamide;

[0520] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(2-fluoropyridin-3-yl)ethoxy)pyridin-2-yl)acetamide;

[0521] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methylthiazo-4-yl)methoxy)pyridin-2-yl)acetamide;

[0522] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4,6-dimethylpyrimidin-5-yl)methoxy)pyridin-2-yl)acetamide;

[0523] 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;

[0524] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1r,3r)-3-fluorocyclobutyl)methoxy)pyridin-2-yl)acetamide;

[0525] N-(5-((5-cyanofuran-2-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0526] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methylthiazo-5-yl)methoxy)pyridin-2-yl)acetamide;

[0527] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methylisoxazol-4-yl)methoxy)pyridin-2-yl)acetamide;

[0528] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-fluorobutoxy)pyridin-2-yl)acetamide;

[0529] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methoxytetrahydro-2H-pyran-4-yl)methoxy)pyridin-2-yl)acetamide;

[0530] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4,5-dimethyloxazol-2-yl)methoxy)pyridin-2-yl)acetamide;

[0531] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-fluorobutoxy)pyridin-2-yl)acetamide;

[0532] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-(fluoromethyl)tetrahydro-2H-pyran-4-yl)methoxy)pyridin-2-yl)acetamide;

[0533] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methyloxazol-2-yl)methoxy)pyridin-2-yl)acetamide;

[0534] N-(5-((5-cyclopropyloxazol-2-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0535] 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;

[0536] N-(5-((2-Cyclopropyloxazol-5-yl)methoxy)-4-((2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0537] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methoxypyrimidin-2-yl)methoxy)pyridin-2-yl)acetamide;

[0538] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6-methoxypyrimidin-4-yl)methoxy)pyridin-2-yl)acetamide;

[0539] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1s,4s)-4-methyl-2-oxabicyclo[2.2.2]oct-1-yl)methoxy)pyridin-2-yl)acetamide;

[0540] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(pyridin-2-ylmethoxy)pyridin-2-yl)acetamide;

[0541] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((3,4-difluorobenzyl)oxy)pyridin-2-yl)acetamide;

[0542] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((1r,3r)-3-methoxycyclobutoxy)pyridin-2-yl)acetamide;

[0543] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((1s,3s)-3-methoxycyclobutoxy)pyridin-2-yl)acetamide;

[0544] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((1r,3r)-3-fluorocyclobutoxy)pyridin-2-yl)acetamide;

[0545] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((1s,3s)-3-fluorocyclobutoxy)pyridin-2-yl)acetamide;

[0546] N-(5-((1-cyclobutyl-1H-pyrazol-4-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0547] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyridin-3-ylmethoxy)pyridin-2-yl)acetamide;

[0548] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methoxypyrazin-2-yl)oxy)pyridin-2-yl)acetamide;

[0549] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6-methoxypyrazin-2-yl)oxy)pyridin-2-yl)acetamide;

[0550] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6-methoxypyridazine-3-yl)oxy)pyridin-2-yl)acetamide;

[0551] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)pyridin-2-yl)acetamide;

[0552] Methyl (4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)carbamate;

[0553] N-(4-((2-(1,1-difluoroethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(ethoxy-d5)pyridin-2-yl)acetamide;

[0554] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(ethoxy-d5)pyridin-2-yl)acetamide;

[0555] N-(4-((2-(1,1-difluoroethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0556] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(ethoxy-1,1-d2)pyridin-2-yl)acetamide;

[0557] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(pyridin-2-ylmethoxy)pyridin-2-yl)acetamide;

[0558] N-(4-((2-(1,1-difluoroethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0559] N-(4-((2-(1,1-difluoroethyl)-6-(5-methylpyridin-3-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0560] N-(4-((2-(1,1-difluoroethyl)-6-(6-ethylpyridin-3-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0561] N-(4-((2-(1,1-difluoroethyl)-6-(6-methoxypyridin-3-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0562] N-(4-((2-(1,1-difluoroethyl)-6-(5-methoxypyridin-3-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0563] N-(4-((2-(1,1-difluoroethyl)-6-(1-isobutyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0564] N-(4-((6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0565] N-(4-((2-(1,1-difluoroethyl)-6-(3-fluoropyridin-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0566] N-(4-((6-(1-cyclobutyl-1H-pyrazole-4-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0567] N-(4-((2-(1,1-difluoroethyl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0568] N-(4-((6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0569] N-(4-((2-(1,1-difluoroethyl)-6-(1-(oxecyclobutane-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0570] N-(4-((6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0571] N-(4-((2-(1,1-difluoroethyl)-6-(1-(2-morpholinylethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0572] N-(4-((2-(1,1-difluoroethyl)-6-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0573] 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;

[0574] N-(4-((2-(1,1-difluoroethyl)-6-(pyridin-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0575] N-(4-((2-(1,1-difluoroethyl)-6-(5-fluoro-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0576] N-(4-((2-(1,1-difluoroethyl)-6-(5-fluoropyridin-2-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0577] N-(4-((2-(1,1-difluoroethyl)-6-(5-fluoro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0578] N-(4-((2-(1,1-difluoroethyl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0579] N-(4-((2-(1,1-difluoroethyl)-6-(2-methylthiazo-5-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0580] N-(4-((2-(1,1-difluoroethyl)-6-(pyridin-3-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0581] N-(4-((2-(1,1-difluoroethyl)-6-(5-methylpyridin-3-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0582] N-(4-((2-(1,1-difluoroethyl)-2'-morpholino-[4,5'-bipyrimidin]-6-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0583] N-(4-((2-(1,1-difluoroethyl)-6-(6-methoxypyridin-3-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0584] N-(4-((2-(1,1-difluoroethyl)-6-(1-isobutyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0585] N-(4-((6-(4-cyanophenyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0586] N-(4-((6-(3-cyano-4-fluorophenyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0587] N-(4-((2-(1,1-difluoroethyl)-6-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0588] N-(4-((2-(1,1-difluoroethyl)-6-(7-fluoro-2-methyl-2H-indazol-5-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0589] 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;

[0590] 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;

[0591] N-(4-((2-(1,1-difluoroethyl)-6-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0592] N-(4-((2-(1,1-difluoroethyl)-6-(2,7-dimethyl-2H-indazol-5-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0593] 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;

[0594] 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;

[0595] 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;

[0596] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-fluoroethoxy)pyridin-2-yl)acetamide;

[0597] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(3-fluoropropoxy)pyridin-2-yl)acetamide;

[0598] N-(4-((2-(2-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0599] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-fluoroethoxy)pyridin-2-yl)acetamide;

[0600] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-((1r,3r)-3-methoxycyclobutoxy)pyridin-2-yl)acetamide;

[0601] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-((1s,3s)-3-methoxycyclobutoxy)pyridin-2-yl)acetamide;

[0602] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-((1r,3r)-3-fluorocyclobutoxy)pyridin-2-yl)acetamide;

[0603] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-((1s,3s)-3-fluorocyclobutoxy)pyridin-2-yl)acetamide;

[0604] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1s,3s)-3-fluorocyclobutoxy)pyridin-2-yl)acetamide;

[0605] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-((1s,3s)-3-fluorocyclobutoxy)pyridin-2-yl)acetamide;

[0606] 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;

[0607] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(methoxy-d3)pyridin-2-yl)acetamide;

[0608] N-(4-((2-(1,1-difluoroethyl)-6-(1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0609] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-fluorotetrahydro-2H-pyran-3-yl)methoxy)pyridin-2-yl)acetamide;

[0610] 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;

[0611] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((6,6-dimethyl-1,4-dioxane-2-yl)methoxy)pyridin-2-yl)acetamide;

[0612] (S)-N-(5-(2-cyclobutyl-2-fluoroethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0613] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1r,4s)-1-(fluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)methoxy)pyridin-2-yl)acetamide;

[0614] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(spiro[2.2]pent-1-ylmethoxy)pyridin-2-yl)acetamide;

[0615] N-(5-(((1r,4r)-7-oxabicyclo[2.2.1]hept-1-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0616] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxybutoxy)pyridin-2-yl)acetamide;

[0617] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1S,2S)-2-fluorocyclopropyl)methoxy)pyridin-2-yl)acetamide;

[0618] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1S,2R)-2-fluorocyclopropyl)methoxy)pyridin-2-yl)acetamide;

[0619] (S)-N-(5-(2-(tert-butoxy)propoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0620] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1R,2S)-2-(fluoromethyl)cyclopropyl)methoxy)pyridin-2-yl)acetamide;

[0621] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-fluoro-3-methylbutoxy)pyridin-2-yl)acetamide;

[0622] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5,5-dimethyl-1,4-dioxane-2-yl)methoxy)pyridin-2-yl)acetamide;

[0623] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methyltetrahydrofuran-3-yl)methoxy)pyridin-2-yl)acetamide;

[0624] N-(5-(((1R,3R)-5-oxaspiro[2.4]hept-1-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0625] (R)-N-(5-((6-oxaspiro[3.4]oct-7-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0626] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-(tetrahydrofuran-2-yl)propoxy)pyridin-2-yl)acetamide;

[0627] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-methyltetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-yl)acetamide;

[0628] N-(5-methoxy-4-((4-methyl-6-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)acetamide;

[0629] N-(4-((6-cyclopropoxy-2-(trifluoromethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0630] N-(5-methoxy-4-((4-methoxy-6-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)acetamide;

[0631] N-(4-((6-(2-fluoroprop-2-yl)pyrazin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0632] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-methoxy-2-methylpropoxy)pyridin-2-yl)acetamide;

[0633] N-(4-((4-(2-fluoroprop-2-yl)-6-methylpyrimidin-2-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0634] 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;

[0635] (S)-N-(5-((5,8-dioxaspiro[3.5]non-6-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0636] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-fluorobutoxy)pyridin-2-yl)acetamide;

[0637] (S)-N-(5-((1,4-dioxane-2-yl)methoxy)-4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0638] N-(4-((6-cyclopropoxy-2-(2-fluoroprop-2-yl)pyrimidin-4-yl)amino)-5-(2-methoxyethoxy)pyridin-2-yl)acetamide;

[0639] Methyl (4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(dimethylamino)ethoxy)pyridin-2-yl)carbamate;

[0640] N-(4-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0641] N-(5-methoxy-4-((6-methyl-2-(1-methyl-2-oxabicyclo[2.1.1]hex-4-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0642] N-(5-methoxy-4-((2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0643] N-(5-methoxy-4-((6-methyl-2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0644] N-(5-methoxy-4-((2-methoxy-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0645] (S)-N-(5-((1,4-dioxane-2-yl)methoxy)-4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0646] (R)-N-(5-((1,4-dioxane-2-yl)methoxy)-4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0647] N-(4-((6-cyclobutoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0648] N-(4-((6-((1s,3s)-3-cyanocyclobutoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0649] N-(4-((2-(1,1-difluoroethyl)-6-((1r,3r)-3-fluorocyclobutoxy)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0650] N-(4-((2-(1,1-difluoroethyl)-6-((1s,3s)-3-fluorocyclobutoxy)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0651] N-(4-((6-(3,3-difluorocyclobutoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0652] N-(4-((6-(3,3-difluorocyclobutoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0653] N-(4-((2-(1,1-difluoroethyl)-6-((1s,3s)-3-fluorocyclobutoxy)pyrimidin-4-yl)amino)-5-methoxypyridin-2-yl)acetamide;

[0654] N-(4-((6-cyclobutoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0655] N-(4-((2-(1,1-difluoroethyl)-6-((1s,3s)-3-methylcyclobutoxy)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0656] N-(4-((6-((1s,3s)-3-cyanocyclobutoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0657] N-(5-((3,3-difluorocyclobutyl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0658] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-fluorobenzyl)oxy)pyridin-2-yl)acetamide;

[0659] N-(5-((3,4-difluorobenzyl)oxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0660] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-methoxybenzyl)oxy)pyridin-2-yl)acetamide;

[0661] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((2-methylpyridin-3-yl)methoxy)pyridin-2-yl)acetamide;

[0662] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-methylpyridin-3-yl)methoxy)pyridin-2-yl)acetamide;

[0663] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methylpyridin-2-yl)methoxy)pyridin-2-yl)acetamide;

[0664] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-methoxypyridin-2-yl)methoxy)pyridin-2-yl)acetamide;

[0665] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyridin-4-ylmethoxy)pyridin-2-yl)acetamide;

[0666] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)acetamide;

[0667] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)acetamide;

[0668] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(pyridin-2-yl)ethoxy)pyridin-2-yl)acetamide;

[0669] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)acetamide;

[0670] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methylpyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide;

[0671] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methylpyrrolidin-2-yl)methoxy)pyridin-2-yl)acetamide;

[0672] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methylpyrrolidin-3-yl)methoxy)pyridin-2-yl)acetamide;

[0673] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)acetamide;

[0674] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-isopropoxyethoxy)pyridin-2-yl)acetamide;

[0675] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((3-fluorooxetane-3-yl)methoxy)pyridin-2-yl)acetamide;

[0676] N-(5-(benzo[d][1,3]dioxacyclopenten-5-ylmethoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0677] N-(4-((2-(1,1-difluoroethyl)-6-(methylamino)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0678] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-hydroxypyridin-2-yl)acetamide;

[0679] N-(5-(benzyloxy)-4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0680] N-(4-((6-(cyclobutylamino)-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(ethoxy-d5)pyridin-2-yl)acetamide;

[0681] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(ethoxy-d5)pyridin-2-yl)acetamide;

[0682] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0683] N-(5-ethoxy-4-((6-methoxy-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide;

[0684] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxy-2-methylpropoxy)pyridin-2-yl)acetamide;

[0685] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methoxycyclobutyl)methoxy)pyridin-2-yl)acetamide;

[0686] (S)-N-(5-((1-cyclopropylpyrrolidone-3-yl)methoxy)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0687] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(isoxazo-3-ylmethoxy)pyridin-2-yl)acetamide;

[0688] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methyl-1H-imidazol-2-yl)methoxy)pyridin-2-yl)acetamide;

[0689] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-methylisoxazol-3-yl)methoxy)pyridin-2-yl)acetamide;

[0690] 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;

[0691] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-oxotetrahydrofuran-2-yl)methoxy)pyridin-2-yl)acetamide;

[0692] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-oxopyrrolidone-2-yl)methoxy)pyridin-2-yl)acetamide;

[0693] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(1-methylpyrrolidin-2-yl)ethoxy)pyridin-2-yl)acetamide;

[0694] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((5-oxopyrrolidone-2-yl)methoxy)pyridin-2-yl)acetamide;

[0695] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((4-isopropylmorpholin-2-yl)methoxy)pyridin-2-yl)acetamide;

[0696] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(isoxazo-4-ylmethoxy)pyridin-2-yl)acetamide;

[0697] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(oxazol-4-ylmethoxy)pyridin-2-yl)acetamide;

[0698] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methylazacyclobutane-3-yl)methoxy)pyridin-2-yl)acetamide;

[0699] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-ethoxyethoxy)pyridin-2-yl)acetamide;

[0700] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methyl-1H-pyrazol-4-yl)methoxy)pyridin-2-yl)acetamide;

[0701] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-ethyl-1H-pyrazol-4-yl)methoxy)pyridin-2-yl)acetamide;

[0702] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-isopropyl-5-oxopyrrolidine-3-yl)methoxy)pyridin-2-yl)acetamide;

[0703] (S)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((1-methyl-5-oxopyrrolidone-3-yl)methoxy)pyridin-2-yl)acetamide;

[0704] 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;

[0705] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1R,3S)-3-methoxycyclopentyl)oxy)pyridin-2-yl)acetamide;

[0706] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(((1s,4s)-4-methyl-2-oxabicyclo[2.1.1]hex-1-yl)methoxy)pyridin-2-yl)acetamide;

[0707] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(ethoxy-d5)pyridin-2-yl)acetamide;

[0708] N-(4-((2-(1,1-difluoropropyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0709] N-(4-((2-(1,1-difluoroethyl)-5-methoxypyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0710] (R)-N-(4-((2-(2,2-dimethylcyclopropyl)-6-methylpyrimidin-4-yl)amino)-5-ethoxypyridin-2-yl)acetamide;

[0711] N-(5-ethoxy-4-((6-(((1r,3r)-3-methoxycyclobutoxy)-2-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0712] 1-(5-cyano-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)-3-methylurea;

[0713] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(4-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)acetamide;

[0714] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxyethoxy)-[2,3'-bipyridine]-6'-yl)acetamide;

[0715] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxyethoxy)-[2,3'-bipyridine]-6'-yl)acetamide;

[0716] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((difluoromethoxy)methyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0717] N-(5-cyano-4'-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide;

[0718] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide;

[0719] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methoxypyridazine-3-yl)pyridin-2-yl)acetamide-2,2,2-d3;

[0720] 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;

[0721] 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;

[0722] N-(5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-4-((2-(2-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0723] N-(5-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)-4-((2-(2-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0724] N-(5-([1,2,4]triazolo[4,3-a]pyrazin-6-yl)-4-((2-(2-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0725] N-(4-((2-(2-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(imidazo[1,2-a]pyrimidin-7-yl)pyridin-2-yl)acetamide;

[0726] N-(5-([1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-4-((2-(2-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0727] 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;

[0728] 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;

[0729] 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;

[0730] N-(4-((2-(2-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyridin-2-yl)acetamide;

[0731] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidin-2-yl)acetamide;

[0732] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyridin-2-yl)acetamide;

[0733] 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;

[0734] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(ethylsulfonyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0735] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(methanesulfonyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0736] N-(4-((2-(2-oxabicyclo[2.1.1]hex-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;

[0737] 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;

[0738] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(difluoromethyl)pyridazine-3-yl)pyridin-2-yl)acetamide;

[0739] (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;

[0740] (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;

[0741] N-(4-((2-(2-methoxyethoxy)pyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0742] N-(4-((4-(2-methoxyethoxy)pyrimidin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0743] N-(4-((2-methoxy-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0744] N-(4-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0745] N-(4-((4-methoxypyrimidin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0746] N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-methyl-2-(1-methyl-2-oxabicyclo[2.1.1]hex-4-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0747] N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-methyl-2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0748] N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0749] N-(4-((2-(2-oxabicyclo[2.2.1]hept-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0750] N-(4-((2-(1-fluorocyclopropyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0751] N-(4-((2-(2-methoxyethoxy)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0752] N-(4-((2-((1s,4s)-1-(fluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0753] N-(4-((2-(1-(methoxymethyl)-2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0754] N-(4-((2-(2-oxabicyclo[2.1.1]hex-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0755] N-(4-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide;

[0756] N-(4-((2-(2-oxabicyclo[2.1.1]hex-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;

[0757] N-(4'-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0758] N-(4'-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-ethylpyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0759] N-(5-(methoxymethyl)-4'-((2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0760] N-(5-(methoxymethyl)-4'-((6-methyl-2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0761] N-(4'-((6-ethyl-2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0762] N-(5-(methoxymethyl)-4'-((6-(methoxymethyl)-2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0763] N-(5-(methoxymethyl)-4'-((6-methyl-2-(tetrahydro-2H-pyran-3-yl)pyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0764] N-(4'-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(difluoromethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0765] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6,7-dihydro-4H-pyrano[4,3-d]thiazo-2-yl)pyridin-2-yl)acetamide;

[0766] N-(4'-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-morpholino-[2,3'-bipyridine]-6'-yl)acetamide;

[0767] N-(4'-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(1-methoxyethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0768] N-(4'-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-4-(difluoromethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0769] N-(4'-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(1-fluoroethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0770] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methyloxazol-4-yl)pyridin-2-yl)acetamide;

[0771] N-(5-(1-cyclobutyl-1H-pyrazol-4-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0772] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridine]-6'-yl)acetamide;

[0773] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methyloxazol-4-yl)pyridin-2-yl)acetamide;

[0774] N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridine]-6'-yl)acetamide;

[0775] N-(5-cyano-4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0776] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-methyloxazol-4-yl)pyridin-2-yl)acetamide;

[0777] N-(4-((2-(1,1-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin-4-yl)amino)-5-(pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0778] N-(5-fluoro-4'-((6-methoxypyrazin-2-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0779] 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;

[0780] N-(4'-((6-(difluoromethoxy)pyrazin-2-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0781] N-(4'-((2-(1,1-difluoroethyl)-5-methoxypyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0782] N-(4-((2-(1,1-difluoroethyl)-5-methoxypyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0783] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0784] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methyloxazol-2-yl)pyridin-2-yl)acetamide;

[0785] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-methyl-[2,3'-bipyridine]-6'-yl)acetamide;

[0786] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridine]-6'-yl)acetamide;

[0787] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methylpyrimidin-2-yl)pyridin-2-yl)acetamide;

[0788] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(oxazol-4-yl)pyridin-2-yl)acetamide;

[0789] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-methyl-1H-pyrazol-1-yl)pyridin-2-yl)acetamide;

[0790] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-fluoropyrazin-2-yl)pyridin-2-yl)acetamide;

[0791] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-methoxy-[2,3'-bipyridine]-6'-yl)acetamide;

[0792] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methyloxazol-5-yl)pyridin-2-yl)acetamide;

[0793] N-(5-(2-cyano-1-methyl-1H-imidazol-4-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0794] N-(5-(1-cyclopropyl-1H-pyrazol-3-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0795] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-isopropyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0796] N-(5-(1-cyclobutyl-1H-pyrazole-4-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridine-2-yl)acetamide;

[0797] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(thiazo-2-yl)pyridin-2-yl)acetamide;

[0798] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methylthiazo-4-yl)pyridin-2-yl)acetamide;

[0799] 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;

[0800] 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;

[0801] 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;

[0802] 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;

[0803] 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;

[0804] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-isopropylthiazo-4-yl)pyridin-2-yl)acetamide;

[0805] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0806] N-(5-(1-(cyclopropylmethyl)-1H-pyrazol-3-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0807] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-propyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0808] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-fluoro-1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0809] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-methoxythiazo-4-yl)pyridin-2-yl)acetamide;

[0810] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-yl)acetamide;

[0811] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1,5-dimethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0812] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrazin-2-yl)pyridin-2-yl)acetamide;

[0813] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methoxy-6-methylpyrimidin-2-yl)pyridin-2-yl)acetamide;

[0814] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-fluoro-5-methoxy-[2,3'-bipyridine]-6'-yl)acetamide;

[0815] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-fluoro-[2,3'-bipyridine]-6'-yl)acetamide;

[0816] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-4-fluoro-[2,3'-bipyridine]-6'-yl)acetamide;

[0817] N-(6'-bromo-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[3,3'-bipyridine]-6-yl)acetamide;

[0818] N-(5-bromo-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0819] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-4-(dimethylamino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0820] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-morpholino-[2,3'-bipyridine]-6'-yl)acetamide;

[0821] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(dimethylamino)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0822] N-(6-cyano-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0823] N-(4-cyano-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0824] N-(5-cyano-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-3-fluoro-[2,3'-bipyridine]-6'-yl)acetamide;

[0825] N-(6-cyano-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridine]-6'-yl)acetamide;

[0826] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0827] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-methoxy-[2,3'-bipyridine]-6'-yl)acetamide;

[0828] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(methoxymethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0829] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5,6-dimethoxy-[2,3'-bipyridine]-6'-yl)acetamide;

[0830] (S)-N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(1-hydroxyethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0831] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(tetrahydrofuran-2-yl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0832] (S)-N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(4-methylmorpholin-2-yl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0833] (S)-N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(4-methylmorpholin-2-yl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0834] (R)-N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(4-methylmorpholin-2-yl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0835] (R)-N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methylmorpholin-2-yl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0836] (S)-N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methylmorpholin-2-yl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0837] (R)-N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methylmorpholin-3-yl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0838] (S)-N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methylmorpholin-3-yl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0839] (S)-N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(tetrahydro-2H-pyran-2-yl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0840] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-((dimethylamino)methyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0841] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(morpholinylmethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0842] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-6-(morpholinylmethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0843] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methylpiperazin-1-yl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0844] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(dimethylamino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0845] N-(6-(2-cyanopropyl-2-yl)-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0846] N-(6-(2-cyanopropyl-2-yl)-4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0847] N-(5-(5-cyanopyrimidin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0848] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methoxypyrimidin-2-yl)pyridin-2-yl)acetamide;

[0849] N-(5-(4-cyano-6-methylpyrimidin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0850] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methoxypyrimidin-2-yl)pyridin-2-yl)acetamide;

[0851] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-fluoro-4-methoxypyrimidin-2-yl)pyridin-2-yl)acetamide;

[0852] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(difluoromethoxy)pyrimidin-2-yl)pyridin-2-yl)acetamide;

[0853] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(methoxymethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0854] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(((difluoromethoxy)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0855] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methoxy-5-methylpyrimidin-2-yl)pyridin-2-yl)acetamide;

[0856] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(2-methoxyethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0857] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(methoxymethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0858] N-(5-(4-cyclopropylpyrimidin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0859] N-(5-(6-cyclopropylpyrazin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0860] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrimidin-2-yl)pyridin-2-yl)acetamide;

[0861] N-(5-(5-chloropyrimidin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0862] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(difluoromethyl)pyrimidin-2-yl)pyridin-2-yl)acetamide;

[0863] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methylpyrimidin-2-yl)pyridin-2-yl)acetamide;

[0864] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(methoxymethyl)pyrimidin-2-yl)pyridin-2-yl)acetamide;

[0865] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-fluoro-4-methylpyrimidin-2-yl)pyridin-2-yl)acetamide;

[0866] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-morpholinylpyrimidin-2-yl)pyridin-2-yl)acetamide;

[0867] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-((dimethylamino)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0868] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-methoxypyridazine-3-yl)pyridin-2-yl)acetamide;

[0869] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-oxo-6,7-dihydro-5H-cyclopentano[b]pyridin-2-yl)pyridin-2-yl)acetamide;

[0870] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5,7-dihydrofurano[3,4-d]pyrimidin-2-yl)pyridin-2-yl)acetamide;

[0871] 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;

[0872] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(imidazo[1,2-b]pyridazin-6-yl)pyridin-2-yl)acetamide;

[0873] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(imidazo[1,2-a]pyrazin-6-yl)pyridin-2-yl)acetamide;

[0874] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(7-oxo-5,7-dihydrofurano[3,4-d]pyrimidin-2-yl)pyridin-2-yl)acetamide;

[0875] (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;

[0876] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazo-2-yl)pyridin-2-yl)acetamide;

[0877] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(pyrimidin-2-yl)pyridin-2-yl)acetamide;

[0878] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5,6-dimethoxypyrazin-2-yl)pyridin-2-yl)acetamide;

[0879] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2,6-dimethoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0880] N-(5-(6-(cyanomethyl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0881] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(difluoromethoxy)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0882] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(oxetane-3-yloxy)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0883] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(2-methoxyethoxy)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0884] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(((difluoromethoxy)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0885] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methylpyrazin-2-yl)pyridin-2-yl)acetamide;

[0886] N-(5-(5-cyclopropylpyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0887] N-(5-(5-(1,1-difluoroethyl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0888] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(methoxymethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0889] N-(5-(5-chloropyrimidin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0890] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-3-fluoro-[2,3'-bipyridine]-6'-yl)acetamide;

[0891] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-fluoro-4-methoxy-[2,3'-bipyridine]-6'-yl)acetamide;

[0892] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-4-methyl-[2,3'-bipyridine]-6'-yl)acetamide;

[0893] N-(5-cyano-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-4-methyl-[2,3'-bipyridine]-6'-yl)acetamide;

[0894] N-(5-((6-oxa-3-azabicyclo[3.1.1]hept-3-yl)methyl)-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0895] N-(5-((2-oxa-6-azaspiro[3.4]oct-6-yl)methyl)-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[0896] N-(5-(1-(cyclopropylmethyl)-1H-pyrazol-3-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0897] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(1-propyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0898] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0899] N-(5-(2-cyano-1-methyl-1H-imidazol-4-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0900] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-isopropyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide;

[0901] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-ethyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide;

[0902] 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;

[0903] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(methoxymethyl)-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide;

[0904] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-methoxythiazo-4-yl)pyridin-2-yl)acetamide;

[0905] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(2-fluoroprop-2-yl)thiazolyl-4-yl)pyridin-2-yl)acetamide;

[0906] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-ethyl-1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide;

[0907] N-(5-(5-(tert-butyl)-1,3,4-thiadiazol-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0908] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-yl)acetamide;

[0909] N-(5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0910] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-oxo-6,7-dihydro-5H-cyclopentano[b]pyridin-2-yl)pyridin-2-yl)acetamide;

[0911] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(pyrimidin-2-yl)pyridin-2-yl)acetamide;

[0912] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(methoxymethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0913] 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;

[0914] N-(4'-((5-(2-fluoroprop-2-yl)pyridin-3-yl)amino)-5-(2-hydroxyprop-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide;

[0915] N-(4-((2-(2-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(5-fluoropyrimidin-2-yl)pyridin-2-yl)acetamide;

[0916] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0917] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(dimethylamino)pyridin-2-yl)acetamide;

[0918] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(pyrrolidin-1-yl)pyridin-2-yl)acetamide;

[0919] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-morpholinylpyridin-2-yl)acetamide;

[0920] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-methyl-1H-pyrazol-1-yl)pyridin-2-yl)acetamide;

[0921] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methyl-1H-pyrazol-1-yl)pyridin-2-yl)acetamide;

[0922] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-methoxy-1H-pyrazol-1-yl)pyridin-2-yl)acetamide;

[0923] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-methoxy-1H-pyrazol-1-yl)pyridin-2-yl)acetamide;

[0924] N-(5-(4-cyano-1H-pyrazol-1-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0925] N-(5-(4-cyano-1H-pyrazol-1-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0926] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-2-yl)acetamide;

[0927] 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;

[0928] 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;

[0929] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(((dimethylamino)methyl)thiazo-2-yl)pyridin-2-yl)acetamide;

[0930] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(pyrrolidin-1-ylmethyl)thiazolyl-2-yl)pyridin-2-yl)acetamide;

[0931] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-5-(morpholinylmethyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0932] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-4-((dimethylamino)methyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0933] (R)-N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(1-(dimethylamino)ethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0934] (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;

[0935] (S)-N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-4-(1-(dimethylamino)ethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0936] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide;

[0937] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(2-methoxyethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0938] N-(4-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0939] N-(4-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)acetamide;

[0940] N-(4-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0941] N-(4-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide;

[0942] N-(4-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-methoxypyrimidin-4-yl)pyridin-2-yl)acetamide;

[0943] N-(4'-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-cyano-[2,3'-bipyridine]-6'-yl)acetamide;

[0944] N-(4'-((2-(2-oxabicyclo[2.1.1]hex-4-yl)-6-methylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridine]-6'-yl)acetamide;

[0945] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methoxypyridazine-3-yl)pyridin-2-yl)acetamide;

[0946] 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;

[0947] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(methoxymethyl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)acetamide;

[0948] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(2-methoxyethyl)thiazolyl-2-yl)pyridin-2-yl)acetamide;

[0949] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0950] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(2-methoxypropyl-2-yl)-1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0951] 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;

[0952] 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;

[0953] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(isothiazo-3-yl)pyridin-2-yl)acetamide;

[0954] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(3-(methoxymethyl)-1,2,4-thiadiazol-5-yl)pyridin-2-yl)acetamide;

[0955] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(dimethylamino)-1,2,4-thiadiazol-3-yl)pyridin-2-yl)acetamide;

[0956] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-(2-methoxyethyl)-1H-pyrazol-1-yl)pyridin-2-yl)acetamide;

[0957] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-(methoxymethyl)-1H-pyrazol-1-yl)pyridin-2-yl)acetamide;

[0958] N-(5-(6-cyanopyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0959] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(difluoromethoxy)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0960] 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;

[0961] 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;

[0962] 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;

[0963] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(4-methylpiperazin-1-yl)thiazo-4-yl)pyridin-2-yl)acetamide;

[0964] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-((2-methoxyethyl)(methyl)amino)thiazolyl-4-yl)pyridin-2-yl)acetamide;

[0965] 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;

[0966] 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;

[0967] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(difluoromethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0968] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(2-methoxyethoxy)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0969] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-(2-methoxyethoxy)pyrimidin-2-yl)pyridin-2-yl)acetamide;

[0970] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(2-morpholinylethyl)-2H-1,2,3-triazol-4-yl)pyridin-2-yl)acetamide;

[0971] 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;

[0972] 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;

[0973] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(methoxymethyl)thiazo-2-yl)pyridin-2-yl)acetamide;

[0974] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(((dimethylamino)methyl)thiazo-2-yl)pyridin-2-yl)acetamide;

[0975] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(((4-methylpiperazin-1-yl)methyl)thiazo-2-yl)pyridin-2-yl)acetamide;

[0976] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-((dimethylamino)methyl)thiazolyl-2-yl)pyridin-2-yl)acetamide;

[0977] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(4-((4-methylpiperazin-1-yl)methyl)thiazo-2-yl)pyridin-2-yl)acetamide;

[0978] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-((dimethylamino)methyl)thiazolyl-4-yl)pyridin-2-yl)acetamide;

[0979] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-((4-methylpiperazin-1-yl)methyl)thiazo-4-yl)pyridin-2-yl)acetamide;

[0980] N-(5-(2-(azacyclobutan-1-yl)thiazo-4-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0981] N-(5-(2-(2-oxa-6-azaspiro[3.3]hept-6-yl)thiazolyl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0982] N-(5-(2-cyanothiazol-4-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[0983] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(pyrrolidin-1-ylmethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0984] 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;

[0985] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(morpholinylmethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[0986] 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;

[0987] 1-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)pyridin-2-yl)-3-methylurea;

[0988] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[4,5-c]pyridin-2-yl)pyridin-2-yl)carboxamide;

[0989] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[4,5-c]pyridin-2-yl)pyridin-2-yl)acetamide;

[0990] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)pyridin-2-yl)acetamide;

[0991] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0992] N-(4-((2-(2-fluoroprop-2-yl)-6-methylpyrimidin-4-yl)amino)-5-(pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0993] N-(4-((6-ethyl-2-(2-fluoroprop-2-yl)pyrimidin-4-yl)amino)-5-(pyrimidin-4-yl)pyridin-2-yl)acetamide;

[0994] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(2-(dimethylamino)propyl-2-yl)-1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[0995] 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;

[0996] 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;

[0997] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-4-(pyrrolidin-1-ylmethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0998] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-4-(morpholinylmethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[0999] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(((dimethylamino)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1000] N-(4-((2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1001] N-(4-((2-(1,1-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1002] N-(5-((1R,2S)-2-cyanocyclopropyl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1003] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[1004] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)acetamide;

[1005] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide;

[1006] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-fluoro-1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;

[1007] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-methoxypyrazin-2-yl)pyridin-2-yl)acetamide;

[1008] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoropyridin-2-yl)acetamide;

[1009] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-fluoropyridin-2-yl)acetamide;

[1010] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-fluoropyridin-2-yl)acetamide;

[1011] N-(4-((2-(1,1-difluoroethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-fluoropyridin-2-yl)acetamide;

[1012] N-(4-((6-(1,1-difluoroethyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide;

[1013] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide;

[1014] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide;

[1015] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(pyrazin-2-yl)pyridin-2-yl)acetamide;

[1016] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(pyrazin-2-yl)pyridin-2-yl)acetamide;

[1017] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(difluoromethoxy)pyrimidin-2-yl)pyridin-2-yl)acetamide;

[1018] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(difluoromethoxy)-[2,3'-bipyridine]-6'-yl)acetamide;

[1019] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(difluoromethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1020] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methoxypyrazin-2-yl)pyridin-2-yl)acetamide;

[1021] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-methoxypyrazin-2-yl)pyridin-2-yl)acetamide;

[1022] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-methoxypyrazin-2-yl)pyridin-2-yl)acetamide;

[1023] 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;

[1024] N-(4-((2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)amino)-5-(6-methoxypyridazine-3-yl)pyridin-2-yl)acetamide;

[1025] N-(4-((6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-methoxypyridazine-3-yl)pyridin-2-yl)acetamide;

[1026] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(methoxymethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1027] N-(4-((2-(2-fluoroprop-2-yl)pyrimidin-4-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide;

[1028] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(methoxymethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1029] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(2-(1,1-difluoroethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[1030] N-(5-(5-cyanopyrazin-2-yl)-4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1031] N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-hydroxypropyl-2-yl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1032] (R)-N-(5-(5-(1,4-dioxane-2-yl)pyrimidin-2-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1033] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(dimethylamino)pyridazin-3-yl)pyridin-2-yl)acetamide;

[1034] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(dimethylamino)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1035] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(pyrrolidin-1-yl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1036] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-morpholinylpyrazin-2-yl)pyridin-2-yl)acetamide;

[1037] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(pyrrolidin-1-yl)pyridazin-3-yl)pyridin-2-yl)acetamide;

[1038] N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1039] N-(5-(5-cyanopyrimidin-2-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1040] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(difluoromethoxy)pyrimidin-2-yl)pyridin-2-yl)acetamide;

[1041] N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(difluoromethoxy)-[2,3'-bipyridine]-6'-yl)acetamide;

[1042] N-(5-(5-cyanopyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1043] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1044] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-hydroxypropyl-2-yl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1045] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(2-hydroxypropyl-2-yl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1046] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(difluoromethoxy)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1047] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(2-hydroxypropyl-2-yl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1048] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(dimethylamino)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1049] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(methylamino)-[2,3'-bipyridine]-6'-yl)acetamide;

[1050] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(difluoromethoxy)pyridazin-3-yl)pyridin-2-yl)acetamide;

[1051] N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(methylamino)-[2,3'-bipyridine]-6'-yl)acetamide;

[1052] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(methylamino)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1053] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-morpholinylpyrazin-2-yl)pyridin-2-yl)acetamide;

[1054] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(6-(dimethylamino)pyridazin-3-yl)pyridin-2-yl)acetamide;

[1055] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(6-morpholinylpyridazine-3-yl)pyridin-2-yl)acetamide;

[1056] N-(5-(5-cyanopyrazin-2-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1057] 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;

[1058] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-((2-methoxyethyl)(methyl)amino)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1059] (R)-N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(3-methoxypyrrolidin-1-yl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1060] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(3-methoxy-3-methylazacyclobutane-1-yl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1061] N-(5-(5-(2-oxa-6-azaspiro[3.4]oct-6-yl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1062] N-(5-(5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1063] N-(5-(5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1064] N-(5-(5-(6-oxa-2-azaspiro[3.4]oct-2-yl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1065] (R)-N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(3-methoxypyrrolidin-1-yl)pyridazin-3-yl)pyridin-2-yl)acetamide;

[1066] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-(3-methoxy-3-methylazacyclobutane-1-yl)pyridazin-3-yl)pyridin-2-yl)acetamide;

[1067] N-(5-(6-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridazin-3-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1068] N-(5-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)pyridazin-3-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1069] N-(5-(6-(6-oxa-2-azaspiro[3.4]oct-2-yl)pyridazin-3-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1070] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(pyrrolidin-1-ylmethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1071] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(((2-methoxyethyl)(methyl)amino)methyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1072] (R)-N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((3-methylmorpholino)methyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1073] (S)-N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((3-methoxypyrrolidin-1-yl)methyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1074] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((3-methoxy-3-methylazacyclobutane-1-yl)methyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1075] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1076] N-(5-((2-oxa-6-azaspiro[3.3]hept-6-yl)methyl)-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[1077] N-(5-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[1078] N-(5-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[1079] N-(5-(5-((1R,5S)-6-oxa-3-azabicyclo[3.1.1]hept-3-yl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1080] N-(5-(5-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1081] N-(5-((6-oxa-2-azaspiro[3.4]oct-2-yl)methyl)-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[1082] N-(5-(6-(2-oxa-6-azaspiro[3.4]oct-6-yl)pyrazin-3-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1083] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(6-(difluoromethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[1084] (S)-N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((3-methylmorpholino)methyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1085] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(5-(pyrrolidin-1-ylmethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1086] N-(5-(5-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1087] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(((dimethylamino)methyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1088] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(5-(2-methoxypropyl-2-yl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1089] N-(5-(6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)pyridazin-3-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1090] (R)-N-(5-(5-(1,4-dioxane-2-yl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1091] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(5-(morpholinylmethyl)pyrazin-2-yl)pyridin-2-yl)acetamide;

[1092] N-(5-(5-(((1R,5S)-6-oxa-3-azabicyclo[3.1.1]hept-3-yl)methyl)pyrazin-2-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1093] N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(pyrrolidin-1-ylmethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1094] N-(5-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)-4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[1095] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(pyrrolidin-1-ylmethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[1096] N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-6-(pyrrolidin-1-ylmethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1097] N-(5-(6-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)pyrimidin-4-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1098] N-(6-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)-4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridine]-6'-yl)acetamide;

[1099] N-(5-(2-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)pyrimidin-4-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1100] N-(6-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)-4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridine]-6'-yl)acetamide;

[1101] N-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(2-(morpholinylmethyl)pyrimidin-4-yl)pyridin-2-yl)acetamide;

[1102] N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-6-(morpholinylmethyl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1103] N-(4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-6-((dimethylamino)methyl)-5-fluoro-[2,3'-bipyridine]-6'-yl)acetamide;

[1104] N-(5-(((1R,5S)-6-oxa-3-azabicyclo[3.1.1]hept-3-yl)methyl)-4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-[2,3'-bipyridine]-6'-yl)acetamide;

[1105] N-(5-(2-(((1R,5S)-6-oxa-3-azabicyclo[3.1.1]hept-3-yl)methyl)pyrimidin-4-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1106] N-(5-(6-(((1R,5S)-6-oxa-3-azabicyclo[3.1.1]hept-3-yl)methyl)pyrimidin-4-yl)-4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1107] N-(6-(((1R,5S)-6-oxa-3-azabicyclo[3.1.1]hept-3-yl)methyl)-4'-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-fluoro-[2,3'-bipyridine]-6'-yl)acetamide;

[1108] N-(4'-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(dimethylphosphoryl)-[2,3'-bipyridine]-6'-yl)acetamide;

[1109] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(6-(dimethylphosphoryl)pyridazin-3-yl)pyridin-2-yl)acetamide;

[1110] 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;

[1111] 1-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(pyrazin-2-yl)pyridin-2-yl)-3-methylurea;

[1112] 1-(4-((2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)amino)-5-(pyrazin-2-yl)pyridin-2-yl)urea;

[1113] N-(4-((2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)amino)-5-(5-(difluoromethyl)pyrazin-2-yl)pyridin-2-yl)acetamide; and

[1114] N-(5-(2-(cyanomethyl)thiazo-4-yl)-4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide;

[1115] or a pharmaceutically acceptable salt thereof.

[1116] In the fifty-second embodiment, this disclosure provides a pharmaceutical composition comprising a compound of this disclosure (e.g., according to the first aspect or any of the foregoing embodiments) or a pharmaceutically acceptable salt thereof.

[1117] The compounds and intermediates described herein can be isolated and used as the compounds themselves. Alternatively, when a salt-forming moiety is present, the compound or intermediate can be isolated and used as its corresponding salt. As used herein, the term "salt" refers to the acid addition salt or base addition salt of the compounds described herein. "Salt" particularly includes "pharmaceutically acceptable salt." The term "pharmaceutically acceptable salt" means a salt that retains the biological efficacy and properties of the compounds described herein and is generally not biologically or otherwise undesirable. In many cases, the compounds of this disclosure are capable of forming acidic and / or basic salts due to the presence of amino and / or carboxyl groups or similar groups.

[1118] Pharmaceutically acceptable acid addition salts can form with inorganic or organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromoates, bicarbonates / carbonates, hydrogen sulfates / sulfates, camphor sulfonates, chlorides / hydrochlorides, theophylline salts, citrates, ethanedisulfonates, fumarates, gluconate, gluconate, gluuronates, hippurates, hydroiodates / iodides, hydroxyethyl sulfonates, lactates, lacturonates, lauryl sulfates, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, naphthates, naphthalenesulfonates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propions, stearates, succinates, sulfates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates.

[1119] Inorganic acids that can produce salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[1120] Organic acids that can produce salts include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc.

[1121] Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases.

[1122] Inorganic bases that can produce salts include, for example, ammonium salts and metals from rows I through XII of the periodic table. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[1123] Organic bases that can produce salts include, for example, primary, secondary, and tertiary amines. Substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Some organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[1124] Salts can be synthesized from compounds containing basic or acidic moieties using conventional chemical methods. Generally, these salts are prepared by reacting these compounds, in their free acid form, with a stoichiometric amount of a suitable base (such as Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, or similar bases), or by reacting these compounds, in their free base form, with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water, in an organic solvent, or in a mixture of both. Generally, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred where feasible. Additional lists of suitable salts can be found, for example, in “Remington's Pharmaceutical Sciences,” 20th edition, Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[1125] The isotopically labeled compound of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying examples and preparations, using a suitable isotopically labeled reagent instead of a previously used unlabeled reagent. In one embodiment, this disclosure provides the deuterated compound described herein or a pharmaceutically acceptable salt thereof.

[1126] Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be substituted with an isotope, such as D2O, d6-acetone, and d6-DMSO.

[1127] Those skilled in the art will recognize that the compounds of the present invention may contain a chiral center and therefore may exist in different stereoisomeric forms. As used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that may exist with respect to a given compound of this disclosure. It should be understood that substituents may be attached at the chiral center of a carbon atom. Therefore, this disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[1128] "Enantiomers" are a pair of stereoisomers that are mirror images of each other and do not overlap. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the terms "racemic" or "rac" are used to designate racemic mixtures. When specifying the stereochemistry of the compounds of the present invention, a single stereoisomer having relative and absolute configurations with two known chiral centers is specified using the conventional RS system (e.g., (1S,2S)). "Diarrhetomers" are stereoisomers having at least two asymmetric atoms that are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by R or S. Resolved compounds with unknown absolute configurations may be specified as (+) or (-) according to the direction (dextrorotatory or levorotatory) in which they rotate plane-polarized light at the wavelength of the sodium D line. Alternatively, the separated compounds can be defined by the corresponding retention times of the enantiomers / diastereomers obtained via chiral HPLC.

[1129] Some of the compounds described herein contain one or more asymmetric centers or axes and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)-.

[1130] Unless otherwise specified, the compounds disclosed herein are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-stereomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separation on chiral SFC or HPLC columns, such as CHIRALPAKRTM and CHIRALCELRTM, available from DAICL Corp., using a suitable solvent or mixture of solvents for good separation). If the compound contains a double bond, the substituents may be E or Z configurations. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may have cis or trans configurations. All tautomers are also intended to be included.

[1131] How to use

[1132] 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 reduction in TYK2 activity in vivo or in vitro (e.g., a reduction of at least 10% in TYK2 activity, as measured by a given assay such as those described in the examples and known in the art).

[1133] In some embodiments, this disclosure provides a method for treating a disease or condition that responds to inhibition of TYK2 activity (referred to herein as a "TYK2-mediated disease or condition" or "TYK2-mediated disease or condition") in a subject requiring treatment. The method comprises administering to the subject a compound described herein (e.g., a compound of formula (I) according to any one of embodiments one to forty-two) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1134] In some embodiments, this disclosure provides the use of the compounds described herein (e.g., compounds of formula (I) according to any one of embodiments one to forty-two) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for treating TYK2-mediated symptoms or diseases in subjects requiring treatment.

[1135] In some embodiments, this disclosure provides compounds described herein (e.g., compounds of formula (I) according to any one of embodiments one to forty-two) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds described herein or pharmaceutically acceptable salts thereof, for treating TYK2-mediated conditions or diseases in subjects requiring treatment.

[1136] In some implementations, diseases or conditions that respond to inhibition of TYK2 activity include inflammation, autoimmune diseases, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular diseases, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, traumatic brain injury, neurodegeneration, liver disease, inflammatory bowel disease, and Crohn's disease. Ischemic 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 diseases, osteoporosis, multiple sclerosis, endometriosis, menstrual pain, vaginitis, candidiasis, cancer, fibrosis, systemic sclerosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, hair loss, Alzheimer's disease, flushing, eczema, psoriasis, atopic dermatitis, or sunburn.

[1137] In some embodiments, this disclosure relates to the aforementioned method, wherein the subject is a mammal. In some embodiments, the subject is a primate. In some embodiments, the subject is a human.

[1138] As used herein, the terms "effective dose" and "therapeutic effective dose" are used interchangeably. It refers to an amount that is effective in treating one or more of the diseases, conditions, or ailments listed herein, or in reducing their severity. In some implementations, the effective dose may be between 10 μg and 500 mg.

[1139] The compounds and compositions according to the methods of this disclosure may be administered in any amount and by any route of administration in a manner that is effective in treating one or more of the diseases, symptoms or ailments listed above or in reducing their severity.

[1140] In some embodiments, this disclosure relates to the aforementioned methods, wherein the compound is administered parenterally. In some embodiments, this disclosure relates to the aforementioned methods, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, via the lungs, rectum, intrathecally, locally, or intranasally. In some embodiments, this disclosure relates to the aforementioned methods, wherein the compound is administered systemically.

[1141] The compounds of this invention can be used in pharmaceutical compositions (e.g., compounds of this invention and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceuticalally acceptable carrier" includes solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, pharmaceutical stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.) and combinations thereof (see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pp. 1289-1329). The use of any conventional carrier in therapeutic or pharmaceutical compositions is covered unless it is incompatible with the active ingredient. For the purposes of this disclosure, solvates and hydrates are considered pharmaceutical compositions comprising the compounds of this invention and a solvent (i.e., a solvate) or water (i.e., a hydrate).

[1142] 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 stable 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 excipients described above. The compounds of the present invention are typically formulated into pharmaceutical dosage forms to provide easily controlled drug dosages and to give patients an aesthetically pleasing and easily handleable product.

[1143] Pharmaceutical compositions (or formulations) for application can be packaged in various ways depending on the method of administration. Generally, articles for dispensing include containers in which a pharmaceutical formulation of a suitable form is disposed. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. Containers may also include tamper-evident components to prevent easy access to the contents of the package. Additionally, the container has a label placed thereon describing the contents of the container. The label may also include appropriate warnings.

[1144] Pharmaceutical compositions containing compounds disclosed herein are typically formulated for use as parenteral or oral administration or alternatively as suppositories.

[1145] For example, the oral pharmaceutical compositions of this disclosure may be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including but not limited to solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical processes such as sterilization and / or may contain conventional inert diluents, lubricants, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[1146] Typically, pharmaceutical compositions are in the form of tablets or gelatin capsules, containing active ingredients and

[1147] a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[1148] b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; also included in tablets.

[1149] c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone; and if necessary, also...

[1150] d) Disintegrants, such as starch, agar, alginate, or their sodium salts or foaming mixtures; and / or

[1151] e) Absorbents, colorants, flavor enhancers and sweeteners.

[1152] Tablets can be film-coated or enteric-coated according to methods known in the art.

[1153] Suitable compositions for oral administration include compounds of this disclosure in the form of tablets, lozenges, 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 manufacturing pharmaceutical compositions, and said compositions may contain one or more agents selected from the group consisting of sweeteners, flavor enhancers, colorants, and preservatives to provide a pharmaceutically aesthetically pleasing and palatable formulation. Tablets may contain the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacturing. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use may be presented 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 an aqueous or oily medium such as peanut oil, liquid paraffin, or olive oil.

[1154] Parenteral compositions (e.g., intravenous (IV) preparations) are aqueous isotonic solutions or suspensions. Parenteral compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting or emulsifiers, solubilizers, salts and / or buffers for adjusting osmotic pressure. Additionally, they may contain other substances of therapeutic value. Compositions are typically prepared according to conventional mixing, granulation or coating methods and contain approximately 0.1-75%, or approximately 1-50%, of the active ingredient.

[1155] The compounds or pharmaceutical compositions thereof disclosed herein, when used on a subject (e.g., a human), are typically administered orally or parenterally in therapeutic doses. When administered intravenously via infusion, the dose may depend on the infusion rate of the IV formulation. Generally, the therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof depends on the individual's species, weight, age, and condition of the subject, the condition or disease being treated, or its severity. A skilled physician, pharmacist, clinician, or veterinarian can readily determine the effective amount of each of the active ingredients required to prevent, treat, or inhibit the progression of a condition or disease.

[1156] The above-described dosage characteristics can be advantageously demonstrated through in vitro and in vivo testing in mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues, and their products. The compounds of the invention can be applied in vitro in solution, such as an aqueous solution, and in vivo via the intestine, parenteral, or advantageously intravenously, for example, as a suspension or aqueous solution. In vitro doses can be in the range of about 10⁻³ mol to 10⁻⁹ mol concentrations.

[1157] definition

[1158] As used herein, the terms "patient," "subject," or "individual" are used interchangeably and refer to humans or non-human animals. The term includes mammals such as humans. Generally, animals are mammals. Subject also refers to, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the subject is a primate. Preferably, the subject is a human.

[1159] As used herein, the term “inhibit / inhibition / inhibiting” means reducing or suppressing a given ailment, symptom, condition, or disease, or significantly reducing the baseline activity of a biological activity or process.

[1160] As used herein, the term "treat / treating / treatment" for any disease, ailment, or condition refers to the management and care of a patient for the purpose of combating the disease, ailment, or condition, and includes administering the compounds of the present invention to achieve the desired pharmacological and / or physiological effects. These effects may be therapeutic and may include partially or substantially achieving one or more of the following results: partial or complete reduction of the severity of the disease, ailment, or condition; relief or improvement of clinical symptoms, complications, or indicators associated with the disease, ailment, or condition; or delaying, inhibiting, or reducing the likelihood of disease, ailment, or condition progression; or eliminating the disease, ailment, or condition. In some embodiments, the effects may be the prevention of the onset of symptoms or complications of the disease, ailment, or condition.

[1161] As used herein, the term "cancer" has the meaning generally accepted in the art. In a broader sense, the term can refer to abnormal cell growth.

[1162] As used herein, the term "autoimmune disease" has the meaning generally accepted in the art. In a broader sense, the term can refer to diseases in which the host's immune system targets or attacks the host's normal or healthy tissues.

[1163] As used herein, the term "myelination" has the meaning generally accepted in the art. In a broader sense, the term may refer to the process of myelin production.

[1164] As used herein, the terms "myelin-related disease or condition" and "demyelinating disorder" have the meanings generally accepted in the art. These terms can be broadly interpreted to refer to diseases or conditions involving damage to myelin.

[1165] As used herein, a subject “needs” the treatment (preferably, a person) if the subject will benefit from the treatment biologically, medically, or in terms of quality of life.

[1166] As used herein, the phrase “optionally substituted” and the phrase “substituted or unsubstituted” are used interchangeably. Generally, the term “optionally substituted” means that a hydrogen group in a given structure is replaced by a group of a specific substituent. Specific substituents are described in the definition and in the description of the compound and its examples. Unless otherwise indicated, an optionally substituted group may have a substituent at each substituted position of said group, and said substituents may be the same or different at each position when more than one position in any given structure may be substituted by more than one substituent selected from the specified group. In some embodiments, an optionally substituted group may be substituted by one or more substituents, each substituent may be the same or different. In some embodiments, “one or more” substituents may be 1, 2, 3, 4, 5, 6, etc., each substituent may be the same or different. In some embodiments, “one or more” substituents may be 1 to 6, 1 to 4, 1 to 3, or 1 to 2 substituents, each substituent may be the same or different. For bicyclic heteroaryl groups and bicyclic, fused, spiro, or bridged heterocyclic or carbocyclic groups, the substituents may optionally be selected on any or all rings. For example, when a bicyclic heteroaryl group is described as follows, the substituent R... 3c It can be used on a 6-membered ring or a 5-membered ring.

[1167]

[1168] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. The term "C"... 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms. The term "C" is also used in this context. 1-3 "alkyl" and "C" 1-2 "alkyl" can be understood accordingly. "C" 1-4Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Similarly, the alkyl moiety of an alkoxy group (i.e., the alkyl portion) has the same definition as above. When indicated as "optionally substituted," the alkane group or alkyl moiety may be unsubstituted or substituted with one or more substituents (typically one to three substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[1169] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety connected via an oxygen bridge (i.e., --O--C). 1-4 Alkyl, wherein C 1-4 Alkyl groups are defined herein. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, etc. Preferably, the alkoxy group has about 1-4 carbons, more preferably about 1-2 carbons. The term "C" is used in this context. 1-2 The term "alkoxy group" can be understood accordingly.

[1170] As used in this article, the term "C" 1-4 Alkoxy C 1-4 "alkyl" refers to C as defined in this article. 1-4 Alkyl group, wherein at least one hydrogen atom is formed by C 1-4 Alkyl substitution. C 1-4 Alkoxy C 1-4 The alkyl group is connected to the rest of the molecule described herein via the alkyl group.

[1171] The number of carbon atoms in a group is determined by the prefix "C" in this paper. x-xx "Specifies that x and xx are integers. For example, "C 1-3 "Alkyl" refers to an alkyl group having 1 to 3 carbon atoms.

[1172] "Halogen" or "halogenated group" can be fluorine, chlorine, bromine or iodine.

[1173] As used in this article, the term "halogenated C" 1-4 "alkyl" or "C" 1-4 "Halogenated alkyl" refers to C as defined herein. 1-4 Alkyl group, wherein at least one hydrogen atom is replaced by a halogen atom. C 1-4 Haloalkyl groups can be monohalogenated -C 1-4 Alkyl, dihalo-C 1-4 Alkyl or polyhalogenated -C 1-4 Alkyl groups, including fully halogenated -C 1-4 Alkyl group. Monohalogenated group -C 1-4 Alkyl groups may contain an iodine, bromine, chlorine, or fluorine atom. Dihalogroup -C 1-4 Alkyl and polyhalogenated -C 1-4Alkyl groups may have two or more identical halogen atoms or combinations of different halogen atoms within the alkyl group. Typically, polyhalogenated groups are -C 1-4 The alkyl group contains at most 9, 8, 7, 6, 5, 4, 3, or 2 halogroups. C 1-4 Non-limiting examples of alkyl halogens include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. Perhalogenated group -C 1-4 Alkyl groups are C360 atoms in which all hydrogen atoms are replaced by halogen atoms. 1-4 alkyl.

[1174] The term "aryl" refers to an aromatic carbocyclic monocyclic or two fused-ring system containing 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[1175] The term "heteroaryl" refers to a 5- to 12-membered aromatic group containing 1-4 heteroatoms selected from N, O, and S. In some cases, the nitrogen atom in the heteroaryl group may be quaternarily ammonized. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroarylene." Heteroaryl groups can be monocyclic or bicyclic. Monocyclic heteroaryl groups include, for example, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, furanyl, oxadiazolyl, thiophene, etc. Bicyclic heteroaryl groups include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include pyrazolopyridyl, pyrazolopyridyl, benzotriazolyl, imidazopyridyl, and indole.

[1176] The term "carbocyclic" or "carbocyclic group" refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring and can exist as a monocyclic, bicyclic (including fused, spiro, or bridged carbocyclic) or spirocyclic ring. Bicyclic carbocyclic groups include, for example, unsaturated carbocyclic groups fused to another unsaturated carbocyclic group, cycloalkyl, or aryl group, such as 2,3-dihydroindenyl, decahydronaphthyl, and 1,2,3,4-tetrahydronaphthyl. Unless otherwise specified, the carbocyclic ring typically contains 4 to 10 ring members.

[1177] The term "C 3-6 "Cycloalkyl" refers to a fully saturated carbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[1178] The term "heterocycle" or "heterocyclic group" refers to a 4- to 12-membered saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O, and S. The heterocyclic group can be monocyclic or bicyclic (e.g., bridged, fused, or spirobicyclic). Examples of monocyclic saturated or partially unsaturated heterocyclic groups include, but are not limited to, oxobutyryl, tetrahydrofuranyl, tetrahydropyranyl, and piperidinyl. Bicyclic heterocyclic groups include, for example, unsaturated heterocyclic groups fused to another unsaturated heterocyclic group, cycloalkyl, aryl, or heteroaryl ring, such as tetrahydro-3H-[1,2,3]triazolo[4,5-c]pyridyl, 2-oxa-6-azaspiro[3.3]heptyl, 5-oxabicyclo[2.1.1]hexyl, and 9-azabicyclo[3.3.1]nonyl. In some embodiments, the heterocyclic group is a 4- to 6-membered monocyclic heterocyclic group. In some embodiments, the heterocyclic group is a 4- to 6-membered monocyclic saturated heterocyclic group. In some embodiments, the heterocyclic group is an 8- to 10-membered bicyclic heterocyclic group. In some embodiments, the heterocyclic group is an 8- to 10-membered bicyclic saturated heterocyclic group.

[1179] As used herein, the term "spiro" ring refers to a bicyclic system in which two rings share a common atom. Examples of spiro rings include 2-oxa-6-azaspiro[3.3]heptyl, etc.

[1180] The term “fused” ring refers to two ring systems that share two adjacent ring atoms. Fused heterocycles have at least one ring system containing a ring atom selected as a heteroatom of O, N and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[1181] As used herein, the term “bridging” refers to a 5- to 10-membered ring portion that connects two non-adjacent ring atoms (e.g., 5-oxabicyclo[2.1.1]hexane).

[1182] The phrase “pharmaceutically acceptable” indicates that a substance, composition, or dosage form must be chemically and / or toxicologically compatible with the other components constituting the formulation and / or the mammals thereby treated.

[1183] Unless otherwise specified, the term "compound of this disclosure" refers to compounds of formula (I), as well as all stereoisomers (including diastereomers and enantiomers), rotational isomers, tautomers, and isotopically labeled compounds (including deuterium-substituted compounds). It also includes salts, especially pharmaceutically acceptable salts, where a salt-forming moiety is present.

[1184] As used herein, unless otherwise indicated herein or clearly contradicted by the context, the terms “a / an,” “the,” and similar terms used in the context of this invention (especially in the context of the claims) should be understood to cover both the singular and the plural. Any and all instances or exemplary language (e.g., “such as”) provided herein are intended only to better illustrate the invention and do not constitute a limitation on the scope of the invention as otherwise claimed.

[1185] The intermediates and compounds of this invention may also exist in different tautomer forms, and all such forms are covered within the scope of this invention. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can be interconverted via a low-energy barrier. For example, proton tautomers (also called proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions through the rearrangement of some bond electrons.

[1186] In one embodiment, this disclosure relates to a compound of formula (I) as defined herein in its free form. In another embodiment, this disclosure relates to a compound of formula (I) as defined herein in its salt form. In another embodiment, this disclosure relates to a compound of formula (I) as defined herein in its acid addition salt form. In yet another embodiment, this disclosure relates to a compound of formula (I) as defined herein in its pharmaceutically acceptable salt form. In yet another embodiment, this disclosure relates to a compound of formula (I) as defined herein in its pharmaceutically acceptable acid addition salt form. In yet another embodiment, this disclosure relates to any of the examples of compounds in their free form. In yet another embodiment, this disclosure relates to any of the examples of compounds in their salt form. In yet another embodiment, this disclosure relates to any of the examples of compounds in their acid addition salt form. In yet another embodiment, this disclosure relates to any of the examples of compounds in their pharmaceutically acceptable acid addition salt form.

[1187] The compounds disclosed herein can be synthesized via synthetic routes that include methods similar to those well known in chemical techniques, especially given the descriptions contained herein. Starting materials are generally available from commercial sources (such as Sigma-Aldrich) or readily prepared using methods well known to those skilled in the art (e.g., by methods generally described in the following references: Lou is F. Fieser and Mary Fieser, Reagents for Organic Synthesis, Vols. 1–19, Wiley, New York (1967–1999 editions), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed., Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[1188] For illustrative purposes, the reaction schemes described below provide potential pathways for synthesizing the disclosed compounds and key intermediates. For a more detailed description of individual reaction steps, see the Examples section below. Although specific starting materials and reagents are described in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions.

[1189] According to the first method, compound (I) can be prepared from compounds (II') and (III'), as shown in Scheme 1.

[1190]

[1191] Hal 1 It is a halogen, preferably Br or Cl.

[1192] According to method step (a) Buchwald-Hartwig cross-coupling reaction, compound (I) can be prepared from compounds (II') and (III'). Typical conditions include reacting compound (II') with the amine of formula (III') at high temperature in a suitable solvent, in the presence of a suitable inorganic base and a suitable palladium catalyst with a suitable phosphine ligand. Preferred conditions include reacting compounds (II') and (III') at temperatures between 80°C and 120°C in a suitable solvent such as dioxane, DMA, DMF, or toluene, 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 Xantphos or BINAP, and Pd(OAc)2 or Pd2(dba)3 or Xantphos and Xantphos Pd G3.

[1193] According to the second method, compound (I) can be prepared from compounds (IV') and (V'), as shown in Scheme 2.

[1194]

[1195] Hal 2 Halogens are preferred, with Br, Cl, or I being the most suitable.

[1196] According to the method step (a) Buchwald reaction as previously described in Scheme 1, compound (I) can be prepared from compounds (IV') and (V').

[1197] According to the third method, compound (I) can be prepared from compounds (II'), (VI'), (VII'), (VIII'), (IX') and (XV'), as shown in Scheme 3.

[1198]

[1199] Hal 3 Halogen, preferably Br or I.

[1200] Hal 4 For halogens, Cl is preferred.

[1201] According to step (b) of the method, the alkylation reaction, at a temperature between rt and high temperature, in the presence of a suitable inorganic base and a suitable aprotic polar solvent, allows the preparation of compound (VII') from compounds (VI') and (II'). Preferred conditions include reacting compound (VI') with compound (II') in DMF or THF, in the presence of Cs₂CO₃ or K₂CO₃, at a temperature between rt and 35°C.

[1202] Alternatively, the compound of formula (VII') can be prepared from the compounds of formula (VI') and (II') according to the method step (a) Buchwald reaction as previously described in scheme 1.

[1203] Among them, R 2 It consists of 4 to 11 cyclic monocyclic or bicyclic heterocyclic rings, C 1-6 Alkyl or C 3-7 Cycloalkyl groups, according to method step (c) palladium-catalyzed cross-coupling reactions, such as the Suzuki reaction, can be derived from compounds of formula (VII') and R. 2 BPin or R 2 Preparation of B(OH)₂. Typical cross-coupling reaction conditions include between rt and the reflux temperature of the reaction, in the presence of an inorganic base in a suitable aqueous solvent, and a palladium catalyst containing a suitable phosphine ligand. Preferred conditions include between 70°C and 100°C, in a suitable solvent such as aqueous dioxane, DME, EtOH, or 2-MeTHF, in the presence of SPhos-Pd-G₃, Pd(PCy₃)₂, Pd(PPh₃)₄, XPhosPd(crotonyl)Cl, Pd(dppf)Cl₂, or Pd(OAc)₂ and P(Cy)₃, and a suitable base such as K₃PO₄, Na₂CO₃, or K₂CO₃, causing the compound of formula (VII') and R to react. 2 BPin reaction.

[1204] Among them, R 2 For -OR 2A or -N(R 2b ) 2， According to method steps (a) or (b) as previously described in schemes 1 and 2, compound (VIII') can be produced from compound (VII') and HOR. 2A or HN(R) 2b )2 Preparation.

[1205] Among them, R 2 It consists of 4 to 11 cyclic monocyclic or bicyclic heterocyclic rings, C 1-6 Alkyl or C 3-7 Cycloalkyl groups, according to method step (c) as described in Scheme 3, undergo a palladium-catalyzed cross-coupling reaction, and compounds of formula (XV') can be formed from compounds of formula (VI') and R. 2 BPin or R 2 B(OH)₂ preparation. Among them, R... 2 For -OR 2A or -N(R 2b ) 2， According to method steps (a) or (b) as previously described in schemes 1 and 2, compound (XV') can be produced by compound (VI') and HOR.2A or HN(R) 2b )2 Preparation.

[1206] Compound (VIII') can be prepared from compounds (XV') and (II') according to method steps (a) or (b) as described above.

[1207] According to the method step (a) Buchwald reaction as previously described in Scheme 1, compound (I) can be produced from compound (VIII') and R. 1 C(O)NR N1 preparation.

[1208] According to the fourth method, compounds of formula (III') and (V') can be prepared from compounds of formula (IX'), (X'), (XI'), (XII'), (XIII') and (XIV'), as shown in Scheme 4.

[1209]

[1210] PG is a suitable N protecting group, usually a carbamate or a substituted benzyl group, and preferably Boc or PMB.

[1211] LG is a suitable leaving group, such as Cl or -OC(O)R 1 .

[1212] According to the method step (a) Buchwald reaction as previously described in Scheme 1, compound (XI') can be produced by compound (X') and R. N2 NHPG preparation.

[1213] Alternatively, according to the Curtius rearrangement modified in step (d), the compound of formula (XI') can be prepared from the carboxylic acid of formula (XII'). 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.

[1214] According to the method step (a) Buchwald reaction as previously described in Scheme 1, compound (V') can be prepared from compounds (X') and (IX').

[1215] Alternatively, according to method step (f) amide bond formation, the compound of formula (V') can be formed from an amine of formula (XIV') and R. 1 C(O)LG preparation. Preferred conditions include, at about rt, optionally in the presence of an organic base such as DIPEA in a suitable solvent such as pyridine, reacting the amine of formula (XIV') with R. 1 C(O)LG reaction.

[1216] According to the method step (a) Buchwald reaction as previously described in Scheme 1, the compound of formula (XIII') can be prepared from the compounds of formulas (XI') and (IX').

[1217] Alternatively, according to the method step (a) Buchwald reaction as previously described in Scheme 1, the compound of formula (XIII') can be produced by the compound of formula (V') and R. N2 NHPG preparation.

[1218] According to method step (e) for the deprotection reaction, compound (III') can be prepared from compound (XIII'). Typical conditions include reacting compound (XIII') where PG is Boc in DCM or HFIP at rt with a suitable acid such as TFA or HCl, or in DCM with 2,6-dimethylpyridine and TMSOTf. Alternatively, where PG is PMB, typical conditions include cerium ammonium nitrate in aqueous MeCN at rt.

[1219] According to the fifth method, where R 2 Compounds of formula (I) that are 4-11 member monocyclic or bicyclic heterocyclic can be prepared from compounds of formulas (II'), (XX'), (XIX'), (XVIII'), (XVII'), (XVI') and (XXVI'), as shown in Scheme 5.

[1220]

[1221] W represents borate ester or boric acid.

[1222] Compounds of formula (XVII') can be prepared from compounds of formula (XVI') via a halogenation reaction, typically a bromination reaction (h). Preferred conditions include reacting the compound of formula (XVI') with NBS in acetonitrile at 70°C.

[1223] Alternatively, compounds of formula (XVII') can be prepared from compounds of formula (XXVI') via method step (o) amide formation. Preferred conditions include reacting the amine of formula (XXVI') with R in THF or dioxane at about 1 t in the presence of an organic base such as DIPEA. 1 COCl reaction.

[1224] The compound of formula (XVIII') can be prepared from the compound of formula (XVII') using the method step (e) as previously described in scheme 3.

[1225] The compound of formula (XIX') can be prepared from the compounds of formulas (XVIII') and (II') using the method step (a) as previously described in scheme 1.

[1226] According to step (i), the formation of a borate ester by treatment with a suitable boric acid such as (BPin)2, between rt and high temperature, in a suitable nonpolar solvent, 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, Pd2(dba)3 and a suitable phosphine ligand such as bis(1-adamantyl)butylphosphine, Pd(PPh3)Cl2 or Pd(PPh3)4, the compound of formula (XX') can be prepared from the compound of formula (XIX').

[1227] According to method step (c), as described above in scheme 3, the Suzuki-type boric acid cross-coupling reaction, compound (I) can be produced by compound (XX') and R. 2 Hal 1 preparation.

[1228] Alternatively, according to method step (p), a copper-catalyzed Suzuki cross-coupling reaction can be performed, in which compound (I) can be formed from compound (XX') and R. 2 Hal 1 Preparation. Preferred conditions include reacting the compound of formula (XX') with R in MeCN at about 40°C in the presence of a copper catalyst such as Cu(OAc)2 and DMAP. 2 Hal 1 reaction

[1229] Alternatively, via step (j), compound (I) can be obtained from compound (XIX') by an in-situ method that does not separate compound (XX'). Preferred conditions include causing compound (XIX') and R to react at a temperature between 80°C and 120°C, in a suitable solvent such as toluene, MeOH, or water, in the presence of bis(pinacol)diboron (W2), Pd(OAc)2, and in the presence of a suitable phosphine ligand such as bis(1-adamantyl)-butylphosphine and a suitable base such as CsF. 2 -Hal 1 reaction.

[1230] According to the sixth method, compound (XIII') can be obtained from compounds (XVII') and (XXI'), as shown in scheme 6.

[1231]

[1232] where R 2 It is a 4-11 member monocyclic or bicyclic heterocyclic compound, and according to method step (j) as previously described in Scheme 5, the compound of formula (XIII') can be produced by the compound of formula (XVII') and R. 2 Hal 1 preparation.

[1233] Alternatively, the compound of formula (XXI') can be prepared according to method step (i) as previously described in Scheme 5. According to method step (c) as previously described in Scheme 3, the compound of formula (XIII') can be prepared from the compound of formula (XXI') and R. 2 Hal 1 preparation.

[1234] Alternatively, according to method step (r), a Stille-type cross-coupling reaction, compound (XIII') can be produced by compound (XVII') and R. 2 -SnBu3 preparation. Preferred conditions include reacting the compound of formula (XVII') with R in DMF at about 100°C in the presence of a suitable catalyst such as PdCl2(PPh3)2. 2 SnBu3 reaction

[1235] where R 2 The compound is alkyl or cycloalkyl, and according to method step (q), palladium-catalyzed Suzuki coupling yields compound (XIII') from compound (XVII') and KR. 2 BF3. Preferred conditions include reacting the compound of formula (XVII') and KR in an aqueous toluene solution at about 90°C in the presence of a catalyst, cataCXium A and KOAc, and a suitable base such as Cs2CO3. 2 BF3 reaction

[1236] According to the seventh method, where R 2 Compounds of formula (XIII') that are C2-C6 alkyl can be obtained from compounds of formulas (XVII'), (XXII') and (XXIII'), as shown in Scheme 7.

[1237]

[1238] R 3 -C≡C is R 2 unsaturated precursors

[1239] Compound (XXII') can be prepared from compounds (XVII') and (XXIII') via method step (k) a Sonogashira-type cross-coupling reaction. Typical conditions involve reacting compound (XVII') with alkyne (XXIII') at high temperature in a suitable solvent, in the presence of a suitable palladium catalyst with a suitable phosphine ligand, a Cu salt, and a base. Preferred conditions involve reacting compounds (XVII') and (XXIII') at temperatures between 80°C and 120°C in a solvent such as DMF, in the presence of Pd(PPh3)2Cl2·DCM, CuI, and a suitable base such as TEA.

[1240] Compound (XIII') can be prepared from compound (XXII') via hydrogenation in step (l). Typical conditions include reacting compound (XXII') in THF at rt in the presence of a Pd catalyst and H2.

[1241] According to the eighth method, where R 2 Compounds of formula (I) that are 4-11 member monocyclic or bicyclic heterocyclic can be obtained from compounds of formulas (XXIV'), (XXV') and (XIII'), as shown in scheme 8.

[1242]

[1243] X is a carbonyl group, preferably a carboxylic ester or a nitrile.

[1244] Using standard chemical transformations (m) known to those skilled in the art to convert carboxylic esters or other carboxyl derivatives into heterocycles, compounds of formula (I) can be prepared from compounds of formula (XXIV') or (XXV'). For example, methyl ester (XXIV'), X = CO2Me, can be hydrolyzed with LiOH to carboxylic acid (XXIV'), X = CO2H, and subsequently treated with N'-hydroxyacetamidine (acetamidooxime) to obtain 3-methyl-1,2,4-oxadiazole.

[1245] Using standard chemical transformations (n) known to those skilled in the art to convert nitrile or other carboxyl derivatives into heterocycles, compounds of formula (XIII') can be obtained from compounds of formula (XXV'). For example, nitrile (XXV'), X = CN, can be reacted with hydroxylamine and subsequently with N'-1,1-dimethoxy-N,N-dimethylethyl-1-amine to obtain 5-methyl-1,2,4-oxadiazole.

[1246] According to the ninth method, where R N2 Compounds of formula (I) with H can be obtained from compounds of formulas (XXVII') and (XXVIII'), as shown in scheme 9.

[1247]

[1248] Compound (XXVIII') can be obtained from compounds (XXVII') and (II') by alkylation reaction as described previously in scheme 3 by step (b).

[1249] The reaction is protected according to method step (e) as previously described in scheme 4, wherein R N2 Compounds of formula (I) with H can be obtained by deprotection of compounds of formula (XXVIII').

[1250] According to the tenth method, where R 2It is a heteroalkyl or alkyl group, and compounds of formula (I) can be obtained from compounds of formula (XIX'), as shown in scheme 10.

[1251]

[1252] According to the photocatalytic cross-coupling reaction in step (s), compound (I) can be obtained from compound (XIX') and R. 2 CO2H. Preferred conditions include reacting the compound of formula (XIX') with R under rt, under an LED light source, in DMF, in the presence of Ir[dF(CF3)ppy]2(dtbpy)PF6, NiBr2(dtbbpy) and (2-tert-butyl-1,1,3,3-tetramethyl-guanidine). 2 CO2H reaction.

[1253] 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 is commercially available or can be prepared using methods similar to those known in the literature or the methods described in the experimental section below.

[1254] Compounds of formulas (I), (III'), (IV'), (V'), (VII'), (VIII'), (XI'), (XIII'), (XIV')(XV'), (XIX')(XXIV')(XXVI'), and (XXVII') can be converted, respectively, into alternative compounds of formulas (I), (III'), (IV'), (V'), (VII'), (VIII')(XI'), (XIII'), (XIV')(XV'), (XIX')(XXIV')(XXVI'), and (XXVII') through standard chemical transformations known to those skilled in the art. Examples of these transformations include, but are not limited to:

[1255] ● Alkylating heteroatoms such as N or O using alkyl or aryl halides, suitable inorganic or organic bases.

[1256] ● Reductive amination of the nitrogen atom to provide a secondary or tertiary amine.

[1257] ●In the presence of an inorganic base, aryl or heteroaryl halides react with alcohols to provide aryl or heteroaryl ethers.

[1258] ● In the presence of a base, alkyl halides react with primary or secondary amines or alcohols to provide secondary or tertiary amines or ethers.

[1259] ● Under Mitsunobu conditions, primary alcohols react with alternative alcohols to provide ethers.

[1260] ● Fluorinate aryl chlorides with fluorinating agents such as TBAF to provide aryl fluorides.

[1261] ●Demethylate the alkylmethoxy group to provide an alkyl hydroxyl group.

[1262] ● Photocatalytic reaction of aryl or heteroaryl halides with (1,3-dioxoisoindolin-2-yl)alkyl, cycloalkyl, or heterocyclic carboxylic acid esters to provide alkyl, cycloalkyl, or heterocyclic substituted aryl or heterocyclic groups.

[1263] ● Cross-coupling of transition metal-catalyzed aromatic or heteroaryl halides with each of the following

[1264] ○ Under Suzuki reaction conditions, cross-coupling with suitable boric acid or borate esters, as described in steps (c), (p), or (q),

[1265] ○ Cross-coupling with suitable alkyl or heteroaryl zinc compounds under Negishi-type reaction conditions

[1266] ○ Cross-coupling with suitable alkyl or heteroaryltinanes under Stille-type reaction conditions

[1267] ○ Under Buchwald-type conditions, cross-coupling with amines or alcohols, as described in method step (a).

[1268] In order to provide corresponding substituted aromatic or heteroaromatic groups.

[1269] Those skilled in the art will understand that for compounds of formula (I), a suitable protecting group strategy may be required. Typical protecting groups may include urethane groups, preferably Boc for protecting amines, benzyl for protecting phenol OH, or TBS for protecting alkyl OH.

[1270] It should be further understood that in order to provide the compounds required by the present invention, conversions may be performed in a different order than that described in the scheme, or modifications to one or more of the conversions may be necessary or desirable.

[1271] illustration

[1272] abbreviation:

[1273] AcOH = Acetic acid;

[1274] Ac₂O = Acetic anhydride;

[1275] Aq.=water;

[1276] Bn = benzyl;

[1277] BnOH = benzyl alcohol;

[1278] Boc = tert-butoxycarbonyl;

[1279] Boc2O = di-tert-butyl dicarbonate;

[1280] br = width;

[1281] 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;

[1282] t-BuOH = tert-butanol;

[1283] t-BuONa = sodium tert-butyl oxide;

[1284] n-BuLi = n-Butyllithium;

[1285] ℃ = degrees Celsius;

[1286] CDCl3 = deuterated chloroform;

[1287] Cs₂CO₃ = cesium carbonate;

[1288] CuI = Copper Iodide (I);

[1289] δ = chemical shift;

[1290] d = bimodal;

[1291] DAST = Diethylaminosulfur trifluoride;

[1292] dd = double peak;

[1293] DCE = 1,2-dichloroethane;

[1294] DCM = dichloromethane;

[1295] DIPEA = N-ethyl diisopropylamine or N,N-diisopropylethylamine;

[1296] DMAP = 4-(dimethylamino)pyridine;

[1297] DME = 1,2-dimethoxyethane;

[1298] DMF = N,N-dimethylformamide;

[1299] DMSO = dimethyl sulfoxide;

[1300] DMSO-d6 = hexadeuterium dimethyl sulfoxide;

[1301] DPPA = diphenylphosphohydride;

[1302] Et = Ethyl;

[1303] EtOH = ethanol;

[1304] EtOAc = Ethyl acetate;

[1305] Eq. = equivalent;

[1306] g = grams;

[1307] HCl = hydrochloric acid;

[1308] HCO2H = formic acid;

[1309] 1 H NMR = Proton Nuclear Magnetic Resonance;

[1310] H2O = water;

[1311] HPLC = High-performance liquid chromatography;

[1312] h = hours;

[1313] IPA = 2-propanol;

[1314] Josiphos Pd G3={(R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine}[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate;

[1315] K2CO3 = potassium carbonate;

[1316] KF = Potassium fluoride;

[1317] KOH = potassium hydroxide;

[1318] KOtBu = Potassium tert-butyl oxide;

[1319] K3PO4 = Tripotassium phosphate;

[1320] L = liter;

[1321] LCMS = Liquid Chromatography-Mass Spectrometry;

[1322] LiAlH4 = Lithium aluminum hydride;

[1323] m = multiplet;

[1324] M = mole;

[1325] m-CPBA = 3-chloroperoxybenzoic acid;

[1326] Me = methyl;

[1327] MeCN = Acetonitrile;

[1328] MeI = iodomethane;

[1329] MeOH = methanol;

[1330] MeOH-d4 = deuterated methanol;

[1331] mg = milligram;

[1332] MgSO4 = Magnesium sulfate;

[1333] MHz = Megahertz;

[1334] mins = minutes;

[1335] mL = milliliters;

[1336] mmol = millimole;

[1337] MorDalPhos Pd G3 = methanesulfonyl(2-(di-1-adamantylphosphino)morpholinone)[2-(2′-amino-1,1′-biphenyl)]palladium(II);

[1338] MS m / z = mass spectrum peak;

[1339] MTBE = tert-butyl methyl ether;

[1340] N2 = Nitrogen gas;

[1341] NaBH4 = Sodium borohydride;

[1342] NaBH3CN = Sodium cyanoborohydride;

[1343] Na2CO3 = Sodium carbonate;

[1344] NaH = Sodium hydride;

[1345] NaHCO3 = Sodium bicarbonate;

[1346] NaOH = Sodium hydroxide;

[1347] NaOMe = Sodium methoxide;

[1348] Na2SO3 = sodium thiosulfate;

[1349] Na2SO4 = Sodium sulfate;

[1350] NBS = N-bromosuccinimide;

[1351] NH2Boc = tert-butyl carbamate;

[1352] NH3 = ammonia;

[1353] NH4Cl = ammonium chloride;

[1354] NH4OH is ammonium hydroxide;

[1355] NMP = 1-methyl-2-pyrrolidone;

[1356] PE = petroleum ether;

[1357] Pd(dppf)Cl2=[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride;

[1358] Pd(OAc)2 = Palladium(II) acetate;

[1359] Pd2(dba)3=tris(dibenzylacetone)dipalladium(0);

[1360] Pd(PPh3)2Cl2 = bis(triphenylphosphine)palladium(II) chloride;

[1361] POCl3 = Phosphorus oxychloride (V);

[1362] q = four peaks;

[1363] rt = room temperature;

[1364] RT = Retention Time;

[1365] s = unimodal;

[1366] sat. = saturated;

[1367] soln. = solution;

[1368] t = triple peak;

[1369] TBSCl = tert-butyldimethylsilyl chloride;

[1370] TEA = Triethylamine;

[1371] TFA = trifluoroacetic acid;

[1372] THF = Tetrahydrofuran;

[1373] TLC = Thin-layer chromatography;

[1374] μL = microliter;

[1375] μmol = micromolar;

[1376] Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran;

[1377] Xantphos Pd G3 = [(4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate.

[1378] General approach

[1379] Preparative HPLC conditions:

[1380] 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

[1381] Method B: Column: Welch Xtimate C18 150*25mm*5um; Conditions: Water (10mM NH4HCO3)-MeCN; Gradient time (min): 11; 100% B retention time (min): 2; Flow rate (mL / min): 25; Detection wavelength: 220nm

[1382] Method C: Column: Boston Prime C18 150*30mm*5um; Conditions: Water (10mM NH4HCO3)-MeCN; Gradient time (min): 10; 100% B retention time (min): 2; Flow rate (mL / min): 25; Detection wavelength: 220nm

[1383] Method D: Column: Boston Green ODS150*30mm*5um; Conditions: Water (FA)-MeCN; Gradient time (min): 10; 100% B retention time (min): 2; Flow rate (mL / min): 25

[1384] Method E: Column: Boston Uni C18 40*150*5um; Conditions: Water (TFA)-MeCN; Gradient time (min): 10; 100% B retention time (min): 2; Flow rate (mL / min): 60

[1385] Method F: Column: Shapsil-T C18 50*250mm 8um; Conditions: Water (0.1% FA)-MeCN; Gradient: Gradient time: 20 min; Flow rate: 80 mL / min

[1386] Method G: Column: Boston Green ODS150*30mm*5um; Conditions: Water (NH4HCO3)-MeCN; Gradient time (min): 11; Flow rate (mL / min): 25

[1387] Method H: Column: Boston Green ODS150*30mm*5um; Conditions: Water (HCl)-MeCN; Gradient time (min): 10; 100% B retention time (min): 2; Flow rate (mL / min): 25

[1388] Method I: YMC-Actus Triart C18 150*30mm*5um, conditions: water (TFA)-MeCN; gradient time (min): 10.5; 100% B retention time (min): 1.5; flow rate (mL / min): 40

[1389] Method J: Waters Sunfire Prep C18, 5 μm, 19 mm × 100 mm column with mobile phase H2O and MeCN (0.2% NH4HCO3 final v / v% conditioner), flow rate 30 mL / min.

[1390] Method K: Column: Boston Prime C18 150*30mm*5um; Conditions: Water (NH3·H2O+NH4HCO3)-MeCN; Gradient time (min): 10; 100% B retention time (min): 2; Flow rate (ml / min): 25.

[1391] Method L: Column: Welch Xtimate C18 150*25mm*5um; Conditions: Water (ammonia hydroxide v / v)-MeCN; Gradient time (min): 11; 100% B retention time (min): 2; Flow rate (ml / min): 25;

[1392] Method M: Column: Boston Prime C18 150*30mm*5um; Conditions: Water (FA)-MeCN; Gradient time (min): 12; 100% B retention time (min): 2; Flow rate (ml / min): 25.

[1393] Method N: Column: Phenomenex C18 150*25mm*10um; Mobile phase: Water (NH4HCO3)-MeCN; Gradient time (min): 10; 100% B retention time (min): 2; Flow rate (ml / min): 25.

[1394] Method O: Column: Phenomenex C18 150*40mm*5um; Conditions: Water (NH3·H2O+NH4HCO3)-MeCN; Gradient time (min): 10; 100% B retention time (min): 2; Flow rate (ml / min): 25.

[1395] Method P: Column: Waters Xbridge BEH C18 100*30mm*10um; Conditions: Water (NH4HCO3)-MeCN; Gradient time (min): 11; 100% B retention time (min): 3; Flow rate (ml / min): 25.

[1396] Method Q: Column: Phenomenex Gemini-NX 150*30mm*5um; Conditions: Water (NH3H2O+NH4HCO3)-MeCN; Gradient time (min): 15; 100% B retention time (min): 3; Flow rate (ml / min): 25.

[1397] Method R: Column: Phenomenex Gemini-NX 150*30mm*5um: Water (NH4HCO3)-MECN; Gradient time (min): 11; Flow rate (ml / min): 25.

[1398] Method S: Column: C18-1 150*30mm*5um; Conditions: Water (NH4HCO3)-MECN; Start B: Gradient time (min): 11; Flow rate (ml / min): 25.

[1399] Method T: Column: Boston Green ODS150 x 30 mm, 5 mm; MeCN / H2O (TFA).

[1400] Method U: Column: Waters XSelect CSH C18, 5 μm, 30 mm × 100 mm column with mobile phase H2O (A) and MeCN (B) (0.2% NH4OH final v / v% conditioner), flow rate 60 mL / min.

[1401] Method V: Column: Waters Sunfire Prep C18 OBD 5um 19x100mm, gradient: MeCN in water, conditioner 0.1% TFA, gradient time 12min, flow rate 30ml / min.

[1402] Method W: Column: Waters Xbridge BEH C18 100*30mm*10um, Conditions: Water (HCl)-MeCN; Gradient time (min): 11; Flow rate (ml / min): 50.

[1403] Method X: Column: Waters Xbridge BEH C18 100*30mm*10um; Conditions: Water (FA)-MeCN; Gradient time (min): 11; 100% B retention time (min): 3; Flow rate (ml / min): 50.

[1404] Method Y: Column: Phenomenex luna C18 150*25mm*10um; Conditions: Water (FA)-MeCN; Gradient over 10 min, flow rate 25 mL / min.

[1405] Method Z: Waters Xbridge BEH C18 100x 30mm, 10mm; MeCN / H2O(TFA))

[1406] Method AA: Column: Agela DuraShell C18 150*25mm*5um; Conditions: Water (NH3.H2O)-MECN; B%: Gradient over 10 min.

[1407] Preparation 1

[1408] 2-Bromo-5-ethoxypyridine 1-oxide

[1409] m-CPBA (46.1 g, 267 mmol) was added to a solution of 2-bromo-5-ethoxypyridine (27.0 g, 134 mmol) in DCE (300 mL), and the reaction was stirred at 80 °C for 2 h. The mixture was adjusted to pH 10 with ethylene-1,2-diamine (16.1 g, 267 mmol), concentrated under vacuum, diluted with water (150 mL), and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude substance was purified by silica gel chromatography (EtOAc) to give 2-bromo-5-ethoxypyridine 1-oxide (23.0 g, 78.6% yield) as a white solid. LCMS m / z = 218.0 [M+H] + .

[1410] Preparation 2

[1411] 2-Bromo-5-ethoxy-4-nitropyridine 1-oxide

[1412] HNO3 (12.0 mL) was added dropwise to a solution of 2-bromo-5-ethoxypyridine 1-oxide (Preparation 1, 11.0 g, 50.5 mmol) in H2SO4 (12.0 mL), and the reaction was stirred at 25 °C for 16 h. The mixture was poured into an ice / water mixture (200 mL). The solid was collected by filtration and washed with ice / water to give 15.2 g of crude 2-bromo-5-ethoxy-4-nitropyridine 1-oxide as a pale yellow solid. 1 H NMR: (400MHz, CDCl3) δppm: 8.27 (s, 1H), 8.25 (s, 1H), 4.19 (q, J = 6.8Hz, 2H), 1.53 (t, J = 6.8Hz, 3H)

[1413] Preparation 3

[1414] 2-Bromo-5-ethoxypyridine-4-amine

[1415] Iron (15.9 g, 284 mmol) was added to a solution of 2-bromo-5-ethoxy-4-nitropyridine 1-oxide (Preparation 2, 15.0 g, 56.8 mmol) in AcOH (50.0 mL). The reaction was stirred at 25 °C for 30 min, and the mixture was then diluted with water (500 mL) and extracted with EtOAc (400 mL x 3). The combined organic phases were washed with brine (100 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated to give 2-bromo-5-ethoxypyridine-4-amine (5.64 g, 45.7% yield) as a brown solid. LCMS m / z = 219.0 [M+H] + .

[1416] Preparation 4

[1417] (2-bromo-5-ethoxypyridin-4-yl)(tert-butoxycarbonyl)tert-butyl carbamate

[1418] DMAP (3.2 g, 25.9 mmol) and Boc₂O (22.6 g, 104 mmol) were added to a solution of 2-bromo-5-ethoxypyridin-4-amine (preparation 3, 5.6 g, 25.9 mmol) and TEA (7.0 g, 69.2 mmol) in DCM (50 mL), and the reaction was stirred at 25 °C for 2 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (70 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude material was purified by silica gel chromatography (PE / EtOAc 1 / 0 to 3 / 1) to give tert-butyl (2-bromo-5-ethoxypyridin-4-yl)(tert-butyloxycarbonyl)carbamate (1.7 g, 15.5% yield) as a yellow solid. LCMS m / z = 419.0 [M+H] + .

[1419] Preparation 5

[1420] (2-acetamido-5-ethoxypyridin-4-yl)(tert-butoxycarbonyl) tert-butyl carbamate

[1421] Acetamide (260 mg, 4.40 mmol), Cs₂CO₃ (2.6 g, 8.00 mmol), and BrettPhos Pd G₃ (363 mg, 0.40 mmol) were added to a solution of (2-bromo-5-ethoxypyridin-4-yl)(tert-butoxycarbonyl)carbamate (Preparation 4, 1.7 g, 4.00 mmol) in dioxane (20 mL), and the reaction was stirred at 100 °C for 1 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel chromatography (PE / EtOAc 1 / 0 to 2 / 1) to give tert-butyl (2-acetamido-5-ethoxypyridin-4-yl)(tert-butoxycarbonyl)carbamate (1.3 g, 82.1% yield) as a pale yellow solid. LCMS m / z = 396.2 [M+H] + .

[1422] Preparation 6

[1423] 2-Chloro-5-(difluoromethoxy)-4-iodopyridine

[1424]

[1425] A solution of 6-chloro-4-iodopyridin-3-ol (1 g, 3.91 mmol) in DMF (20 mL) was added with sodium 2-chloro-2,2-difluoroacetate (1.2 g, 7.83 mmol) and Cs₂CO₃ (2.6 g, 7.83 mmol), and the reaction was stirred at 100 °C under N₂ for 4 h. The mixture was quenched with H₂O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (20 mL x 2), dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give 2-chloro-5-(difluoromethoxy)-4-iodopyridinium (1.2 g, 97% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ: ppm 8.17 (s, 1H), 7.84 (s, 1H), 6.76-6.40 (m, 1H).

[1426] Preparation 7

[1427] 2-Chloro-5-cyclobutoxy-4-iodopyridine

[1428]

[1429] Following the procedure described in Preparation 6, 2-chloro-5-cyclobutoxy-4-iodopyridine was obtained from 6-chloro-4-iodopyridine-3-ol and bromocyclobutane, 940 mg, in 77.6% yield. LCMS m / z = 309.8 [M+H] +

[1430] Preparation of 8

[1431] 2-Chloro-4-iodo-5-isopropoxypyridine

[1432]

[1433] Following the procedure described in Preparation 6, 2.2 g of 2-chloro-4-iodopyridin-3-ol and 2-iodopropane were reacted to yield 94.4% of 2-chloro-4-iodo-5-isopropoxypyridine as a yellow liquid. ¹H NMR (500 MHz, CDCl₃) δppm: 7.82 (s, ¹H), 7.73 (s, ¹H), 4.66–4.59 (m, ¹H), 1.45–1.38 (m, 6H).

[1434] Preparation 9

[1435] (2-chloro-5-(difluoromethoxy)pyridin-4-yl)tert-butyl carbamate

[1436]

[1437] A solution of 2-chloro-5-(difluoromethoxy)-4-iodopyridine (preparation 6, 1.1 g, 3.44 mmol) in dioxane (20 mL) was added with 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 was stirred at 100 °C under N₂ for 16 h. The cooled mixture was concentrated, and the residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give tert-butyl (2-chloro-5-(difluoromethoxy)pyridin-4-yl)carbamate (940 mg, 93.0% yield) as a yellow oil. 1 H NMR: (400MHz, 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).

[1438] Preparation 10

[1439] (2-chloro-5-cyclobutoxypyridin-4-yl)tert-butyl carbamate

[1440]

[1441] Cs₂CO₃ (2.94 g, 9.01 mmol), Pd₂(dba)₃ (275.13 mg, 0.3 mmol), and Xantphos (347.70 mg, 0.6 mmol) were added to a solution of 2-chloro-5-cyclobutoxy-4-iodopyridine (7,930 mg, 3.0 mmol) and NH₂Boc (387.2 mg, 3.31 mmol) in dioxane (15 mL), and the reaction was stirred at 100 °C under N₂ for 1.5 h. The cooled mixture was diluted with water (50 mL) and extracted with EtOAc (70 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over anhydrous Na₂SO₄, and concentrated to give tert-butyl (2-chloro-5-cyclobutoxypyridine-4-yl)carbamate (1.4 g, crude) as a white solid. LCMS m / z = 299.1 [M+H] +

[1442] Preparation 11

[1443] (2-chloro-5-isopropoxypyridin-4-yl)tert-butyl carbamate

[1444]

[1445] Following the procedure described in Preparation 9, the title compound, 1.03 g, was obtained as a yellow solid from 2-chloro-4-iodo-5-isopropoxypyridine (Preparation 8) and NH2Boc, in 49% yield. 1 H NMR (400MHz, CDCl3) δppm: 8.09 (s, 1H), 7.84 (s, 1H), 7.18 (s, 1H), 4.66-4.59 (m, 1H), 1.54 (s, 9H), 1.40 (d, J = 6.4Hz, 6H).

[1446] Preparation 12

[1447] 2-Bromo-5-(2-Methoxyethoxy)isonicotinic acid

[1448]

[1449] t-BuONa (21.8 g, 227 mmol) was added to a solution of 2-bromo-5-fluoroisonicotinic acid (10.0 g, 45.5 mmol) and 2-methoxyeth-1-ol (100 mL), and the reaction was stirred at 70 °C for 1 h. The mixture was concentrated, and the residue was dissolved in H₂O (10 mL) and adjusted to pH 4 with 2NHCl. The precipitate was separated by filtration, dissolved in EtOAc (25 mL), and washed with brine (25 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated to give 2-bromo-5-(2-methoxyethoxy)isonicotinic acid (10.0 g, 79.7% yield) as a yellow solid. 1 H NMR: (400MHz, DMSO-d6) δppm: 13.63 (br s, 1H), 8.35 (s, 1H), 7.69 (s, 1H), 4.29-4.27 (m, 2H), 3.67-3.64 (m, 2H), 3.30 (s, 3H).

[1450] Preparation 13

[1451] 2-Bromo-5-ethoxyisonicotinic acid

[1452]

[1453] t-BuONa (120.13 g, 1.25 mol) was added to a solution of 2-bromo-5-fluoroisonicotinic acid (110 g, 500 mmol) in EtOH (1500 mL), and the reaction was stirred at 90 °C under N2 for 12 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water (500 mL). The aqueous phase was adjusted to pH 4 with 12 M HCl, the resulting mixture was filtered, and the filter cake was washed with water (200 mL x 2) and concentrated under reduced pressure to give 2-bromo-5-ethoxyisonicotinic acid (115 g, 93.5% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δppm 8.32 (s, 1H), 7.68 (s, 1H), 4.21 (q, J = 6.8 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H).

[1454] Preparation 14

[1455] 2-Bromo-5-(2,2,2-trifluoroethoxy)isonicotinic acid

[1456]

[1457] 2,2,2-trifluoroethoxy-1-ol (2.7 g, 27.27 mmol) and t-BuONa (4.4 g, 45.46 mmol) were added to a solution of 2-bromo-5-fluoroisonicotinic acid (2.0 g, 9.09 mmol) in THF (20.0 mL), and the reaction was stirred at 70 °C under N2 for 12 h. The mixture was concentrated under reduced pressure, the residue was diluted with water (20 mL), and the pH was adjusted to 4 with 12 M HCl. The mixture was filtered, the filter cake was washed with water (10 mL x 2) and dried under reduced pressure to give 2-bromo-5-(2,2,2-trifluoroethoxy)isonicotinic acid (2.4 g, 88% yield) as a white solid. 1 H NMR: (500MHz, DMSO-d6) δppm: 13.88 (br s, 1H), 8.44 (s, 1H), 7.80 (s, 1H), 4.97 (q, J = 8.5Hz, 2H).

[1458] Preparation 15

[1459] 2-Bromo-5-(2,2-difluoroethoxy)isonicotinic acid

[1460]

[1461] Following the procedure described in Preparation 14, 2-bromo-5-(2,2-difluoroethoxy)isonicotinic acid, 1.5 g, was obtained as a brown solid from 2-bromo-5-fluoroisonicotinic acid and 2,2-difluoroethoxy-1-ol, in a yield of 58.5%.1 H NMR: (400MHz, MeOH-d4) δppm: 8.32 (s, 1H), 7.78 (s, 1H), 6.38-6.10 (m, 1H), 4.47-4.39 (m, 2H).

[1462] Preparation of 16

[1463] 2-Bromo-5-(2-(dimethylamino)ethoxy)isonicotinic acid

[1464]

[1465] Following the procedure described in Preparation 14, 2.03 g of 2-bromo-5-(2-(dimethylamino)ethoxy)isonicotinic acid, 76.9%, was obtained as a yellow solid from 2-bromo-5-fluoroisonicotinic acid and 2-(dimethylamino)ethane-1-ol. LCMS m / z = 291.0 [M+H] +

[1466] Preparation of 17

[1467] 5-(benzyloxy)-2-bromoisonicotinic acid

[1468]

[1469] Following the procedure described in Preparation 14, 5-(benzyloxy)-2-bromoisonicotinic acid was obtained as a yellow solid, 25 g, in 93.9% yield, from 2-bromo-5-fluoroisonicotinic acid and benzyl alcohol. LCMS m / z = 307.9 [M+H] + .

[1470] Preparation of 18

[1471] 2-Bromo-5-((3-methoxycyclobutyl)methoxy)isonicotinic acid

[1472]

[1473] A solution of 2-bromo-5-fluoroisonicotinic acid (1 g, 4.55 mmol) in THF (10 mL) was added with (3-methoxycyclobutyl)methanol (580.80 mg, 5.0 mmol) and t-BuONa (873.68 mg, 9.09 mmol), and the reaction was stirred at 70 °C for 2 h. The mixture was concentrated and purified by preparative HPLC (Method E, gradient: 25 to 55%) to give 2-bromo-5-((3-methoxycyclobutyl)methoxy)isonicotinic acid (340 mg, 23.7% yield) as a white solid. 1H NMR: (400MHz, CDCl3) δppm 8.26 (s, 1H), 8.10 (s, 1H), 4.31 (d, J = 6.4Hz, 2H), 3.92-3.85 (m, 1H), 3.26 (s, 3H), 2.56-2.46 (m, 3H), 1.89-1.79 (m, 2H).

[1474] Preparation of 19

[1475] 2-Bromo-5-(cyclopropylmethoxy)isonicotinic acid

[1476]

[1477] t-BuONa (20.75 g, 215.9 mmol) was added to a solution of 2-bromo-5-fluoroisonicotinic acid (19 g, 86.37 mmol) and cyclopropylmethanol (12.45 g, 172.73 mmol) in THF (250 mL). The reaction mixture was stirred at 90 °C for 16 h. The reaction was concentrated to give a residue, which was adjusted with HCl (2N) until the pH reached 5. The mixture was filtered and the solid was dried under vacuum to give 2-bromo-5-(cyclopropylmethoxy)isonicotinic acid (20 g, 85.1% yield) as a white solid. 1H NMR: (400MHz, CDCl3) δppm: 13.66 (br s,1H),8.31(s,1H),7.69(s,1H),4.03(d,J=7.2Hz,2H),1.30-1.13(m,1H),0.62-0.51(m,2H),0.40-0.30(m,2H)

[1478] Preparation 20

[1479] 2-Bromo-5-(ethoxy-d5)isonicotinic acid

[1480]

[1481] While stirring at rt, 1,1,1,2,2-pentadeuterium-2-deuteroxy-ethane (1.2 g, 23.03 mmol) was added to a solution of t-BuONa (2.18 g, 22.73 mmol) and THF (20 mL). After 5 minutes, 2-bromo-5-fluoro-pyridine-4-carboxylic acid (2 g, 9.09 mmol) was added, and the reaction was heated to 65 °C. The reaction was allowed to be stirred for 1 h, then diluted and concentrated with water (40 mL) to remove THF. While stirring at rt, the resulting aqueous mixture was acidified by adding HCl (2 M, 13.64 mL). The thick slurry was filtered to collect the resulting solid. This was then dissolved in MeOH (50 mL), diluted with MeCN (25 mL), and concentrated to give 2-bromo-5-(ethoxy-d5)isonicotinic acid (2.2 g, 96.4% yield) as a brown solid. LCMS m / z = 250.9(M+H) + . 1 H NMR(DMSO-d6)δ:14.14-13.10(m,1H),8.32(s,1H),7.68(s,1H).

[1482] Preparation 21

[1483] (2-Bromo-5-(cyclopropylmethoxy)pyridin-4-yl)tert-butyl carbamate

[1484]

[1485] DPPA (19.01 mL, 88.20 mmol) was added to a solution of 2-bromo-5-(cyclopropylmethoxy)isonicotinic acid (19, 20 g, 73.50 mmol) and TEA (8.93 g, 88.20 mmol) in t-BuOH (200 mL), and the reaction was stirred at 90 °C for 16 h. The mixture was partitioned between EtOAc (3 x 150 mL) and water (250 mL). The organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by silica gel column chromatography (PE / EtOAc = 20 / 1-10 / 1) to give tert-butyl (2-bromo-5-(cyclopropylmethoxy)pyridin-4-yl)carbamate as a yellow solid (22 g, 87.2% yield). 1 HNMR: (400MHz, CDCl3) δppm: 8.23 ​​(s, 1H), 7.81 (s, 1H), 3.90 (d, J = 6.8Hz, 2H), 1.55 (s, 9H), 1.38-1.22 (m, 1H), 0.80-0.61 (m, 2H), 0.47-0.30 (m, 2H).

[1486] Preparation 22

[1487] (2-bromo-5-(2-methoxyethoxy)pyridin-4-yl)tert-butyl carbamate

[1488]

[1489] TEA (7.3 g, 72.4 mmol) and DPPA (9.9 g, 36.2 mmol) were added to a solution of 2-bromo-5-(2-methoxyethoxy)isonicotinic acid (Preparation 12, 10.0 g, 36.2 mmol) in t-BuOH (100 mL), and the reaction was stirred at 90 °C under N2 for 16 h. The mixture was concentrated under reduced pressure, and the residue was diluted with H2O (30 mL) and extracted with EtOAc (35 mL x 3). The combined organic layers were washed with brine (35 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE / EtOAc 1 / 0 to 5 / 1) to give tert-butyl (2-bromo-5-(2-methoxyethoxy)pyridin-4-yl)carbamate (9.03 g, 71.8% yield) as white crystals. LCMS m / z = 349.1 [M+H] + .

[1490] Preparation 23

[1491] (2-Bromo-5-ethoxypyridin-4-yl)tert-butyl carbamate

[1492]

[1493] Following the procedure described in Preparation 22, tert-butyl (2-bromo-5-ethoxyisonicotinic acid) was obtained as a yellow solid from 2-bromo-5-ethoxyisonicotinic acid (Preparation 13) and DPPA, 85 g, 73.3% yield. ¹H NMR: (400 MHz, DMSO-d6) δppm 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).

[1494] Preparation 24 to 29

[1495] Following a reaction similar to that described in Preparation 22, the compounds in the table below are obtained from suitable 2-bromoisonicotinic acid and DPPA.

[1496]

[1497]

[1498] Preparation 30

[1499] (2-Bromo-5-(2-(dimethylamino)ethoxy)pyridin-4-yl)tert-butyl carbamate

[1500]

[1501] TEA (1.40 g, 13.83 mmol) and DPPA (1.90 g, 6.92 mmol) were added to a solution of 2-bromo-5-(2-(dimethylamino)ethoxy)isonicotinic acid (preparation 16, 2 g, 6.92 mmol) in t-BuOH (20 mL), and the reaction was stirred at 90 °C under N2 for 16 h. The reaction mixture was purified by preparative HPLC (Method D, 20% isocratic gradient) to give tert-butyl (2-bromo-5-(2-(dimethylamino)ethoxy)pyridin-4-yl)carbamate as a white solid (800 mg, 32.1% yield). LCMS m / z = 361.8 [M+H] +

[1502] Preparation 31

[1503] (2-Bromo-5-(ethoxy-d5)pyridin-4-yl)tert-butyl carbamate

[1504]

[1505] DIPEA (2.26 g, 17.52 mmol) was added to a mixture of 2-bromo-5-(ethoxy-d5)isonicotinic acid (Preparation 20, 2.2 g, 8.76 mmol) and tBuOH (25 mL). The solution was stirred at rt for 10 min, and then DPPA (2.89 g, 10.51 mmol) was added. After 5 min, the reaction was heated to 75 °C and the cap was loosened to allow N2 to escape for 2 h. The cooled reaction was concentrated to remove tBuOH, then diluted with NaHCO3 (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were concentrated to dryness and the crude substance was purified by silica gel chromatography (40 g, heptane to EtOAc) to give tert-butyl (2-bromo-5-(ethoxy-d5)pyridin-4-yl)carbamate (1.42 g, 50.30% yield) as a white crystalline solid. LCMS m / z = 322.0 [M+H] + .1H NMR (DMSO-d6) δ: 8.62 (br s, 1H), 8.03 (d, J = 4.9Hz, 2H), 1.49 (s, 9H).

[1506] Preparation of 32

[1507] (2-acetamido-5-(2-methoxyethoxy)pyridin-4-yl)tert-butyl carbamate

[1508]

[1509] Cs₂CO₃ (25.1 g, 76.9 mmol) and BrettPhos Pd G₃ (2.3 g, 2.56 mmol) were added to a solution of (2-bromo-5-(2-methoxyethoxy)pyridin-4-yl)carbamate (22, 8.9 g, 25.6 mmol) and acetamide (7.6 g, 128 mmol) in dioxane (80 mL), and the reaction was stirred at 100 °C under N₂ for 1 h. The mixture was concentrated, diluted with H₂O (50 mL), extracted with EtOAc (60 mL x 2), and the combined organic extracts were washed with brine (50 mL x 2). The organic phase was concentrated and the residue was purified by silica gel chromatography (PE / EtOAc 5 / 0 to 0 / 1) to give tert-butyl (2-acetamido-5-(2-methoxyethoxy)pyridin-4-yl)carbamate as a brown solid (8.0 g, 95.9% yield). LCMS m / z = 326.2 [M+H] + . 1 H NMR: (400MHz, CDCl3) δppm: 8.88 (br s, 1H), 8.27 (br s,1H),7.83-7.79(m,2H),4.14-4.10(m,2H),3.70-3.67(m,2H),3.46(s,3H),2.15(s,3H),1.54(s,9H).

[1510] Preparation of 33

[1511] (2-acetamido-5-(cyclopropylmethoxy)pyridin-4-yl)tert-butyl carbamate

[1512]

[1513] Acetamide (77.4 mg, 1.31 mmol), BrettPhos Pd G3 (39.6 mg, 0.0437 mmol), and Cs2CO3 (427 mg, 1.31 mmol) were added to a solution of (2-bromo-5-(cyclopropylmethoxy)pyridin-4-yl)carbamate (preparation 21, 150 mg, 0.437 mmol) in dioxane (5 mL). The reaction was stirred at 100 °C under N2 for 2 h. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and then purified by silica gel chromatography (PE / EtOAc 15 / 1 to 0 / 1) to give tert-butyl 2-acetamido-5-(cyclopropylmethoxy)pyridin-4-yl)carbamate (130 mg, 92.6% yield) as a white solid. 1 H NMR: (400MHz, CDCl3) δppm: 8.85 (br s, 1H), 7.89 (br s,1H),7.71(s,1H),3.87(d,J=7.2Hz,2H),2.16(s,3H),1.56(s,9H),1.30-1.25(m,1H),0.70-0.66(m,2H),0.38-0.35(m,2H).

[1514] Preparation 34 to 39

[1515] The compounds in the table below are prepared by following a procedure similar to that described in Preparation 33, using a suitable 2-bromo or 2-chloropyridine and acetamide.

[1516]

[1517]

[1518] Purification by preparative TLC (DCM / MeOH = 10 / 1)

[1519] **Use DMF instead of dioxane**

[1520] Preparation of 40

[1521] (2-acetamido-5-(ethoxy-d5)pyridin-4-yl)tert-butyl carbamate

[1522]

[1523] 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 to (2-bromo-5-(ethoxy-d5)pyridin-4-yl)carbamate (Preparation 31, 1.42 g, 4.41 mmol), followed by the addition of dioxane (15 mL). The mixture was degassed by bubbling N₂ under rt for 10 min and then heated to 100 °C for 1 h. The reaction mixture was diluted with EtOAc (25 mL) via... Filter, wash with EtOAc (15 mL), and concentrate to dryness. Purify the crude material by silica gel chromatography (40 g, heptane to EtOAc) to give tert-butyl (2-acetamido-5-(ethoxy-d5)pyridin-4-yl)carbamate (1.26 g, 94.9% yield) as a white solid. LCMS m / z = 301.1 [M+H]+.1H NMR (DMSO-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).

[1524] Preparation 41

[1525] (2-acetamido-5-isopropoxypyridin-4-yl) tert-butyl carbamate

[1526]

[1527] Acetamide (618 mg, 10.46 mmol), Pd2(dba)3 (638.68 mg, 0.7 mmol), Cs2CO3 (2.27 g, 6.97 mmol), and Xantphos (807.13 mg, 1.39 mmol) were added to a solution of (2-chloro-5-isopropoxypyridin-4-yl)carbamate (11, 1 g, 3.49 mmol) in dioxane (10 mL), and the reaction was stirred at 120 °C under N2 for 16 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 0 to 1 / 1) to give (2-acetamido-5-isopropoxypyridin-4-yl)aminomethyl tert-butyrate as a yellow solid (830 mg, 76.9% yield). 1H NMR (500MHz, CDCl3) δppm: 8.83 (s, 1H), 7.95 (s, 1H), 7.76 (s, 1H), 7.15 (s, 1H), 4.60-4.52 (m, 1H), 2.16 (s, 3H), 1.56 (s, 9H), 1.38 (d, J=6.0Hz, 6H)

[1528] Preparation 42

[1529] (2-acetamido-5-cyclopropoxypyridin-4-yl)tert-butyl carbamate

[1530]

[1531] Following the procedure described in Preparation 41, tert-butyl (2-bromo-5-cyclopropoxypyridin-4-yl)carbamate (Preparation 25) and acetamide were used to obtain 130 mg of (2-acetamido-5-cyclopropoxypyridin-4-yl)carbamate as a yellow solid, in 34.8% yield. LCMS m / z = 308.1 [M+H] +

[1532] Preparation 43

[1533] (2-acetamido-5-(2,2,2-trifluoroethoxy)pyridin-4-yl)tert-butyl carbamate

[1534]

[1535] Following the procedure described in Preparation 41, tert-butyl 2-(2-bromo-5-(2,2,2-trifluoroethoxy)pyridin-4-yl)carbamate (Preparation 27) and acetamide were used to obtain 733 mg of tert-butyl 2-(2-acetamido-5-(2,2,2-trifluoroethoxy)pyridin-4-yl)carbamate as a white solid, in 74% yield. 1 H NMR (400MHz, CDCl3) δppm: 8.93 (br s, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 7.06 (s, 1H), 4.42 (q, J = 8.0Hz, 2H), 2.18 (s, 3H), 1.55 (s, 9H).

[1536] Preparation of 44

[1537] (2-acetamido-5-((3-methoxycyclobutyl)methoxy)pyridin-4-yl)tert-butyl carbamate

[1538]

[1539] Following the procedure described in Preparation 41, tert-butyl 2-bromo-5-((3-methoxycyclobutyl)methoxy)pyridin-4-yl)carbamate (Preparation 26) and acetamide were used to obtain tert-butyl 2-acetamido-5-((3-methoxycyclobutyl)methoxy)pyridin-4-yl)carbamate as a yellow oil, 98 mg, 43.3% yield. 1 H NMR: (500MHz, CDCl3) δppm8.84(s,1H),7.76(s,1H),7.71(s,1H),7.28(s,1H),4.02(d,J=5.5Hz,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).

[1540] Preparation of 45

[1541] (5-ethoxy-2-propionylaminopyridin-4-yl)tert-butyl carbamate

[1542]

[1543] Cs₂CO₃ (1.2 g, 3.78 mmol) and BrettPhos Pd G₃ (114.3 mg, 0.13 mmol) were added to a solution of (2-bromo-5-ethoxypyridin-4-yl)carbamate (preparation 23, 400.0 mg, 1.26 mmol) and propionamide (460.9 mg, 6.31 mmol) in dioxane (5.0 mL), and the reaction was stirred at 100 °C under N₂ for 1 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (PE / EtOAc = 3 / 1 to 0 / 1) to give (5-ethoxy-2-propionylaminopyridin-4-yl)carbamate (255 mg, 65.4% yield) as a white solid. LCMS m / z = 310.2 [M+H] +

[1544] Preparation of 46

[1545] (5-ethoxy-2-(2-methoxyacetamido)pyridin-4-yl)tert-butyl carbamate

[1546]

[1547] Following the procedure described in Preparation 45, tert-butyl 5-ethoxy-2-(2-methoxyacetamido)pyridin-4-yl)carbamate (Preparation 23) was prepared as a yellow solid, yielding 600 mg of tert-butyl 5-ethoxy-2-(2-methoxyacetamido)pyridin-4-yl)carbamate in 82.2% yield. 1 H NMR(400MHz, CDCl3)δ:ppm 8.90(s,1H),8.68(s,1H),7.77(s,1H),7.18(s,1H),4.13(q,J=6.8Hz,2H),4.01(s,2H),3.48(s,3H),1.55(s,9H),1.47(t,J=7.2Hz,3H).

[1548] Preparation 47

[1549] (5-ethoxy-2-(3-methoxypropionylamino)pyridin-4-yl)tert-butyl carbamate

[1550]

[1551] Following a similar procedure to that described in Preparation 45, tert-butyl 5-ethoxypropionamide and (2-bromo-5-ethoxypyridin-4-yl)carbamate (Preparation 23) were used to obtain tert-butyl 5-ethoxy-2-(3-methoxypropionamide)pyridin-4-yl)carbamate as a white solid, 372 mg, in 86.9% yield. 1 H NMR (500MHz, CDCl3) δppm: 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=6.0Hz,2H ),3.42(s,3H),2.63(t,J=6.0Hz,2H),1.55(s,9H),1.46(t,J=7.0Hz,3H)

[1552] Preparation of 48

[1553] (2-(cyclopropanecarbamoylamino)-5-ethoxypyridin-4-yl)tert-butyl carbamate

[1554]

[1555] A solution of (2-bromo-5-ethoxypyridin-4-yl)carbamate tert-butyl ester (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 to cyclopropaneformamide (64.4 mg, 0.757 mmol), and the reaction was stirred at 100 °C under N2 for 2 h. 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 to 1 / 1) to give (210 mg) of (2-(cyclopropaneformamide)-5-ethoxypyridin-4-yl)carbamate as a yellow solid. LCMS m / z = 322.1 [M+H] +

[1556] Preparation 49

[1557] 2,4-Dichloro-5-(methoxymethyl)pyridine

[1558]

[1559] At 0 °C, NaH (60.66 mg, 2.53 mmol) was added to a stirred solution of (4,6-dichloro-3-pyridyl)methanol (300 mg, 1.69 mmol) in THF (9 mL). The mixture was stirred at rt for 15 min, and then iodomethane (358.80 mg, 2.53 mmol) was added. The reaction mixture was stirred at rt for 4 h, then quenched with aqueous NH4Cl solution and extracted with EtOAc. The combined organic extracts were concentrated under vacuum and the crude product was purified (0-100% heptane / EtOAc-ethanol (3:1)) to obtain 2,4-dichloro-5-(methoxymethyl)pyridine (225 mg, 69.5% yield) as a colorless liquid. LCMS m / z = 192.0 [M+H] + .

[1560] Preparation of 50

[1561] N-(4-chloro-5-(methoxymethyl)pyridin-2-yl)acetamide

[1562]

[1563] Josiphos Pd G3 (76.28 mg, 0.083 mmol) and K2CO3 (456.27 mg, 3.30 mmol) were added to a stirred solution of 2,4-dichloro-5-(methoxymethyl)pyridine (49,317 mg, 1.65 mmol) and acetamide (97.50 mg, 1.65 mmol) in toluene (2 mL, degassed with N2 for 20 min). The resulting mixture was degassed with N2 and then heated at 90 °C for 16 h. The reaction mixture was then transferred via... The crude product was filtered and purified by silica gel column chromatography using (0-100%) heptane / EtOAc / EtOH (3:1) to obtain N-(4-chloro-5-(methoxymethyl)pyridin-2-yl)acetamide (211 mg, 59.6% yield) as an orange solid. LCMS m / z = 214.0 [M+H] + .

[1564] Preparation 51

[1565] N-(4-chloro-5-methylpyridin-2-yl)acetamide

[1566]

[1567] Ac₂O (85.92 mg, 0.84 mmol) and pyridine (77.67 mg, 0.98 mmol) were added to a solution of 4-chloro-5-methylpyridin-2-amine (100 mg, 0.70 mmol) in DCM (2 mL), and the mixture was stirred at 25 °C for 16 h. The mixture was added to water (10 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude material was purified by silica gel column chromatography (PE / EtOAc = 1 / 0 to 3 / 1) to give N-(4-chloro-5-methylpyridin-2-yl)acetamide (98 mg, 75.7% yield) as a yellow solid. 1 H NMR: (500MHz, CDCl3) δppm: 9.69 (br s, 1H), 8.38 (s, 1H), 7.97 (s, 1H), 2.30 (s, 3H), 2.11 (s, 3H).

[1568] Preparation of 52

[1569] (2-acetamido-5-methylpyridin-4-yl)tert-butyl carbamate

[1570]

[1571] 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 under N₂ for 16 h. The mixture was added to water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 0 to 0 / 1) to give tert-butyl (2-acetamido-5-methylpyridin-4-yl)carbamate as a yellow solid (90 mg, 69.6% yield). ¹H NMR: (500 MHz, CDCl₃) δppm: 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).

[1572] Preparation of 53

[1573] (2-acetamido-5-bromopyridin-4-yl)tert-butyl carbamate

[1574]

[1575] NBS (6.5 g, 36.77 mmol) was added to a solution of (2-acetamidopyridin-4-yl)carbamate tert-butyl ester (8.4 g, 33.43 mmol) in MeCN (90.0 mL), and the reaction was stirred at 70 °C for 1 h. The mixture was concentrated under vacuum, and the crude product was purified by column chromatography (PE / EtOAc = 1 / 1 to 0 / 1) to give (2-acetamido-5-bromopyridin-4-yl)carbamate tert-butyl ester (9.1 g, 82.5% yield) as a white solid. 1 H NMR (500MHz, CDCl3) δppm: 9.07 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.14 (s, 1H), 2.21 (s, 3H), 1.55 (s, 9H).

[1576] Preparation of 54

[1577] (2-acetamido-5-vinylpyridin-4-yl)tert-butyl carbamate

[1578]

[1579] To a solution of (2-acetamido-5-bromopyridin-4-yl)carbamate tert-butyl (preparation 53,500 mg, 1.51 mmol) in dioxane (5.0 mL) and H₂O (1.0 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxane (466.5 mg, 3.03 mmol), Pd(dppf)Cl₂ (110.8 mg, 0.151 mmol), and K₂CO₃ (418.6 mg, 3.03 mmol) were added, and the reaction was stirred at 100 °C under N₂ for 2 h. The mixture was poured into H₂O (50 mL), extracted with EtOAc (50 mL x 3), and the combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1 to 1 / 1) to give tert-butyl (2-acetamido-5-vinylpyridin-4-yl)carbamate as a yellow solid (381.6 mg, 90.9% yield). 1 H NMR (500MHz, CDCl3) δppm: 8.84 (s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 6.71 (s, 1H), 6.62 (dd, J = 17 .5Hz,11.0Hz,1H),5.64(d,J=17.5Hz,1H),5.47(d,J=11.0Hz,1H),2.19(s,3H),1.54(s,9H).

[1580] Preparation of 55

[1581] (2-acetamido-5-(prop-1-en-2-yl)pyridin-4-yl)tert-butyl carbamate

[1582]

[1583] Following the procedure described in Preparation 54, tert-butyl 2-acetamido-5-(prop-1-en-2-yl)pyridin-4-yl)carbamate (Preparation 53) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxane were used to obtain a yellow solid of (2-acetamido-5-(prop-1-en-2-yl)pyridin-4-yl)carbamate, 220 mg, 83.1% yield. ¹H NMR (400 MHz, DMSO-d6) δppm: 10.40 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.02 (s, 1H), 5.28 (s, 1H), 5.00 (s, 1H), 2.06 (s, 3H), 1.06 (s, 9H).

[1584] Preparation of 56

[1585] (2-acetamido-5-(prop-1-yn-1-yl)pyridin-4-yl)tert-butyl carbamate

[1586]

[1587] Tributyl(prop-1-yn-1-yl)stanane (747.6 mg, 2.27 mmol), NaOAc (62.1 mg, 0.757 mmol), and Pd(PPh3)2Cl2 (53.2 mg, 0.076 mmol) were added to a solution of tert-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (53,500 mg, 1.51 mmol) in DMF (6.0 mL), and the reaction was stirred at 100 °C under N2 for 3 h. The mixture was poured into H2O (30 mL), extracted with EtOAc (30 mL x 3), and the combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (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. 1 H NMR (400MHz, CDCl3) δppm: 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).

[1588] Preparation 57

[1589] (2-acetamido-5-ethylpyridin-4-yl)carbamate tert-butyl ester

[1590]

[1591] Pd / C (1.4 g, 1.30 mmol, 10% purity) was added to a solution of (2-acetamido-5-vinylpyridin-4-yl)carbamate (preparation 54, 361.8 mg, 1.30 mmol) in MeOH (5.0 mL), and the reaction was stirred at 20 °C under H2 (15 psi) for 2 h. The reaction was filtered and concentrated under vacuum to give (2-acetamido-5-ethylpyridin-4-yl)carbamate (262.1 mg, 71.9% yield) as a white solid.

[1592] 1H NMR: (400MHz, CDCl3) δppm: 8.81(s,1H),8.11(s,1H),7.94(s,1H),6.50(s, 1H),2.52(q,J=7.6Hz,2H),2.17(s,3H),1.55(s,9H),1.24(t,J=7.6Hz,3H).

[1593] Preparation of 58

[1594] (2-acetamido-5-isopropylpyridin-4-yl)tert-butyl carbamate

[1595]

[1596] Pd / C (730.5 mg, 0.69 mmol, 10% purity) was added to a solution of (2-acetamido-5-(prop-1-en-2-yl)pyridin-4-yl)carbamate (preparation 55, 200 mg, 0.69 mmol) in MeOH (5 mL), and the mixture was stirred at 25 °C under H2 (15 psi) for 16 h. The mixture was filtered, and the filtrate was concentrated under pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 0 to 1 / 2) to give (2-acetamido-5-isopropylpyridin-4-yl)carbamate (120 mg, 59.6% yield) as a white solid. 1H NMR (500MHz, CDCl3) δppm: 8.80 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 6.56 (s, 1H), 2.90-2.82 (m, 1H), 2.18 (s, 3H), 1.54 (s, 9H), 1.30 (d, J=6.5Hz, 6H)

[1597] Preparation 59

[1598] (2-acetamido-5-propylpyridin-4-yl)tert-butyl carbamate

[1599]

[1600] Pd / C (959.3 mg, 0.901 mmol, 10% purity) was added to a solution of (2-acetamido-5-(prop-1-yn-1-yl)pyridin-4-yl)carbamate (preparation 56, 260.8 mg, 0.901 mmol) in THF (5.0 mL), and the reaction was stirred at 20 °C under H2 (15 psi) for 2 h. The reaction was filtered, and the filtrate was concentrated to give (2-acetamido-5-propylpyridin-4-yl)carbamate (223.6 mg, 84.6% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δppm: 8.81 (br s,1H),8.10(s,1H),7.91(s,1H),6.49(s,1H),2.46(t,J=7.6Hz,2H),2.17(s,3H),1.64-1.59(m,2H),1.55(s,9H),0.98(t,J=7.2Hz,3H).

[1601] Preparation of 60

[1602] (2-acetamido-5-cyclopropylpyridin-4-yl)tert-butyl carbamate

[1603]

[1604] 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 to a solution of (2-acetamido-5-cyclopropylpyridin-4-yl)carbamate (preparation 53, 200.0 mg, 0.606 mmol) in dioxane (5.0 mL) and H₂O (0.5 mL), and the reaction was stirred at 100 °C for 2 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 0 / 1) to give (2-acetamido-5-cyclopropylpyridin-4-yl)carbamate (160 mg, 90.7% yield) as a yellow oil. LCMS m / z = 292.1 [M+H] +

[1605] Preparation of 61

[1606] N-(4-amino-5-methoxypyridin-2-yl)acetamide hydrochloride

[1607]

[1608] A solution of tert-butyl (2-acetamido-5-methoxypyridin-4-yl)carbamate (35, 15 g, 53.32 mmol) in dioxane (200 mL) was added with 4 M HCl / dioxane (200 mL), and the reaction was stirred at 20 °C for 1 h. The mixture was filtered, and the filter cake was vacuum dried and then lyophilized to give N-(4-amino-5-methoxypyridin-2-yl)acetamide hydrochloride (10.36 g, 84.21% yield) as a yellow solid. LCMS m / z = 182 [M+H] +

[1609] Preparation of 62N-(4-amino-5-ethoxypyridin-2-yl)acetamide hydrochloride

[1610]

[1611] 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 with 4 M HCl / dioxane (5.0 mL), and the reaction was stirred at 25 °C for 2 h. The mixture was evaporated under reduced pressure to give N-(4-amino-5-ethoxypyridin-2-yl)acetamide hydrochloride (440 mg, crude product) as a pale yellow solid. LCMS m / z = 196.0 [M+H] + .

[1612] Preparation of 63

[1613] N-(4-amino-5-(2-methoxyethoxy)pyridin-2-yl)acetamide hydrochloride

[1614]

[1615] 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 with 4 M HCl / dioxane (10 mL), and the reaction was stirred at 25 °C for 1 h. The mixture was evaporated under reduced pressure to give N-(4-amino-5-(2-methoxyethoxy)pyridin-2-yl)acetamide hydrochloride (810 mg, crude substance) as a brown solid. LCMS m / z = 226.1 [M+H] + . 1H NMR: (500MHz, DMSO-d6) δppm: 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).

[1616] Preparation of 64

[1617] N-(4-amino-5-(cyclopropylmethoxy)pyridin-2-yl)acetamide hydrochloride

[1618]

[1619] A solution of tert-butyl (2-acetamido-5-(cyclopropylmethoxy)pyridin-4-yl)carbamate (preparation 33, 110 mg, 0.342 mmol) in DCM (2 mL) was added with 4 M HCl / dioxane (5 mL), and the reaction was stirred at 25 °C for 3 h. The mixture was evaporated under reduced pressure to give N-(4-amino-5-(cyclopropylmethoxy)pyridin-2-yl)acetamide hydrochloride (70.0 mg, crude product) as a white solid. LCMS m / z = 222.1 [M+H] + .

[1620] Preparation of 65 to 81

[1621] Following a procedure similar to that described in Preparation 64, the compounds in the table below are prepared by protecting the amine with a suitable Boc.

[1622]

[1623]

[1624]

[1625]

[1626] Preparation of 82

[1627] N-(4-amino-5-(benzyloxy)pyridin-2-yl)acetamide hydrochloride

[1628] A solution of tert-butyl (2-acetamido-5-(benzyloxy)pyridin-4-yl)carbamate (38, 19 g, 53.16 mmol) in dioxane (200 mL) was added with 4 M HCl / dioxane (200 mL), and the reaction was stirred at 20 °C for 1 h. The mixture was filtered, and the filter cake was dried under reduced pressure and then lyophilized to give N-(4-amino-5-(benzyloxy)pyridin-2-yl)acetamide hydrochloride (14.93 g, 95.4% yield) as a white solid. LCMS m / z = 258.0 [M+H] +

[1629] Preparation of 83N-(4-amino-5-(ethoxy-d5)pyridin-2-yl)acetamide hydrochloride

[1630]

[1631] HCl (4 M, 5.24 mL) was added to a solution of (2-acetamido-5-(ethoxy-d5)pyridin-4-yl)carbamate (Preparation 40, 1.26 g, 4.19 mmol) in dioxane (10 mL), and the reaction mixture was stirred at 40 °C for 3 h. The reaction mixture was diluted with dioxane (10 mL), filtered through filter paper to collect a white solid, and washed with additional dioxane (10 mL). The solid was dissolved in MeOH (50 mL) and concentrated to dryness, then azeotropically reacted with dioxane to give N-(4-amino-5-(ethoxy-d5)pyridin-2-yl)acetamide hydrochloride (1.06 g, crude substance) as a white solid. LCMS m / z = 201.0 [M+H] + .

[1632] Preparation of 84

[1633] 2-(1,1-Difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine

[1634]

[1635] To a solution of 4-chloro-2-(1,1-difluoroethyl)pyridine (5.84 g, 32.9 mmol) and (1r,3r)-3-methoxycyclobut-1-ol (2.8 g, 27.42 mmol) in DMF (50 mL), NaH (1.32 g, 32.9 mmol, 60% purity) was added. The reaction mixture was stirred at 60 °C for 16 h, quenched with water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1-5 / 1) to give 2-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine (5 g, 75% yield) as a colorless oil. 1H NMR (400MHz, CDCl3) δppm: 8.43 (d, J = 5.6Hz, 1H), 7.04 (d, J = 1.8Hz, 6.4Hz, 1H), 6.73 (dd, J = 2.4, 5.6H z,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=18.8Hz,3H).

[1636] Preparation of 85

[1637] 2-(1,1-Difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine

[1638]

[1639] Following the procedure described in Preparation 84, 2-(1,1-difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine, 3.7 g, 91.4% yield, was obtained from 4-chloro-2-(1,1-difluoroethyl)pyridine and (1s,3s)-3-methoxycyclobutoxy-1-ol as a colorless oil. 1H NMR(400MHz, CDCl3)ppm:8.43(d,J=5.6Hz,1H),7.06(d,J=2.4Hz,1H),6.76(dd,J=2.4,5.6Hz,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=22.4Hz,3H).

[1640] Preparation of 86

[1641] 2-(1,1-Difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine 1-oxide

[1642]

[1643] To a solution of 2-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine (preparation 84, 7 g, 28.78 mmol) in DCM (100 mL), m-CPBA (7.31 g, 37.41 mmol, 80% purity) was added and the reaction was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated Na₂S₂O₃ (280 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1, DCM / MeOH = 10 / 1) to give 2-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine 1-oxide as a colorless oil (7 g, 93.8% yield). 1H NMR: (400MHz, CDCl3) δppm8.14(d,J=7.2Hz,1H),7.09(d,J=7.2Hz,1H),6.65(dd,J=2.4,7.2Hz,1 H), 4.94-4.79 (m, 1H), 4.16-4.08 (m, 1H), 3.28 (s, 3H), 2.53-2.38 (m, 4H), 2.25 (t, J = 19.2Hz, 3H).

[1644] Preparation of 87

[1645] 2-(1,1-Difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine 1-oxide

[1646]

[1647] Following the procedure described in Preparation 86, 2-(1,1-difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine (Preparation 85) and m-CPBA were used to obtain 3.5 g of 1-oxide of 2-(1,1-difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine as a colorless oil, in 88.8% yield. 1H NMR (400MHz, CDCl3) δppm 8.19 (d, J=7.2Hz, 1H), 7.08 (d, J=7.2Hz, 1H), 6.80 (dd, J=3.4, 7.2Hz, 1H), 4.41-4.34 (m, 1H), 3.73-3.70 (m, 1H), 3.30 (s, 3H), 2.97-2.90 (m, 2H), 2.25 (t, J=22.4Hz, 3H), 2.20-2.16 (m, 2H).

[1648] Preparation of 88

[1649] 2-Chloro-6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine

[1650]

[1651] A solution of 2-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine 1-oxide (preparation 86.7 g, 27 mmol) was added with POCl3 (63.6 mL, 682.72 mmol), and the reaction mixture was stirred at 100 °C for 16 h. The mixture was concentrated and dissolved in DCM (20 mL). The solution was poured into water (50 mL) and quenched with saturated NaHCO3 (40 mL) until pH > 8. The aqueous layer was extracted with DCM (80 mL x 3), the combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. 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, 50.7% yield) as a yellow oil. LCMS m / z = 278.1 [M+H] +

[1652] Preparation of 89

[1653] 2-Chloro-6-(1,1-difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine

[1654] Following the procedure described in Preparation 88, 2-chloro-6-(1,1-difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine 1-oxide (Preparation 87) was used to obtain 2-chloro-6-(1,1-difluoroethyl)-4-((1s,3s)-3-methoxycyclobutoxy)pyridine as a yellow oil. LCMS m / z = 278.1 [M+H] +

[1655] Preparation of 90

[1656] 2-(1,1-Difluoroethyl)pyrimidin-4,6-diol

[1657]

[1658] t-BuONa (49.4 g, 514.24 mmol) was added to a solution of malondiamide (15.0 g, 146.9 mmol) in EtOH (500 mL), and the solution was stirred at 25 °C for 30 min. Ethyl 2,2-difluoropropionate (50.7 g, 367.32 mmol) was added, and the reaction was stirred under reflux at 100 °C for 16 h. The reaction was cooled, 4N HCl (75 mL) was added, and the mixture was concentrated. The resulting solid was collected and concentrated to give 2-(1,1-difluoroethyl)pyrimidine-4,6-diol (20.0 g, 77.3% yield) as a yellow solid. LCMS m / z = 177.0 [M+H] +

[1659] Preparation of 91

[1660] 4,6-Dichloro-2-(1,1-difluoroethyl)pyrimidine

[1661]

[1662] A solution of 2-(1,1-difluoroethyl)pyrimidine-4,6-diol (preparation 90, 20.0 g, 113.56 mmol) in POCl3 (200 mL, 2.15 mol) was stirred at 100 °C for 8 h. The mixture was evaporated to dryness, and the residue was diluted with DCM (150 mL) and slowly added to water. The mixture was extracted with DCM (200 mL x 3), the combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude substance was purified by column chromatography (PE 0% to 10% EtOAc) to give 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (23.0 g, 95.1% yield) as a yellow liquid. LCMS m / z = 213.0 [M+H] +

[1663] Preparation of 92

[1664] 4-Chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine

[1665]

[1666] Fe(acac)3 (12.44 g, 35.21 mmol) was added to a solution of 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (Preparation 91, 75.0 g, 352.1 mmol) in THF (750 mL) and NMP (75 mL) at 23 °C. The mixture was purged with N2 and then cooled to -20 °C. CH3MgBr (3 M, 117.4 mL) was added dropwise to the cooled solution, maintaining the internal temperature between -20 and -10 °C during the addition. The resulting mixture was stirred at -20 °C for 2 h. The mixture was poured into a saturated aqueous solution of NH4Cl (1.5 L) and extracted with MTBE (1.0 L). The organic layer was washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concentrated. The resulting slightly reddish-brown liquid was purified by preparative HPLC (Method F, gradient: 40%–58%). The desired fraction was vacuum evaporated to remove MeCN. The mixture was extracted with MTBE (500 mL), the organic phase was washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concentrated to provide a yellow liquid of 4-chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine. LCMS m / z = 193.1 [M+H] + .

[1667] Preparation of 93

[1668] 2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-amine

[1669]

[1670] Pd₂(dba)₃ (47.55 mg, 0.0519 mmol), Xantphos (60.09 mg, 0.104 mmol), and Cs₂CO₃ (676.70 mg, 2.08 mmol) were added to a stirred solution of 4-chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine (preparation 92, 200 mg, 1.04 mmol) in anhydrous dioxane (2 mL). Then, benzophenone imine (225.84 mg, 1.25 mmol) was added, and the reaction mixture was heated to 90 °C for 1 h. The reaction mixture was diluted with EtOAc, washed with water, dried over Na₂SO₄, and concentrated under vacuum. The residue was dissolved in MeOH (15 mL), NaOAc (196.87 mg, 2.40 mmol) and hydroxylamine hydrochloride (254.33 mg, 3.66 mmol) were added, and the reaction mixture was stirred at rt for 30 min. The solvent was evaporated and the residue was redissolved in THF. The THF solution was washed once with a 1N NaOH-salt solution (1:3 v / v), dried over MgSO4, and evaporated under reduced pressure. The residue was purified by silica gel chromatography using 0-100% heptane / EtOAc-EtOH (3:1) to provide 2-(1,1-difluoroethyl)-6-methylpyrimidin-4-amine (80 mg, 44.5% yield).

[1671] 1H NMR (500MHz, MeOH-d4) δ6.35 (s, 1H), 2.29 (s, 3H), 1.87 (t, J = 18.6Hz, 3H).

[1672] Preparation of 94

[1673] 4-Chloro-2-(1,1-difluoroethyl)-6-ethylpyrimidine

[1674]

[1675] Ethylboronic acid (520 mg, 7.04 mmol), K₂CO₃ (1.46 g, 10.6 mmol), and Pd(dppf)Cl₂ (515 mg, 0.70 mmol) were added to a solution of 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (Preparation 91, 1.5 g, 7.04 mmol) in water (3 mL) and dioxane (15 mL). The mixture was stirred at 100 °C under N₂ for 16 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (25 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc 1 / 0 to 10 / 1) to give 4-chloro-2-(1,1-difluoroethyl)-6-ethylpyrimidine (410 mg, 28.2% yield) as a yellow solid. 1 H NMR: (400MHz, CDCl3) δppm: 7.28 (s, 1H), 2.86 (q, J = 7.5Hz, 2H), 2.06 (t, J = 18.5Hz 3H), 1.34 (t, J = 7.5Hz, 3H).

[1676] Preparation of 95

[1677] 4-Chloro-2-(1,1-difluoroethyl)-6-(prop-1-en-2-yl)pyrimidine

[1678]

[1679] Pd(dppf)Cl2 (110 mg, 0.150 mmol) was added to a mixture of 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (preparation 91, 320 mg, 1.50 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxane (252 mg, 1.50 mmol), and K2CO3 (415 mg, 3.00 mmol) in dioxane (10 mL) and water (2 mL), and the reaction was stirred at 70 °C for 1 h. The reaction mixture was concentrated to dryness, and the residue was purified by silica gel chromatography (PE / EtOAc0 / 1 to 3 / 1) to give 4-chloro-2-(1,1-difluoroethyl)-6-(prop-1-en-2-yl)pyrimidine (220 mg, 67.0% yield) as a yellow oil. LCMS m / z = 219.1 [M+H] + .

[1680] Preparation of 96

[1681] 4-Chloro-6-cyclopropyl-2-(1,1-difluoroethyl)pyrimidine

[1682]

[1683] 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) were added 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). The mixture was stirred at 70 °C under N₂ for 2 h. The mixture was diluted with water (15 mL), extracted with EtOAc (20 mL x 3), and the combined organic phases were washed with brine (60 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude substance was purified by column chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give 4-chloro-6-cyclopropyl-2-(1,1-difluoroethyl)pyrimidine as a colorless oil (805.6 mg, 78.5% yield). LCMS m / z = 219.1 [M+H] +

[1684] Preparation of 97

[1685] 4-Chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine

[1686]

[1687] At 0 °C, NaOMe (76.1 mg, 1.41 mmol) was added to a solution of 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (preparation 91, 300 mg, 1.41 mmol) in MeOH (5.0 mL), and the reaction was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc 15 / 1 to 5 / 1) to give 4-chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine (260 mg, 88.5% yield) as a colorless oil. 1 HNMR: (400MHz, CDCl3) δppm: 6.81 (s, 1H), 4.08 (s, 3H), 2.02 (t, J = 18.5Hz, 3H).

[1688] Preparation of 98

[1689] 2,4-Dichloro-5-fluoro-6-methylpyrimidine

[1690]

[1691] MeMgBr (3M, 44.9mL) was slowly added to a solution of 2,4-dichloro-5-fluoropyrimidine (15.0g, 89.84mmol) in DME (150.0mL) at 0°C under N2, and the mixture was stirred at 15°C for 1h. TEA (9.1g, 89.84mmol) was added to THF (10.0mL), and the solution was stirred at 0°C for 5 minutes. Then, I2 (22.8g, 89.84mmol) was slowly added to THF (16.0mL), and the reaction was stirred at 15°C for 2h. The mixture was quenched with H2O (200mL), and the pH was adjusted to 1 with 5NHCl. The mixture was extracted with EtOAc (150.0mL x 3), the combined organic phases were washed with brine (300mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (PE / EtOAc = 0 / 1 to 10 / 1) to give 2,4-dichloro-5-fluoro-6-methylpyrimidine (9.3 g, 57% yield) as a yellow oil. 1 H NMR (500MHz, CDCl3) δppm: 2.56 (d, J=2.5Hz, 3H).

[1692] Preparation of 99

[1693] 4-(benzyloxy)-2-chloro-5-fluoropyrimidine

[1694]

[1695] A solution of BnOH (6.5 g, 59.89 mmol) and t-BuONa (5.8 g, 59.9 mmol) in toluene (150.0 mL) was stirred at 0 °C for 10 min. 2,4-Dichloro-5-fluoropyrimidine (10.0 g, 59.9 mmol) was slowly added, and the resulting mixture was stirred at 20 °C for 1 h. The mixture was poured into H₂O (100 mL), extracted with EtOAc (3 x 100 mL), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1 to 5 / 1) to give 4-(benzyloxy)-2-chloro-5-fluoropyrimidine (12.5 g, 87.5% yield) as a white solid. 1 H NMR: (500MHz, CDCl3) δppm: 8.21 (s, 1H), 7.49-7.42 (m, 2H), 7.41-7.38 (m, 3H), 5.51 (s, 2H).

[1696] Prepare 100

[1697] 4-(benzyloxy)-2-chloro-5-fluoro-6-methylpyrimidine

[1698]

[1699] Following the procedure described in Preparation 99, 4-(benzyloxy)-2-chloro-5-fluoro-6-methylpyrimidine (Preparation 98) and BnOH were used to obtain 7.9 g of 4-(benzyloxy)-2-chloro-5-fluoro-6-methylpyrimidine as a colorless oil, in a yield of 58.2%. 1 H NMR: (500MHz, CDCl3) δppm: 7.48-7.46 (m, 2H), 7.42-7.36 (m, 3H), 5.48 (s, 2H), 2.44 (d, J = 3.0Hz, 3H).

[1700] Preparation 101

[1701] 4-(benzyloxy)-5-fluoropyrimidine-2-carboxylic acid methyl ester

[1702]

[1703] Pd(dppf)Cl2 (1.6 g, 2.18 mmol) and TEA (22.1 g, 217.9 mmol) were added to a solution of 4-(benzyloxy)-2-chloro-5-fluoropyrimidine (preparation 99 g, 26.0 g, 109 mmol) in MeOH (300 mL). The resulting mixture was stirred at 80 °C under CO2 (50 psi) for 16 h. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1 to 3 / 1) to give methyl 4-(benzyloxy)-5-fluoropyrimidine-2-carboxylic acid (12.0 g, 42% yield) as a white solid. 1 HNMR: (400MHz, CDCl3) δppm: 8.44 (d, J=2.0Hz, 1H), 7.53-7.39 (m, 2H), 7.38-7.35 (m, 3H), 5.61 (s, 2H), 4.03 (s, 3H).

[1704] Preparation 102

[1705] 4-(benzyloxy)-5-fluoro-6-methylpyrimidine-2-carboxylic acid methyl ester

[1706]

[1707] Following the procedure described in Preparation 101, methyl 4-(benzyloxy)-5-fluoro-6-methylpyrimidine (Preparation 100) and MeOH were used to obtain 3.1 g of methyl 4-(benzyloxy)-5-fluoro-6-methylpyrimidine-2-carboxylic acid in a yellow oil, yielding 35.8%. 1HNMR: (400MHz, CDCl3) δppm: 7.53-7.51 (m, 2H), 7.40-7.35 (m, 3H), 5.58 (s, 2H), 4.03 (s, 3H), 2.55 (d, J = 2.8Hz, 3H).

[1708] Preparation of 103

[1709] 1-(4-(benzyloxy)-5-fluoropyrimidin-2-yl)ethyl-1-one

[1710]

[1711] At -78 °C, MeMgBr (3 M, 18.30 mL) was added dropwise to a solution of methyl 4-(benzyloxy)-5-fluoropyrimidin-2-carboxylic acid (Preparation 101, 12.0 g, 45.76 mmol) in THF (120 mL), and the solution was stirred under N2 for 2 h. The mixture was quenched with NH4Cl (30 mL saturated) at -78 °C, poured into H2O (60 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1 to 3 / 1) to give 1-(4-(benzyloxy)-5-fluoropyrimidin-2-yl)ethyl-1-one (7.3 g, 64.8% yield) as a white solid. 1 H NMR: (400MHz, CDCl3) δppm: 8.45 (d, J = 2.0Hz, 1H), 7.52-7.49 (m, 2H), 7.42-7.37 (m, 3H), 5.60 (s, 2H), 2.73 (s, 3H).

[1712] Preparation of 104

[1713] 1-(4-(benzyloxy)-5-fluoro-6-methylpyrimidin-2-yl)ethyl-1-one

[1714]

[1715] Following the procedure described in Preparation 103, methyl 4-(benzyloxy)-5-fluoro-6-methylpyrimidin-2-carboxylic acid (Preparation 102, and MeMgBr) was used to obtain 1.6 g of 1-(4-(benzyloxy)-5-fluoro-6-methylpyrimidin-2-yl)ethyl-1-one, a yellow oil, in 54.8% yield. 1 H NMR (400MHz, CDCl3) δppm: 7.51-7.49 (m, 2H), 7.40-7.36 (m, 3H), 5.57 (s, 2H), 2.71 (s, 3H), 2.54 (d, J = 3.2Hz, 3H).

[1716] Preparation 105

[1717] 4-(benzyloxy)-2-(1,1-difluoroethyl)-5-fluoropyrimidine

[1718]

[1719] DAST (23.9 g, 148.23 mmol) was added to a solution of 1-(4-(benzyloxy)-5-fluoropyrimidin-2-yl)ethyl-1-one (Preparation 103, 7.3 g, 29.65 mmol) in DCM (80.0 mL). The resulting mixture was stirred at 20 °C for 12 h. The mixture was slowly poured into H2O (80 mL), extracted with DCM (3 x 80 mL), and the combined organic extracts were washed with brine (2 x 80 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1 to 5 / 1) to give 4-(benzyloxy)-2-(1,1-difluoroethyl)-5-fluoropyrimidin (6.7 g, 84% yield) as a colorless oil. 1 H NMR: (400MHz, CDCl3) δppm: 8.38 (d, J = 2.4Hz, 1H), 7.51-7.40 (m, 2H), 7.39-7.36 (m, 3H), 5.56 (s, 2H), 2.02 (t, J = 18.4Hz, 3H).

[1720] Preparation of 106

[1721] 4-(benzyloxy)-2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidine

[1722]

[1723] Following the procedure described in Preparation 105, 1.6 g of 4-(benzyloxy)-2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidin-2-yl)ethyl-1-one (Preparation 104) was obtained as a yellow oil, yielding 95.9%. 1 H NMR (500MHz, CDCl3) δppm: 7.48-7.46 (m, 2H), 7.38-7.32 (m, 3H), 5.51 (s, 2H), 2.48 (d, J = 3.0Hz, 3H), 1.98 (t, J = 18.0Hz, 3H).

[1724] Preparation of 107

[1725] 2-(1,1-Difluoroethyl)-5-fluoropyrimidine-4-ol

[1726]

[1727] 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 was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1 to 3 / 1) to give 2-(1,1-difluoroethyl)-5-fluoropyrimidine-4-ol (3.2 g, 72.1% yield) as a white solid. 1 H NMR: (400MHz, CDCl3) δppm: 11.61 (br s, 1H), 7.93 (d, J = 2.4Hz, 1H), 2.03 (t, J = 18.8Hz, 3H).

[1728] Preparation of 108

[1729] 2-(1,1-Difluoroethyl)-5-fluoro-6-methylpyrimidin-4-ol

[1730]

[1731] Following the procedure described in Preparation 107, 2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidine (Preparation 106) was prepared as a colorless oil, 780 mg, 73.5%. 1 H NMR: (500MHz, CDCl3) δppm: 2.40 (d, J = 3.5Hz, 3H), 2.02 (t, J = 18.5Hz, 3H).

[1732] Preparation 109

[1733] 4-Chloro-2-(1,1-difluoroethyl)-5-fluoropyrimidine

[1734]

[1735] 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 x 60 mL). The combined organic phases were washed with brine (2 x 50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1 to 5 / 1) to give 4-chloro-2-(1,1-difluoroethyl)-5-fluoropyrimidin (2.3 g, 65.1% yield) as a colorless oil. LCMS m / z = 197.1 [M+H] +

[1736] Preparation of 110

[1737] 4-Chloro-2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidine

[1738]

[1739] Following the procedure described in Preparation 109, 3.1 g of 4-chloro-2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidin-4-ol (Preparation 108) was obtained as a colorless oil, in 90.7% yield. LCMS m / z = 211 [M+H] +

[1740] Preparation 111

[1741] 4-Chloro-2-(1,1-difluoroethyl)-6-((1r,3r)-3-methoxycyclobutoxy)pyrimidine

[1742] A solution of 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (preparation 91, 400 mg, 1.88 mmol) and Cs₂CO₃ (1.9 g, 5.63 mmol) in DMF (6.0 mL) was added with (1r,3r)-3-methoxycyclobut-1-ol (211 mg, 2.07 mmol) and the reaction was stirred at 25 °C for 1 h. The mixture was diluted with water (80 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give 4-chloro-2-(1,1-difluoroethyl)-6-((1r,3r)-3-methoxycyclobutoxy)pyrimidine (450 mg, 86.0% yield) as a yellow oil. LCMS m / z = 278.9 [M+H] + . 1H NMR: (400MHz, CDCl3) δppm: 6.77 (s, 1H), 5.47-5.41 (m, 1H), 4.15-4.08 (m, 1H) ), 3.27 (s, 3H), 2.57-2.49 (m, 2H), 2.43-2.40 (m, 2...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 H, C 1-6 Alkyl, -OR 1a 、-NR 1b R 1c , a 3- to 7-membered monocyclic carbocyclic group or a 4- to 7-membered monocyclic heterocyclic group, wherein R 1 The C 1-6 The alkyl, 3- to 7-membered monocyclic carbocyclic group and 4- to 7-membered monocyclic heterocyclic group are each optionally substituted by one or more R 1d replace; R 1a , R 1b and R 1c Each independently is H, C 1-4 Alkyl or 3- to 4-membered monocyclic carbocyclic group; Each R 1d are 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 Selected from 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 group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R 2 The C 1-6 Alkyl, C 3-7 The cycloalkyl, 5- to 11-membered monocyclic or bicyclic heterocyclic group and 5- to 6-membered monocyclic heteroaryl group are each optionally substituted by 1 to 3 R 20 replace; R 2a Selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 7-membered monocyclic heterocyclic radical having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R 2a The C 1-6 Alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl and 4- to 7-membered monocyclic heterocyclyl are optionally substituted by 1 to 3 R 20 replace; Each R 2b Independently H, C 1-4 Alkyl, C 1-3 Alkyl-C 1-3 Alkoxy, C 1-4 Alkoxy or 4- to 6-membered monocyclic heterocyclic group; R 20 Each occurrence is independently selected from 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, 5- to 10-membered bicyclic carbocyclic ring, 4- to 10-membered monocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R 20 The C 1-4 Alkyl, phenyl, C 3-7 Cycloalkyl, 5- to 10-membered bicyclic carbocyclic ring, 4- to 10-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl are each optionally substituted by 1 to 3 R 200 replace; Each R 20b Independently H, C 1-4 Alkyl or C 1-4 Alkoxy; R 20c H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl or 4 to 6 membered monocyclic heterocyclic group, wherein the C 1-4 The alkyl group is optionally replaced by C 1-3 Alkoxy substitution; R 200 Each occurrence is independently selected from halo, -CN, C 1-4 Alkyl, C 1-3 Alkyl-C 1-3 Alkoxy, C 1-4 Haloalkyl, -OH, -N(R 20b 2. C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-7 Cycloalkyl and optionally 1 to 3 C 1-3 Alkyl or C 1-3 an alkoxy-substituted 5- to 10-membered monocyclic or bicyclic heterocyclic group; Ring B is phenyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, 3- to 7-membered monocyclic carbocyclyl, or 4- to 7-membered monocyclic heterocyclyl, each of which is optionally substituted by one or more R B replace; Each R B independently selected from 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 carbocyclic radicals, 4 to 7 membered monocyclic or bicyclic heterocyclic radicals having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5 to 10 membered monocyclic or bicyclic heteroaryl radicals having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R B The C 1-6 Alkyl, C 2-6 alkenyl, phenyl, 3 to 7 membered monocyclic carbocyclyl, 4 to 7 membered monocyclic heterocyclyl and 5 to 10 membered monocyclic or bicyclic heteroaryl are each optionally substituted by one or more R B1 replace; Each R B1 are independently selected from 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 Independently H, C 1-4 Alkyl, C 3-7 Cycloalkyl or 4 to 8 membered monocyclic or bicyclic heterocyclic group, wherein R Ba The C 1-4 Alkyl, C 3-7 The cycloalkyl group and the 4- to 8-membered monocyclic or bicyclic heterocyclic group are each optionally substituted by 1 or 2 R B0 replace; Each R B0 are independently halo, -CN, -OH, C 1-4 Alkyl or C 1-4 Alkoxy; Each R Bb Independently H, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 Cycloalkyl; R Bc C 1-6 Alkyl or C 3-7 Cycloalkyl; R Bd –C(O)OR Ba 、-N(R Bb )2.-OR Ba , a 3- to 7-membered monocyclic carbocyclyl or a 4- to 8-membered monocyclic heterocyclyl; and R N1 and R N2 Each independently is H or C 1-4 alkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R 1 H, C 1-6 Alkyl, -OR 1a 、-NR 1b R 1c , a 3- to 7-membered monocyclic carbocyclic group or a 4- to 7-membered monocyclic heterocyclic group, wherein R 1 The C 1-6 The alkyl, 3- to 7-membered monocyclic carbocyclic group and 4- to 7-membered monocyclic heterocyclic group are each optionally substituted by one or more R 1d replace; R 1a , R 1b and R 1c Each independently is H, C 1-4 Alkyl or 3- to 4-membered monocyclic carbocyclic group; Each R 1d are 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 Selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, -OR 2a 、-N(R 2b ) 2. a 4- to 11-membered monocyclic or bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R 2 The C 1-6 Alkyl, C 3-7 The cycloalkyl, 5- to 11-membered monocyclic or bicyclic heterocyclic group and 5- to 6-membered monocyclic heteroaryl group are each optionally substituted by 1 to 3 R 20 replace; R 2a Selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl and 4 to 7 membered monocyclic heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R 2a The C 1-6 Alkyl, C 3-7 Cycloalkyl and 4 to 7 membered monocyclic heterocyclic groups are optionally substituted by 1 to 3 R 20 replace; Each R 2b Independently H, C 1-4 Alkyl or C 1-4 Alkoxy; R 20 Each occurrence is independently selected from halo, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, -N(R 20b )2, phenyl, C 3-7 Cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclic radicals having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered monocyclic heteroaryl radicals having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R 20 The phenyl group, C 3-7 The cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclyl and 5- to 6-membered monocyclic heteroaryl are each optionally substituted by 1 to 3 R 200 replace; Each R 20b Independently H, C 1-4 Alkyl or C 1-4 Alkoxy; R 200 Each occurrence is independently selected from 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 by one or more R B replace; Each R B independently selected from 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 carbocyclic radical, 4 to 7 membered monocyclic heterocyclic radical having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5 to 10 membered monocyclic or bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R B The C 1-6 Alkyl, phenyl, 3 to 7 membered monocyclic carbocyclyl, 4 to 7 membered monocyclic heterocyclyl and 5 to 10 membered monocyclic or bicyclic heteroaryl are each optionally substituted by one or more R B1 replace; Each R B1 are independently selected from 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 Independently H, C 1-4 Alkyl or C 3-7 Cycloalkyl, wherein R Ba The C 1-4 Alkyl and C 3-7 The cycloalkyl groups are each optionally substituted with 1 or 2 R B0 replace; Each R B0 are independently halo, -CN, -OH, C 1-4 Alkyl or C 1-4 Alkoxy; Each R Bb Independently H, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 Cycloalkyl; R Bc C 1-6 Alkyl or C 3-7 Cycloalkyl; R Bd –C(O)OR Ba 、-N(R Bb )2.-OR Ba , a 3- to 7-membered monocyclic carbocyclyl or a 4- to 8-membered monocyclic heterocyclyl; and R N1 and R N2 Each independently is H or C 1-4 alkyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from phenyl, pyridyl, pyrimidinyl and thiazolyl, each of which is replaced by one to three R B replace.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R N1 and R N2 Each is independently H or -CH3.

5. The compound according to any one of claims 1 to 4, wherein the compound is represented by formula (II), (II') or (III): or a pharmaceutically acceptable salt thereof, wherein: A 1 N or CR 5 , A 2 N or CR 6 , and A 3 N or CR 3 , the constraint condition is A 1 , A 2 and A 3 No more than one of them is N; R 3 Selected from H, halo, -OR 3a 、-N(R 3b 2. C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-3 Alkyl-C 1-3 Alkoxy, C2 alkenyl, C 3-7 Cycloalkyl, phenyl and 5 to 10 membered monocyclic or bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl and 5 to 10 membered monocyclic or bicyclic heteroaryl are each optionally substituted by 1 to 3 R 3c replace; R 3a H, C 1-4 alkyl, 4 to 8 membered monocyclic or bicyclic heterocyclic group or C 3-7 Cycloalkyl, each of which is optionally substituted by 1 or 2 R 30 replace; Each R 30 are independently halo, -CN, -OH, C 1-4 Alkyl or C 1-4 Alkoxy; Each R 3b Independently H, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 Cycloalkyl; Each R 3c are independently selected from 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, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 8-membered monocyclic heterocyclyl; R 3d –C(O)OR 3a 、-N(R 3b )2.-OR 3a , a 3- to 7-membered monocyclic carbocyclic group or a 4- to 8-membered monocyclic heterocyclic group; R 4 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-4 Alkoxy, C 1-3 Alkoxy-C 1-3 Alkoxy, C 1-3 Haloalkoxy, -C2 haloalkenyl, -SO2R 4a , a 4- to 8-membered monocyclic or bicyclic heterocyclic group having 1 to 2 heteroatoms selected from nitrogen and oxygen, and C 3-7 Cycloalkyl, wherein the 4 to 8-membered monocyclic or bicyclic heterocyclic group and C 3-6 The cycloalkyl groups are each optionally substituted by 1 to 3 groups independently selected from halo, C 1-4 Alkyl, C 1-3 Haloalkyl and C 1-3 Alkyl-C 1-3 Substitution of alkoxy groups; R 4a C 1-6 alkyl; R 5 is H, halide, C 1-3 Alkyl, C 1-3 haloalkyl or a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R 5 The 5- to 6-membered heteroaryl represented by 50 replace; and R 50 Each occurrence is independently halo, C 1-4 Alkyl or C 1-4 haloalkyl; and R 6 and R 7 are independently H, halo, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-4 Alkoxy.

6. The compound according to any one of claims 1 to 4, wherein the compound is represented by formula (II) or (III): or a pharmaceutically acceptable salt thereof, wherein: A 1 N or CR 5 , A 2 N or CR 6 , and A 3 N or CR 3 , the constraint condition is A 1 , A 2 and A 3 No more than one of them is N; R 3 Selected from H, -OR 3a 、-N(R 3b 2. C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, phenyl and 5 to 10 membered monocyclic or bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl and 5 to 10 membered monocyclic or bicyclic heteroaryl are each optionally substituted by 1 to 3 R 3c replace; R 3a H, C 1-4 Alkyl or C 3-7 Cycloalkyl, each of which is optionally substituted by 1 or 2 R 30 replace; Each R 30 are independently halo, -CN, -OH, C 1-4 Alkyl or C 1-4 Alkoxy; Each R 3b Independently H, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 Cycloalkyl; Each R 3c are independently selected from 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, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 8-membered monocyclic heterocyclyl; R 3d –C(O)OR 3a 、-N(R 3b )2.-OR 3a , a 3- to 7-membered monocyclic carbocyclic group or a 4- to 8-membered monocyclic heterocyclic group; R 4 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-4 Alkoxy, -SO2R 4a , a 4- to 6-membered monocyclic heterocyclic group having 1 to 2 heteroatoms selected from nitrogen and oxygen and optionally substituted by 1 to 3 independently halo or C 1-4 Alkyl substituents substituted C 3-7 Cycloalkyl; R 4a C 1-6 alkyl; R 5 is H, halide, C 1-3 Alkyl, C 1-3 haloalkyl or a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R 5 The 5- to 6-membered heteroaryl represented by 50 replace; and R 50 Each occurrence is independently halo, C 1-4 Alkyl or C 1-4 haloalkyl; and R 6 is H, halide, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-4 Alkoxy.

7. The compound of any one of claims 1 to 4, wherein the compound is represented by formula (IV), (V), (VI), (VII), (VIII) or (IX): or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1 to 4, wherein the compound is represented by formula (IV), (V), (VI) or (VII): or a pharmaceutically acceptable salt thereof.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: R 1 H, C 1-4 Alkyl, -OR 1a 、-NR 1b R 1c or C 3-6 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally replaced by C 1-3 Alkoxy substitution; R 1a C 1-3 alkyl; R 1b and R 1c Each independently is H or C 1-3 alkyl.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 1 C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally replaced by C 1-3 Alkoxy substitution.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 1 Selected from H, -CH3, -CH2CH3, -CH2OCH3, -CH2CH2OCH3, -OCH3, -NH2, -NHCH3 and cyclopropyl.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 1 Selected from -CH3, -CH2CH3, -CH2OCH3, -CH2CH2OCH3 and cyclopropyl.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: R 2 Selected from H, halo, C 1-4 Alkyl, -OR 2a and -N(R 2b )2, where R 2 The C 1-4 The alkyl group is optionally substituted with 1 to 3 R 20 replace; R 2a H, C 1-4 Alkyl, C 3-6 cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered monocyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R 2a The C 1-4 Alkyl, C 3-6 Cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by 1 to 3 R 20 replace; R 20 are independently selected from 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, 5- to 10-membered bicyclic carbocyclic ring, 4- to 10-membered monocyclic or bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said C 1-4 Alkyl, phenyl, C 3-6 Cycloalkyl, 4 to 10 membered monocyclic or bicyclic heterocyclyl and 5 to 6 membered heteroaryl are each optionally substituted by 1 to 3 R 200 replace; R 2b Each occurrence is independently H or C 1-3 alkyl; R 20b Each occurrence is independently H or C 1-3 Alkyl; and R 200 Each occurrence is independently selected from 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.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: R 2 Selected from H, C 1-4 Alkyl, -OR 2a and -N(R 2b )2, where R 2 The C 1-4 The alkyl group is optionally substituted with 1 to 3 R 20 replace; R 2a H, C 1-4 Alkyl, C 3-6 Cycloalkyl or a 4- to 6-membered monocyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R 2a The C 1-4 Alkyl, C 3-6 The cycloalkyl group and the 4- to 6-membered monocyclic heterocyclic group are each optionally substituted by 1 to 3 R 20 replace; R 20 are independently selected from halo, C 1-3 Alkyl, C 1-3 Alkoxy, -N(R 20b )2, phenyl, C 3-6 cycloalkyl, 4 to 10 membered monocyclic or bicyclic heterocyclic radicals having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5 to 6 membered monocyclic heteroaryl radicals having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl, C 3-6 Cycloalkyl, 4 to 10 membered monocyclic or bicyclic heterocyclyl and 5 to 6 membered heteroaryl are each optionally substituted by 1 to 3 R 200 replace; R 2b Each occurrence is independently H or C 1-3 alkyl; R 20b Each occurrence is independently H or C 1-3 Alkyl; and R 200 Each occurrence is independently selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-2 Alkoxy and C 3-5 Cycloalkyl.

15. The compound according to claim 13 or 14 or a pharmaceutically acceptable salt thereof, wherein: R 2 H, C 1-4 Alkyl, -OR 2a or -N(R 2b )2, where R 2 The C 1-4 The alkyl group is optionally substituted by 1 to 3 groups independently selected from halo, C 1-3 Alkoxy and -N(R 20b )2 is substituted with a substituent; and R 2a is H or is optionally substituted by 1 to 3 independently selected from halo, C 1-3 Alkoxy and -N(R 20b )2 substituted with a substituent 1-4 alkyl.

16. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein: R 2 is –OR 2a ; R 2a C 3-6 cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered monocyclic heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, wherein R 2a The C 3-6 Cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by 1 to 3 groups independently selected from halo, C 1-3 Alkyl and C 1-3 The substituents of the alkoxy group are substituted.

17. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein: R 2 is –OR 2a ; R 2a C 3-6 Cycloalkyl or a 4- to 6-membered monocyclic heterocyclic group having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, wherein R 2a The C 3-6 The cycloalkyl or 4 to 6 membered monocyclic heterocyclic groups are each optionally substituted by 1 to 3 groups independently selected from halo, C 1-3 Alkyl and C 1-3 The substituents of the alkoxy group are substituted.

18. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein R 2a is cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, pyrazinyl, pyridazinyl or pyrazolyl, each of which is optionally substituted by 1 to 3 independently selected halo, C 1-3 Alkyl and C 1-3 The substituents of the alkoxy group are substituted.

19. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 2a is cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl or pyrrolidinyl, each of which is optionally substituted by 1 to 3 independently selected halo, C 1-3 Alkyl and C 1-3 The substituents of the alkoxy group are substituted.

20. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R 2a It is represented by: where p is 0, 1, 2, or 3; and each R 20 are independently halo, C 1-3 Alkyl and C 1-3 Alkoxy.

21. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R 2a It is represented by: where p is 0, 1, 2, or 3; and each R 20 are independently halo, C 1-3 Alkyl and C 1-3 Alkoxy.

22. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R 2a It is represented by:

23. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R 2a It is represented by:

24. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein: R 2 For-OR 2a And R 2a For an R 20 Substituted C 1-4 Alkyl; and R 20 Phenyl, C 3-6 cycloalkyl, 5- to 10-membered bicyclic carbocyclic ring, 4- to 10-membered monocyclic or bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl, C 3-6 Cycloalkyl, 5- to 10-membered bicyclic carbocyclic ring, 4- to 10-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl are each optionally substituted by 1 to 3 R 200 replace.

25. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein: R 2 For-OR 2a And R 2a For an R 20 Substituted C 1-4 Alkyl; and R 20 Phenyl, C 3-6 cycloalkyl, 4 to 10 membered monocyclic or bicyclic heterocyclic radicals having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and 5 to 6 membered monocyclic heteroaryl radicals having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl, C 3-6 The cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclyl and 5- to 6-membered monocyclic heteroaryl are each optionally substituted by 1 to 3 R 200 replace.

26. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R 20 independently selected from azetidinyl, benzo[d][1,3]dioxolyl, cyclobutyl, cyclopropyl, spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, 2-oxabicyclo[ 2.1.1]hexyl, 5-oxaspiro[2.4]heptyl, 6-oxaspiro[3.4]octyl, dihydrofuranonyl, 1,3-dioxolane, morpholinyl, piperazinyl, 1,4-dioxacyclohexane, 5,8-dioxaspiro[3.5]nonyl, tetrahydropyranyl, 3-oxabicyclo[ 3.1.1]heptyl, 2-oxabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptyl, imidazolyl, isoxazolyl, morpholinyl, oxabicyclo[2.2.1]hexyl, oxadiazolyl, oxetanyl, oxazolyl, phenyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl and tetrahydrofuranyl, each of which is optionally substituted by 1 to 3 R 200 replace.

27. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 20 is independently selected from azetidinyl, benzo[d][1,3]dioxolyl, cyclobutyl, cyclopropyl, dihydrofuranonyl, imidazolyl, isoxazolyl, morpholinyl, oxabicyclo[2.2.1]hexyl, oxadiazolyl, oxetanyl, oxazolyl, phenyl, pyrazolyl, pyridinyl, pyrrolidinyl and tetrahydrofuranyl, each of which is optionally substituted by 1 to 3 R 200 replace.

28. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R 20 Independently selected from: wherein m is 0, 1 or 2 if the valence permits.

29. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 20 Independently selected from: wherein m is 0, 1 or 2 if the valence permits.

30. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 12, wherein R 2 Selected from H, -F, -CH3, -CH2CH3, -CH2CH2CH3, -CF2CH2CH3, -CH2CH2CH2OCH3, -CH(CH3)2, -CH2CH2CH2N(CH3)2, -CF2-cyclopropyl, cyclopropyl, -CH2OCH3, -OH, -OCH3, -OCD3, -OCHF2, -OCH2CH3, -OCD2CH3, -OCD2CD3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CH2F, -OCH2CH2CH(CH3)F, -OCH(CH3)2, -OCH2CF(CH3)2, -OCH2CH2CH2CH3, -OCH2CHFCH(CH3)2, -OCH2CHF-cyclobutyl, -OCH2CH2OH, -OCH2CH(OCD2CD3), -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CH2F, -OCH2CH2CH(CH3)F, -OCH(CH3)2, -OCH2CF(CH3)2, -OCH2CH2CH2CH3, -OCH2CHFCH(CH3)2, -OCH2CHF-cyclobutyl, -OCH2CH2OH, -OCH2CH(OCD2CD3), - H3)CH2CH3, -OCH2CH2OCH3, -OCH2CH2OCF2H, -OCH2CH2OCH2CH3, -OCH2CH2CH2OCH3, -OCH2CH( CH3)OCH3, -OCH2CH(CH3)CH2OCH3, -OCH(CH3)CH2OCH3, -OCH2CH(CH3)OC(CH3)3, -OCH2CH2CH (CH3)OCH3, -OCH2C(CH3)2OCH3, -OCH2CH2OCH2CH3, -OCH2CH2OCH(CH3)2, -OCH2CH2OC(CH3)3 , -OCH2CH2O-cyclopropyl, -OCH2CH2N(CH3)2, -OCH2C(O)NHCH3, -OCH2C(O)N(CH3)2, -NH2, -N(CH3)2, 31. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 12, wherein R 2 Selected from H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2OCH3, -CH(CH3)2, -CH2CH2CH2N(CH3)2, cyclopropyl, -CH2O CH3, 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, 32. A compound as described in any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 200 Each occurrence is independently selected from F, -CN, -CH3, -CH2F, -CF3, -CH2CH3, -CH(CH3)2, -CH2OCH3, -OCH3, cyclobutyl and cyclopropyl.

33. A compound as described in any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 200 Each occurrence is independently selected from F, -CN, -CH3, -CF3, -CH2CH3, -CH(CH3)2, -OCH3 and cyclopropyl.

34. A compound as described in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R 2 C 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 by 1 to 2 R 20 replace.

35. A compound as described in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of azetidinyl, cyclopropyl, tetrahydropyranyl, dioxino[2,3-d]pyridinyl, pyridazinyl, pyrimidinyl, pyrazinonyl, isoxazolyl, isothiazolyl, morpholinyl, oxazabicyclo[3.1.1]heptyl, 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-[1,2,4]triazolo[1,5-a]pyrimidinyl, hydrogen-5H-cyclopenta[b]pyridin-5-one, furano[3,4-d]pyrimidin-5(7H)-one, 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 by 1 to 2 R 20 replace.

36. A compound as described in any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from azetidinyl, cyclopropyl, dioxino[2,3-d]pyridinyl, isoxazolyl, isothiazolyl, morpholinyl, oxazabicyclo[3.1.1]heptyl, oxazolyl, pyridazinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolidinyl, thiadiazolyl and thiazolyl, each of which is optionally substituted by 1 to 2 R 20 replace.

37. A compound as described in any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from Where n is 0, 1, or 2.

38. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-12 and 34-37, wherein: R 20 Each occurrence is independently 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 5- to 10-membered monocyclic or bicyclic heterocyclic group, Among them, R 20 The C 1-4 The alkyl group is optionally substituted with: -CN, OH, -N(R 20b 2. C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and optionally C 1-4 an alkyl-substituted 5- to 10-membered monocyclic or bicyclic heterocyclic group, R 20c H, C 1-4 Alkyl, C 1-4 A haloalkyl group or a 4-membered monocyclic heterocyclic group, wherein the C 1-4 The alkyl group is optionally replaced by C 1-3 Alkoxy substitution; Among them, R 20 The 5- to 10-membered monocyclic or bicyclic heterocyclic group represented by 1-4 Alkyl or C 1-3 Alkoxy substitution; Each R 20b is independently H or optionally C 1-3 Alkoxy substituted C 1-4 alkyl.

39. A compound as described in any one of claims 1-12 and 34-37, or a pharmaceutically acceptable salt thereof, wherein R 20 Each occurrence is independently halo, -CN, C 1-3 Alkyl, C 1-4 Haloalkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl.

40. The compound of claim 38 or a pharmaceutically acceptable salt thereof, wherein R 20 Each occurrence is independently selected from -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, -C H2OCHF2, -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, Cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, N-methylpiperazinyl, N-methylmorpholinyl and morpholinyl.

41. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein R 20 At each occurrence, is independently selected from F, -CN, -OCH3, -CH3, -CHF2, cyclopropyl and cyclobutyl.

42. A compound according to any one of claims 6 to 41 or a pharmaceutically acceptable salt thereof, wherein: R 3 Selected from 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, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indazolyl, [1,2,4]triazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl or imidazo[1,2-b]pyridazinyl, wherein each of the phenyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indazolyl, [1,2,4]triazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl or imidazo[1,2-b]pyridazinyl groups is optionally substituted by 1 or 2 R 3c replace; R 3a H, C 1-3 alkyl, 4 to 8 membered monocyclic or bicyclic heterocyclic group or C 3-6 Cycloalkyl, wherein R 3a The C 1-3 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted by one or two independently selected from halo, -CN, C 1-2 Alkyl, -OH and C 1-2 Substitution of alkoxy groups; Each R 3b Each time it appears, it is independently H, C 1-3 Alkyl or C 3-5 Cycloalkyl; Each R 3c are independently selected from 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 or morpholinyl; R 3d –C(O)OR 3a 、-N(R 3b )2.-OR 3a , cyclopropyl or morpholinyl.

43. A compound according to any one of claims 6 to 41 or a pharmaceutically acceptable salt thereof, wherein: R 3 Selected from H, C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -OR 3a 、-N(R 3b )2, phenyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indazolyl, [1,2,4]triazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl or imidazo[1,2-b]pyridazinyl, wherein each of the phenyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indazolyl, [1,2,4]triazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl or imidazo[1,2-b]pyridazinyl groups is optionally substituted by 1 or 2 R 3c replace; R 3a H, C 1-3 Alkyl or C 3-6 Cycloalkyl, wherein R 3a The C 1-3 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted by one or two independently selected from halo, -CN, C 1-2 Alkyl, -OH and C 1-2 Substitution of alkoxy groups; Each R 3b Each time it appears, it is independently H, C 1-3 Alkyl or C 3-5 Cycloalkyl; Each R 3c are independently selected from 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 or morpholinyl; R 3d –C(O)OR 3a 、-N(R 3b )2.-OR 3a , cyclopropyl or morpholinyl.

44. The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, -F, -Cl, -CH3, -CH2CH3, -CF2CH3, -CF3, -CH(CH3)2, cyclopropyl, -CH=CH2, -CH2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CH2OCH3, -OCH2CH2CH2OCH3, -NHCH3, Where n is 0, 1, or 2.

45. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, -CH3, -CH2CH3, -CF2CH3, -CH(CH3)2, cyclopropyl, -OCH3, -OCH2CH2-OCH3, -NHCH3, Where n is 0, 1, or 2.

46. ​​A compound as described in any one of claims 6 to 45, or a pharmaceutically acceptable salt thereof, wherein each R 3c 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.

47. A compound as described in any one of claims 6 to 45, or a pharmaceutically acceptable salt thereof, wherein each R 3c 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.

48. A compound as described in any one of claims 6 to 47, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from 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, 5- to 7-membered monocyclic or bicyclic heterocyclic group and C 3-6 Cycloalkyl, wherein the 5- to 7-membered monocyclic or bicyclic heterocyclic group and C 3-6 The cycloalkyl groups are each optionally substituted by 1 to 3 groups independently selected from halo, C 1-3 Haloalkyl, C 1-3 Alkyl-C 1-3 Alkoxy and C 1-3 The alkyl group is substituted with a substituent.

49. A compound as described in any one of claims 6 to 47, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from C 1-4 Haloalkyl and C 3-6 Cycloalkyl, which is optionally substituted by 1 to 3 independently selected halo and C 1-3 The alkyl group is substituted with a substituent.

50. The compound of claim 48 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from -CF2CH3, -CF2CFH2, -CFHCFH2, -CF(CH3)2, -CF(CH3)CFH2, -CH(CH3)CFH2, -CF2CH2CH3, -CF(CH3)2, -OCH3, -OCHF2, -OCH2CH2OCH3, -CF=CH2, 51. The compound of claim 49 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from -CF2CH3, -CF2CFH2, -CFHCFH2, -CF2CH2CH3, -CF(CH3)2 and 52. A compound as described in any one of claims 6 to 51, or a pharmaceutically acceptable salt thereof, wherein R 5 is H or a 5-membered heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R 5 The 5-membered heteroaryl represented by 50 replace.

53. A compound as described in any one of claims 6-51 or a pharmaceutically acceptable salt thereof, wherein R 5 is H or optionally 1 to 3 R 50 Substituted pyrazolyl.

54. A compound as described in any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein R 6 is H, halide, C 1-3 Alkoxy.

55. The compound of claim 54 or a pharmaceutically acceptable salt thereof, wherein R 6 It is H, -F or -OCH3.

56. A compound as described in any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein R 7 For H.

57. The compound of claim 1, wherein the compound is represented by formula (IV-1) or (V-1): or a pharmaceutically acceptable salt thereof, wherein: R 1 C 1-3 alkyl; R 2 For-OR 2a or optionally C 1-3 Alkyl-substituted 5-membered monocyclic heteroaryl; R 2a is optionally R 20 Substituted C 1-4 alkyl; R 20 C 1-3 Alkoxy or optionally C 1-2 Alkoxy substituted C 3-6 Cycloalkyl; R 3 Selected from H, -OR 3a , C 1-3 Alkyl, C 3-6 Cycloalkyl and pyrazolyl, wherein the pyrazolyl is optionally substituted by 1 or 2 R 3c replace; R 3a For optionally C 1-3 Alkoxy substituted C 1-3 Alkyl, or optionally 1 or 2 independently selected from C 1-3 Alkoxy, C 1-3 Alkyl and -OH substituents substituted C 3-6 Cycloalkyl; R 3c C 1-3 Alkyl; and R 4 C 1-3 Halogenated alkyl.

58. The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein R 1 is –CH3.

59. The compound of claim 57 or 58, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from –OCH3, –OCD3, –OCH2CH3, –OCD2CH3, –OCD2CD3, –OCH2CH2OCH3, 60. A compound as described in any one of claims 57-59 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from H, –CH3, –CH2CH3, cyclopropyl, –OCH3, –OCH2CH2OCH3, 61. A compound as described in any one of claims 57-60 or a pharmaceutically acceptable salt thereof, wherein R 3c is –CH3; and R 4 It is –CF2CH3, -CF2CFH2, -CFHCFH2, -CF2CH2CH3, -CF(CH3)2.

62. A compound as described in any one of claims 1-4, wherein the compound is represented by formula (III): ( III) or a pharmaceutically acceptable salt thereof, wherein: R 1 C 1-6 alkyl; R 2 C 1-4 Alkoxy; R 3 H or C 1-6 alkyl; R 4 C 1-4 haloalkyl or a 4- to 6-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen and oxygen; and R N1 and R N2 Each independently is H or C 1-3 alkyl.

63. The compound of claim 62 or a pharmaceutically acceptable salt thereof, wherein R 1 is –CH3.

64. The compound of claim 62 or 63, or a pharmaceutically acceptable salt thereof, wherein R 2 It is –OCH2CH3 or –OCH2CH2OCH3.

65. A compound as described in any one of claims 62-64 or a pharmaceutically acceptable salt thereof, wherein R 3 It is H or -CH3.

66. A compound as described in any one of claims 62-65, or a pharmaceutically acceptable salt thereof, wherein R 4 C 1-3 Halogenated alkyl or tetrahydrofuranyl.

67. The compound of claim 66 or a pharmaceutically acceptable salt thereof, Where R 4 is –CF2CH3 or 68. The compound of claim 1, wherein the compound is represented by formula (X): or a pharmaceutically acceptable salt thereof, wherein: A 1 N or CH; R 2 For-OR 2a , 5 or 6-membered monocyclic heteroaryl or 7 to 10-membered bicyclic heterocyclyl, wherein the 5 or 6-membered monocyclic heteroaryl or 7 to 10-membered bicyclic heterocyclyl is each optionally substituted by one or two R 20 replace; R 2a For optionally C 1-3 Alkoxy substituted C 1-3 alkyl; R 20 is optionally replaced by -N(C 1-3 Alkyl)2-substituted C 1-3 alkyl; R 3 H, C 1-3 Alkyl or -OR 3a ; R 3a C 3-4 Cycloalkyl; R 4 C 1-4 A haloalkyl group or a 5- to 7-membered bicyclic heterocyclic group.

69. The compound of claim 68 or a pharmaceutically acceptable salt thereof, wherein A 1 is N.

70. The compound of claim 68 or 69, or a pharmaceutically acceptable salt thereof, wherein R 2 It is -OCH3, -OCH2CH3 or -OCH2CH2OCH3.

71. The compound of claim 68 or 69, or a pharmaceutically acceptable salt thereof, wherein R 2 is pyrazolyl, pyridinyl, pyrimidinyl or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, each of which is optionally substituted by one or two R 20 replace.

72. The compound of claim 71 or a pharmaceutically acceptable salt thereof, wherein R 2 for Where n is 0, 1, or 2.

73. The compound of claim 72 or a pharmaceutically acceptable salt thereof, wherein R 2 for 74. A compound as described in any one of claims 68, 69 or 71-73, or a pharmaceutically acceptable salt thereof, wherein each R 20 are independently -CH3, -CH2CH3 or -CH2N(CH3)2.

75. A compound as described in any one of claims 68-74 or a pharmaceutically acceptable salt thereof, wherein R 3 It is H, -CH3, -CH2CH3 or -O-cyclopropyl.

76. A compound as described in any one of claims 68-75 or a pharmaceutically acceptable salt thereof, wherein R 4 -CF2CH3 or 77. The compound of claim 1, selected from the compound of any one of Examples 1-923 or a pharmaceutically acceptable salt thereof.

78. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 77 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

79. A method of inhibiting tyrosine kinase 2 (TYK2) activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-77 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 78.

80. A method of treating a disease or condition responsive to inhibition of tyrosine kinase 2 (TYK2) in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1-77 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 78.

81. The method of claim 80, wherein the disease or condition is inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock syndrome, autoimmune diseases, osteoporosis, multiple sclerosis, endometriosis, menstrual pain, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis, and sunburn.

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