MRGX2 antagonists

Abstract

The present invention relates to novel compounds according to formula (I) as MrgX2 antagonists, pharmaceutical compositions comprising the same, and their use in therapy for the treatment of MrgX2-mediated diseases and disorders.

Description

Technical Field

[0001] The present invention relates to compounds that are MrgX2 (Mas-related gene X2) antagonists and are therefore useful as therapeutic agents. Background Art

[0002] Mature mammalian mast cells are typically located near blood vessels or nerves; beneath or within epithelia; within the respiratory, gastrointestinal, and urogenital tracts; and near smooth muscle and mucus-producing glands. Typically, mast cells are activated by IgE antibodies to secrete a variety of substances with local and systemic effects, including histamine, serotonin, proteases, chemokines, and cytokines. In fact, mast cells are associated with the development and / or maintenance of many diseases (Nature Immunology, 6, 135-142 (2005)).

[0003] Recent work has highlighted the role of the Mas-related G protein-coupled receptor (MRGPR) family, particularly Mrgprb2, in mast cell activation (Nature, 519, 237-241 (2015)). Mrgprb2 is a mouse receptor for several cationic molecules (collectively referred to as basic secretagogues) and a direct homolog of the human receptor MRGPRX2 (Adv. Immunol., 136, 12362 (2017)). To date, Mrgprb2 and MRGPRX2 have been reported to be expressed only on certain populations of mast cells (Nature Immunology, 17, 878-887 (2016); Annu. Rev. Immunol., 38, 49–77 (2020)). This knowledge provides an opportunity to target mast cell degranulation in a very precise manner.

[0004] Natural endogenous ligands for Mrgprb2 / MRGPRX2 have been reported, primarily neuropeptides, including substance P (SP), vasoactive intestinal polypeptide (VIP), cortistatin-14, and pituitary adenylate cyclase-activating polypeptide (PACAP). Others include β-defensins, cathelicidin (LL-37), and pro-adrenomedullin N-terminal 20 peptide (PAMP9 20) (Journal of Allergy and Clinical Immunology, 138, 700-710 (2016); J. Immunol., 191, 345-352 (2013); BBRC, 349, 1322-28 (2006)). Given the close proximity of mast cells and sensory nerves in various pathological conditions, it follows that neuropeptide-activated MRGPRX2 may contribute to the symptoms of neurogenic inflammation, including pain, swelling, and itching. Various observations using knockout (KO) mice are consistent with the Mrgprb2 / MRGPRX2 receptor playing a role in mast cell-mediated neurogenic inflammation. For example, Mrgprb2 / MRGPRX2 agonists induce various symptoms such as flushing, swelling, and itching in wild-type mice, but not in Mrgprb2-deficient mice (Nature, 519, 237–241 (2015); Immunity, 50, 1163-1171 (2019)). Mrgprb2-deficient mice also show a significant reduction in inflammation (leukocyte infiltration, including mast cells), swelling, pain, and overall clinical scores in various disease models (Neuron, 101, 412-420 (2019); Immunity, 50, 1163-1171 (2019); Nature Immunology, 20, 1435-1443 (2019)). An important and relevant observation is the demonstration that substance P injection stimulates leukocyte infiltration in wild-type and NKR1 (canonical substance P receptor) KO mice, while the response in Mrgprb2-null mice is significantly blunted (Neuron, 101, 412420 (2019)). This observation expands the role of Mrgprb2 / MRGPRX2 as a key receptor mediating substance P-induced inflammatory responses (including pain) (Neuron, 101, 353-355, (2019)). In fact, the substance P / Mrgprb2 sensory cluster was shown to be crucial in driving clinical scores in severe preclinical models of atopic dermatitis (Nature Immunology, 20, 1435-1443 (2019)).

[0005] In addition to various reports using Mrgprb2-deficient mice, further evidence suggests the role of various ligands of MRGPRX2 in human diseases. For example, in addition to the significant increase in the number of mast cells expressing MRGPRX2 in severe chronic urticaria (Clinical and Molecular Allergy 16, 24 (2018)), PACAP nerve fibers were shown to be very close to tryptase-positive mast cells, providing a morphological basis for the increase in mast cell-sensory interactions (J. Allergy Clin. Immunol., 134, 622-633 (2014)). In support of this, urticaria patients showed enhanced wheal responses compared to healthy individuals when intradermally injected with MRGPRX2 agonists (such as substance P) (Allergy, 54, 46-56 (1999)). In addition, PACAP and the antimicrobial peptide LL-37 associated with skin inflammation have both been shown to be upregulated in rosacea (J. Invest. Dermatol., 15, 53-62, (2011)). In fact, mast cell-deficient mice do not develop inflammation / fluidity after injection of LL-37 (J. Inv. Derm., 134, 2728 (2014)), thus inferring a role for Mrgprb2.

[0006] In addition to skin diseases, the involvement of mast cells has also been highlighted in inflammatory bowel disease (IBD) and arthritis (Immunol. Rev., 217, 38-52 (2007); Pharmacology and Therapeutics, 116, 207-235 (2007)), as well as asthma (Respiratory Research, 19, 1 (2018)) and migraine. In patients with rheumatoid arthritis (RA), the number of degranulated mast cells in synovial tissue is increased and correlates with disease activity, as in patients with IBD. In patients with osteoarthritis and rheumatoid arthritis, a positive correlation exists between serum substance P levels and chronic pain intensity (PLOS ONE, 10, e0139206 ((2015)) and a recent article suggests that the SP-MRGPRX2 axis may play a role in the pathogenesis of rheumatoid arthritis, particularly in the regulation of inflammation and pain (Allerg. Intern., 26, S9-S20 (2017)). Finally, there is increasing evidence for a role for PACAP in the pathogenesis of migraine, mediated through mast cell activation (Frontiers in Cellular Neuroscience, 13, 1-11 (2019)).

[0007] In summary, potent and selective antagonists of MRGPRX2 that block IgE-independent mast cell degranulation are expected to provide therapeutic benefit in mast cell-driven pathologies, including skin diseases such as urticaria, atopic dermatitis, and rosacea, as well as other indications such as inflammatory bowel disease, arthritis, and migraine. Summary of the Invention

[0008] The present invention relates to compounds according to formula (I) or pharmaceutically acceptable salts thereof:

[0009]

[0010] in:

[0011] W is N or CH;

[0012] Each X 1 are independently N or CR 10 ;

[0013] Each X 2 are independently N or CR 11 ;

[0014] Y 1 N or CR 12 ;

[0015] Y 2 N or CR 12 ;

[0016] Z is

[0017]

[0018] n is 0 or 1;

[0019] R 1is hydrogen, halogen, (C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-aryl, 5- or 6-membered heteroaryl (C1-C4) Alkyl-, (C3-C8) cycloalkyl, (C2-C6) alkenyl, -(C2-C6) alkenyl-(C3-C8) cycloalkyl, -OH, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C1-C6) alkyl-aryl, -O-(C1-C6) alkyl-5-6 membered heteroaryl, -O-(C2-C6) alkenyl, -O-(C3-C 8) cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2H, -CO2(C1-C6)alkyl, -CO2(C3-C8)cycloalkyl, -O2C(C1-C6)alkyl, -O2C(C3-C8)cycloalkyl, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)((C1-C6)alkyl), aryl or 5-6 membered heteroaryl wherein any of the (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, -(C1-C6)alkyl-aryl, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-5-6-membered heteroaryl, -C(O)-aryl, aryl or 5-6-membered heteroaryl is optionally replaced by R 14 Replace once, twice or thrice;

[0020] R 2 is hydrogen, halogen, (C1-C6)alkyl, or -OH, wherein any of said (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen;

[0021] R 3 is hydrogen, halogen, (C1-C6)alkyl, or -OH, wherein any of said (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen;

[0022] R 4 is hydrogen, halogen or (C1-C6) alkyl;

[0023] R 5 is hydrogen, halogen or (C1-C6) alkyl;

[0024] R 6is hydrogen, halogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C4) alkoxy, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-O-(C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-NH((C1-C6) alkyl)-OH, -(C1-C6) alkyl-NH (((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl)-OH, -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-NH-(C3-C8) cycloalkyl, -(C1-C6) alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-4- to 6-membered heterocycloalkyl, 6) alkyl-NHC(O)-((C1-C6) alkyl), -(C1-C6) alkyl-SO2-(C1-C6) alkyl, -(C1-C6) alkyl-SO2-NH-(C1-C6) alkyl, -CN, -C(O)NH2, -C(O)NH(C1-C6) alkyl), -C(O)N(C1-C6) alkyl)(C1-C6) alkyl), -NH2, -NH(C1-C6) alkyl, -N((C1-C6) alkyl)((C1-C6) alkyl), -SO2((C1-C6) alkyl ), -SO2-NH((C1-C6)alkyl), or aryl, wherein any of said (C1-C6)alkyl, (C3-C8)cycloalkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice, or three times with halogen;

[0025] R 7 is hydrogen, (C1-C6)alkyl, or -OH;

[0026] R 8 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy;

[0027] R 9 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy;

[0028] Each R 10are independently hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), (C2-C6)alkenyl, -O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)((C1-C6)alkyl), -NCH2, or -CHNH;

[0029] or R 1 and any R 10 together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl;

[0030] Each R 11 are independently hydrogen, halogen, (C1-C6)alkyl or (C2-C6)alkenyl;

[0031] or any R 10 and any R 11 together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl;

[0032] R 12 is hydrogen, halogen or (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted once, twice or three times with halogen;

[0033] R 13 is hydrogen, (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl, wherein said (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl is optionally substituted once, twice, or three times with halogen; and

[0034] Each R 14independently halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -CN, -(C1-C6)-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -OH, (C1-C4)alkoxy, -O-(C3-C8)cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl or 5-6 membered heteroaryl is further optionally substituted with one, two or three substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl or (C1-C4)alkoxy.

[0035] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0036] The present invention relates to a method for treating a MrgX2-mediated disease or disorder in a human in need thereof, comprising administering to said human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0037] Another aspect of the present invention relates to a method for treating a MrgX2-mediated disease or disorder in a human in need thereof, wherein the disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic pruritus, drug-induced anaphylactoid reaction, metabolic syndrome, esophageal reflux, asthma, cough, migraine, chronic induced urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudoallergic reaction or contact urticaria, comprising administering to the human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Another aspect of the present invention relates to a method for treating a MrgX2-mediated disease or disorder in a human in need thereof, wherein the disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain, comprising administering to the human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Another aspect of the present invention relates to a method for treating chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic pruritus, drug-induced anaphylactoid reactions, metabolic syndrome, esophageal reflux, asthma, cough, migraine, chronic induced urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudoallergic reactions, or contact urticaria, comprising administering to the human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Another aspect of the present invention relates to a method for treating chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain or inflammatory pain, comprising administering to a human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0038] In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

[0039] In another aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a MrgX2-mediated disease or disorder.

[0040] In another aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in treating a MrgX2-mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic pruritus, drug-induced anaphylactoid reaction, metabolic syndrome, esophageal reflux, asthma, cough, migraine, chronic induced urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudoallergic reaction or contact urticaria. In another aspect, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a MrgX2-mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain or inflammatory pain.

[0041] In another aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic pruritus, drug-induced anaphylactoid reactions, metabolic syndrome, esophageal reflux, asthma, cough, migraine, chronic induced urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudoallergic reactions, or contact urticaria. In another aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.

[0042] In another aspect, there is provided use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a MrgX2-mediated disease or disorder.

[0043] In another aspect, provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a MrgX2-mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain. In another aspect, provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic pruritus, drug-induced anaphylactoid reaction, metabolic syndrome, esophageal reflux, asthma, cough, or migraine. In another aspect, provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain or inflammatory pain. Detailed Description of the Invention

[0045] The present invention relates to a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof. The present invention further relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof

[0046]

[0047] in:

[0048] W is N or CH;

[0049] Each X 1 are independently N or CR 10 ;

[0050] Each X 2 are independently N or CR 11 ;

[0051] Y 1 N or CR 12 ;

[0052] Y 2 N or CR 12 ;

[0053] Z is

[0054]

[0055] n is 0 or 1;

[0056] R 1is hydrogen, halogen, (C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-aryl, 5- or 6-membered heteroaryl (C1-C4) Alkyl-, (C3-C8) cycloalkyl, (C2-C6) alkenyl, -(C2-C6) alkenyl-(C3-C8) cycloalkyl, -OH, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C1-C6) alkyl-aryl, -O-(C1-C6) alkyl-5-6 membered heteroaryl, -O-(C2-C6) alkenyl, -O-(C3-C 8) cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2H, -CO2(C1-C6)alkyl, -CO2(C3-C8)cycloalkyl, -O2C(C1-C6)alkyl, -O2C(C3-C8)cycloalkyl, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)((C1-C6)alkyl), aryl or 5-6 membered heteroaryl wherein any of the (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, -(C1-C6)alkyl-aryl, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-5-6-membered heteroaryl, -C(O)-aryl, aryl or 5-6-membered heteroaryl is optionally replaced by R 14 Replace once, twice or thrice;

[0057] R 2 is hydrogen, halogen, (C1-C6)alkyl, or -OH, wherein any of said (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen;

[0058] R 3 is hydrogen, halogen, (C1-C6)alkyl, or -OH, wherein any of said (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen;

[0059] R 4 is hydrogen, halogen or (C1-C6) alkyl;

[0060] R 5 is hydrogen, halogen or (C1-C6) alkyl;

[0061] R 6is hydrogen, halogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C4) alkoxy, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-O-(C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-NH((C1-C6) alkyl)-OH, -(C1-C6) alkyl-NH (((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl)-OH, -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-NH-(C3-C8) cycloalkyl, -(C1-C6) alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-4- to 6-membered heterocycloalkyl, 6) alkyl-NHC(O)-((C1-C6) alkyl), -(C1-C6) alkyl-SO2-(C1-C6) alkyl, -(C1-C6) alkyl-SO2-NH-(C1-C6) alkyl, -CN, -C(O)NH2, -C(O)NH(C1-C6) alkyl), -C(O)N(C1-C6) alkyl)(C1-C6) alkyl), -NH2, -NH(C1-C6) alkyl, -N((C1-C6) alkyl)((C1-C6) alkyl), -SO2((C1-C6) alkyl ), -SO2-NH((C1-C6)alkyl), or aryl, wherein any of said (C1-C6)alkyl, (C3-C8)cycloalkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice, or three times with halogen;

[0062] R 7 is hydrogen, (C1-C6)alkyl, or -OH;

[0063] R 8 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy;

[0064] R 9 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy;

[0065] Each R 10are independently hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), (C2-C6)alkenyl, -O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)((C1-C6)alkyl), -NCH2, or -CHNH;

[0066] or R 1 and any R 10 together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl;

[0067] Each R 11 are independently hydrogen, halogen, (C1-C6)alkyl or (C2-C6)alkenyl;

[0068] or any R 10 and any R 11 together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl;

[0069] R 12 is hydrogen, halogen or (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted once, twice or three times with halogen;

[0070] R 13 is hydrogen, (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl, wherein said (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl is optionally substituted once, twice, or three times with halogen; and

[0071] Each R 14independently halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -CN, -(C1-C6)-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -OH, (C1-C4)alkoxy, -O-(C3-C8)cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl or 5-6 membered heteroaryl is further optionally substituted with one, two or three substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl or (C1-C4)alkoxy.

[0072] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein W is N. In some embodiments, W is CH.

[0073] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein each X 1 is independently N. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein each X 1 Independently for CR 10 In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein each X 1 Independently for CR 10 , where each R 10 are independently hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, -NCH2, or -CHNH.

[0074] In some embodiments, each X 1 Independently for CR 10 , where each R 10 X is independently hydrogen, halogen, (C1-C6) alkyl or (C2-C6) alkenyl. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein each X 1 Independently for CR 10 , where each R 10 In some embodiments, each X 1 Independently for CR 10 , where each R 10 For hydrogen.

[0075] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein each X 2is independently N. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein each X 2 Independently for CR 11 , where each R 11 In some embodiments, each X 2 Independently for CR 11 , where each R 11 In some embodiments, each X 2 Independently for CR 11 , where each R 11 It is a halogen.

[0076] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Y 1 is N. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Y 1 CR 12 , where R 12 In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Y 1 CR 12 , where R 12 In some embodiments, Y 1 CR 12 , where R 12 is (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted once, twice or three times with halogen. 1 CR 12 , where R 12 is (C1-C6)alkyl, wherein said (C1-C6)alkyl is substituted once with fluorine. 1 CR 12 , where R 12 is (C1-C6)alkyl, wherein said (C1-C6)alkyl is substituted twice with fluorine. 1 CR 12 , where R 12 is (C1-C6)alkyl, wherein said (C1-C6)alkyl is substituted three times with fluorine. 1 It is -CF3.

[0077] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Y 2 is N. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Y 2 CR 12 , where R12 In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Y 2 CR 12 , where R 12 In some embodiments, Y 2 CR 12 , where R 12 is (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted once, twice or three times with halogen.

[0078] In some embodiments, Y 2 CR 12 , where R 12 is (C1-C6)alkyl, wherein said (C1-C6)alkyl is substituted once with fluorine. 2 CR 12 , where R 12 is (C1-C6)alkyl, wherein said (C1-C6)alkyl is substituted twice with fluorine. 2 CR 12 , where R 12 is (C1-C6)alkyl, wherein said (C1-C6)alkyl is substituted three times with fluorine. 2 It is -CF3.

[0079] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Z is

[0080]

[0081] where R 13 is hydrogen, (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl, wherein the (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen. In some embodiments, R 13 is (C1-C6)alkyl, -(C1-C6)alkyl-aryl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, or -(C1-C6)alkyl-5-6-membered heteroaryl. In some embodiments, R 13 is (C1-C6)alkyl, -(C1-C6)alkyl-aryl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, or -(C1-C6)alkyl-5-6-membered heteroaryl, wherein the (C1-C6)alkyl is substituted three times with halogen. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R13 In some embodiments, R 13 is (C1-C6)alkyl substituted once with halogen. 13 is (C1-C6)alkyl substituted twice by halogen. 13 is (C1-C6)alkyl substituted three times by halogen. 13 is (C1-C6)alkyl substituted three times with fluorine. 13 In some embodiments, R 13 In some embodiments, R 13 is -(C1-C6)alkyl-5-6-membered heteroaryl. In some embodiments, R 13 is methyl, ethyl, isopropyl, -CF3, -CH2CF3, benzyl, -CH2CH2SO2CH3, -CH2-pyridine, or -CH2-oxazole. In some embodiments, R 13 is methyl, ethyl, or isopropyl. In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 is -CH2-pyridine or -CH2-oxazole.

[0082] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Z is

[0083] And R 6 is hydrogen, (C1-C6) alkyl, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-NHC(O)-((C1-C6) alkyl), or -C(O)NH2, wherein any of said (C1-C6) alkyl or -(C1-C6) alkyl-OH is optionally substituted once, twice, or three times with halogen. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Z is

[0084] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Z is

[0085] And R 6is hydrogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NHC(O)-((C1-C6)alkyl), or -C(O)NH2, wherein any of said (C1-C6)alkyl or -(C1-C6)alkyl-OH is optionally substituted three times with halogen. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Z is

[0086] And R 6 is hydrogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NHC(O)-((C1-C6)alkyl), or -C(O)NH2, wherein any of said (C1-C6)alkyl or -(C1-C6)alkyl-OH is optionally substituted three times with fluorine. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Z is

[0087] And R 6 Is hydrogen, methyl, -CH2CF3, -CH2OH, -CH(OH)CF3, -C(O)NH2, -CH2NHC(O)CH3. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Z is

[0088] And R 6 In some embodiments, Z is hydrogen, methyl, -CH2CF3, -CH2OH, -CH(OH)CF3, -C(O)NH2, -CH2NHC(O)CH3.

[0089] And R 6 For hydrogen.

[0090] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Z is

[0091] And R 6 is hydrogen, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl, -C(O)NH2, wherein any of said -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice or three times with halogen. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Z is

[0092] And R 6is hydrogen, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl, -C(O)NH2, wherein any of said -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted two or three times with fluorine.

[0093] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Z is

[0094] And R 6 is hydrogen, -CH2NH2, -CH2-azetidine, or -C(O)NH2, wherein

[0095] -CH2-azetidine is substituted twice by fluorine. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein Z is

[0096] And R 6 For hydrogen.

[0097] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein n is 1. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein n is 0.

[0098] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 1 is halogen, (C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-aryl, 5- or 6-membered heteroaryl (C1-C4) alkyl-, (C3-C8) cycloalkyl, (C2-C6) alkenyl, -(C2-C6) alkenyl-(C3-C8) cycloalkyl, -OH, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C1-C6) alkyl-5-6 membered heteroaryl, -O-(C3-C8) Cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2(C3-C8)cycloalkyl, -NH2, aryl or 5-6 membered heteroaryl, wherein any of said (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, -(C1-C6)alkyl-aryl, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-5-6-membered heteroaryl, -C(O)-aryl, aryl or 5-6 membered heteroaryl is optionally replaced by R 14 Replace once, twice or thrice;

[0099] And each R 14independently halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -CN, -(C1-C6)-OH, -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -OH, (C1-C4)alkoxy, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl or 5-6 membered heteroaryl is further optionally substituted with one, two or three substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl or (C1-C4)alkoxy.

[0100] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 1 is halogen, (C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-aryl, 5- or 6-membered heteroaryl (C1-C4) alkyl-, (C3-C8) cycloalkyl, (C2-C6) alkenyl, -(C2-C6) alkenyl-(C3-C8) cycloalkyl, -OH, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C1-C6) alkyl-5-6 membered heteroaryl, -O-(C3-C8) Cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2(C3-C8)cycloalkyl, -NH2, aryl or 5-6 membered heteroaryl, wherein any of said (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, -(C1-C6)alkyl-aryl, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-5-6-membered heteroaryl, -C(O)-aryl, aryl or 5-6 membered heteroaryl is optionally replaced by R 14 Replace once, twice or thrice;

[0101] And each R 14 independently halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -CN, -(C1-C6)-OH, -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -OH, (C1-C4)alkoxy, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl or 5-6 membered heteroaryl is further optionally substituted with one, two or three substituents independently selected from halogen or (C1-C6)alkyl.

[0102] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 1is halogen, (C1-C6) alkyl, -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-aryl, 5- or 6-membered heteroaryl (C1-C4) alkyl-, (C3-C8) cycloalkyl, -(C2-C6) alkenyl-(C3-C8) cycloalkyl, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C1-C6) alkyl-5-6 membered heteroaryl, -O-(C3-C8) cycloalkyl, -O-aryl, -O -heteroaryl, -C(O)-aryl, -CO2(C3-C8)cycloalkyl, aryl or 5-6 membered heteroaryl, wherein any of said (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, -(C1-C6)alkyl-aryl, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-5-6-membered heteroaryl, -C(O)-aryl, aryl or 5-6 membered heteroaryl is optionally replaced by R 14 Replace once, twice or thrice;

[0103] And each R 14 independently halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -CN, -(C1-C6)-OH, -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -OH, (C1-C4)alkoxy, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl or 5-6 membered heteroaryl is further optionally substituted with one, two or three substituents independently selected from halogen or (C1-C6)alkyl.

[0104] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 1is halogen, (C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-phenyl, 5- or 6-membered heteroaryl (C1-C4) alkyl-, (C3-C8) cycloalkyl, (C2-C6) alkenyl, -(C2-C6) alkenyl-(C3-C8) cycloalkyl, -OH, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C1-C6) alkyl-5-6 membered heteroaryl, -O-(C3-C8) cycloalkyl, -O-phenyl, -O-heteroaryl, -C(O)-phenyl, -CO2(C3-C8) cycloalkyl, -NH 2. aryl or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl; wherein any of the (C1-C6) alkyl, -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-phenyl, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C3-C8) cycloalkyl, -O-phenyl, -O-5-6-membered heteroaryl, -C(O)-phenyl, phenyl or 5-6 membered heteroaryl is optionally replaced by R 14 substituted once, twice or three times, wherein the 5-6 membered heteroaryl is furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl.

[0105] And each R 14 independently halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -CN, -(C1-C6)-OH, -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -OH, (C1-C4)alkoxy, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, phenyl or 5-6 membered heteroaryl is further optionally substituted with one, two or three substituents independently selected from halogen or (C1-C6)alkyl.

[0106] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 1 and any R 10Together with the atoms to which they are attached, they form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 1 and any R 10 Together with the atoms to which they are attached, they form furanyl, thienyl, dihydropyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, or phenyl, wherein the ring is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 1 and any R 10 Together with the atoms to which they are attached, they form a dihydropyrrolyl, pyrrolyl, pyrazolyl, oxazolyl, pyridinyl, or phenyl group, wherein the ring is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl.

[0107] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 2 is hydrogen, halogen or (C1-C6) alkyl. 2 In some embodiments, R 2 is hydrogen, fluoro or methyl. 2 is hydrogen or fluorine.

[0108] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 3 is hydrogen, halogen or (C1-C6) alkyl. 3 In some embodiments, R 2 is hydrogen, fluoro or methyl. 3 is hydrogen or fluorine.

[0109] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R2 and R3 are hydrogen. In some embodiments, R2 and R3 are halogen. In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 2 is hydrogen and R 3 In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 2 is (C1-C6) alkyl and R 3 In some embodiments, R2 and R3 are fluorine. In some embodiments, R 2 is hydrogen and R 3 In some embodiments, R 2 is methyl and R 3 For hydrogen.

[0110] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 4 In some embodiments, R 4 is hydrogen or fluorine.

[0111] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 5 In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 5 is hydrogen or fluorine.

[0112] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 4 and R 5 In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 4 and R 5 In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 4 is hydrogen and R 5 In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 4 is a halogen and R 5 In some embodiments, R 4 and R 5 In some embodiments, R 4 is hydrogen and R 5 In some embodiments, R4 is fluorine and R 5 For hydrogen.

[0113] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 6is hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-NH((C1-C6) alkyl)-OH, -(C1-C6) alkyl-NH((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-NH-(C3-C8) cycloalkyl, -(C1-C6) alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-NHC(O)-((C1-C6) alkyl) -C6)alkyl), -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1-C6)alkyl, -CN, -C(O)NH2, -NH2, -SO2((C1-C6)alkyl), -SO2-NH((C1-C6)alkyl) or aryl, wherein any of the (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice or three times with halogen.

[0114] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 6is hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-NH((C1-C6) alkyl)-OH, -(C1-C6) alkyl-NH((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl -NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl, -(C1-C6)alkyl-NHC(O)-((C1-C6)alkyl), -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1-C6)alkyl, -CN, -C(O)NH2, -NH2, -SO2((C1-C6)alkyl), -SO2-NH((C1-C6)alkyl) -(C1-C6)alkyl) or aryl, wherein any of the (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice, or three times with halogen, wherein aryl is phenyl and the 4- to 6-membered heterocycloalkyl is nitrogen heterocyclobutane, oxetanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathiolanyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-oxathiolanyl, or 1,4-dithianyl.

[0115] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 6is hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-NH((C1-C6) alkyl)-OH, -(C1-C6) alkyl-NH((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-NH-(C3-C8) cycloalkyl, -(C1-C6) alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-NHC(O)-((C1-C6) alkyl) -C6)alkyl), -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1-C6)alkyl, -CN, -C(O)NH2, -NH2, -SO2((C1-C6)alkyl), -SO2-NH((C1-C6)alkyl) or aryl, wherein any of the (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice or three times with halogen.

[0116] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 6is hydrogen, (C1-C6) alkyl, cyclopropyl, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-NH((C1-C6) alkyl)-OH, -(C1-C6) alkyl-NH((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-NH-cyclobutyl, -(C1-C6) alkyl-piperidinyl, -(C1-C6) alkyl-morpholinyl, -(C1-C6) alkyl-NHC(O)-((C1-C6) alkyl) -(C1-C6)alkyl), -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1-C6)alkyl, -CN, -C(O)NH2, -NH2, -SO2((C1-C6)alkyl), -SO2-NH((C1-C6)alkyl), or phenyl, wherein any of said (C1-C6)alkyl, cyclopropyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-cyclobutyl, or -(C1-C6)alkyl-piperidinyl is optionally substituted once, twice, or three times with halogen.

[0117] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 7 In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 7 In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 7 In some embodiments, R 7 It is a methyl group.

[0118] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 8 is hydrogen or (C1-C6) alkyl. In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 It is a methyl group.

[0119] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 9 is hydrogen or (C1-C6) alkyl. In some embodiments, R 9 is hydrogen or methyl.

[0120] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 8 is hydrogen and R 9 In some embodiments, R 8 is hydrogen and R 9 In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 8 is (C1-C6) alkyl and R 9 In some embodiments, R 8 is methyl and R 9 In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein R 8 and R 9 In some embodiments, R 8 and R 9 It is a methyl group.

[0121] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein:

[0122] W is N or CH;

[0123] Each X 1 are independently N or CR 10 ;

[0124] Each X 2 are independently N or CR 11 ;

[0125] Y 1 N or CR 12 ;

[0126] Y 2 N or CR 12 ;

[0127] Z is

[0128]

[0129] n is 0 or 1;

[0130] R 1is hydrogen, halogen, (C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-aryl, 5- or 6-membered heteroaryl (C1-C4) Alkyl-, (C3-C8) cycloalkyl, (C2-C6) alkenyl, -(C2-C6) alkenyl-(C3-C8) cycloalkyl, -OH, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C1-C6) alkyl-aryl, -O-(C1-C6) alkyl-5-6 membered heteroaryl, -O-(C2-C6) alkenyl, -O-(C3-C 8) cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2H, -CO2(C1-C6)alkyl, -CO2(C3-C8)cycloalkyl, -O2C(C1-C6)alkyl, -O2C(C3-C8)cycloalkyl, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)((C1-C6)alkyl), aryl or 5-6 membered heteroaryl wherein any of the (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, -(C1-C6)alkyl-aryl, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-5-6-membered heteroaryl, -C(O)-aryl, aryl or 5-6-membered heteroaryl is optionally replaced by R 14 Replace once, twice or thrice;

[0131] R 2 is hydrogen, halogen, (C1-C6)alkyl, or -OH, wherein any of said (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen;

[0132] R 3 is hydrogen, halogen, (C1-C6)alkyl, or -OH, wherein any of said (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen;

[0133] R 4 is hydrogen, halogen or (C1-C6) alkyl;

[0134] R 5 is hydrogen, halogen or (C1-C6) alkyl;

[0135] R 6is hydrogen, halogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C4) alkoxy, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-O-(C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-NH((C1-C6) alkyl)-OH, -(C1-C6) alkyl-NH ((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl)-OH, -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-NH-(C3-C8) cycloalkyl, -(C1-C6) alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl- )alkyl-NHC(O)-((C1-C6)alkyl), -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1-C6)alkyl, -CN, -C(O)NH2, -C(O)NH(C1-C6)alkyl), -C(O)N(C1-C6)alkyl)(C1-C6)alkyl), -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)((C1-C6)alkyl), -SO2((C1-C6)alkyl) , -SO2-NH((C1-C6)alkyl), or aryl, wherein any of said (C1-C6)alkyl, (C3-C8)cycloalkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice, or three times with halogen;

[0136] R 7 is hydrogen, (C1-C6)alkyl, or -OH;

[0137] R 8 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy;

[0138] R 9 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy;

[0139] Each R 10are independently hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), (C2-C6)alkenyl, -O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)((C1-C6)alkyl), -NCH2, or -CHNH;

[0140] or R 1 and any R 10 together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl;

[0141] Each R 11 are independently hydrogen, halogen, (C1-C6)alkyl or (C2-C6)alkenyl;

[0142] R 12 is hydrogen, halogen or (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted once, twice or three times with halogen;

[0143] R 13 is hydrogen, (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl, wherein said (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl is optionally substituted once, twice, or three times with halogen; and

[0144] Each R 14independently halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -CN, -(C1-C6)-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -OH, (C1-C4)alkoxy, -O-(C3-C8)cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl or 5-6 membered heteroaryl is further optionally substituted with one, two or three substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl or (C1-C4)alkoxy.

[0145] In some embodiments, the present invention relates to compounds of formula (I) and (II), wherein:

[0146] W is N or CH;

[0147] Each X 1 are independently N or CR 10 ;

[0148] Each X 2 are independently N or CR 11 ;

[0149] Y 1 N or CR 12 ;

[0150] Y 2 N or CR 12 ;

[0151] Z is

[0152]

[0153] n is 0 or 1;

[0154] R 1is halogen, (C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-aryl, 5- or 6-membered heteroaryl (C1-C4) alkyl-, (C3-C8) cycloalkyl, (C2-C6) alkenyl, -(C2-C6) alkenyl-(C3-C8) cycloalkyl, -OH, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C1-C6) alkyl-5-6 membered heteroaryl, -O-(C3-C8) Cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2(C3-C8)cycloalkyl, -NH2, aryl or 5-6 membered heteroaryl, wherein any of said (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, -(C1-C6)alkyl-aryl, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-5-6-membered heteroaryl, -C(O)-aryl, aryl or 5-6 membered heteroaryl is optionally replaced by R 14 Replace once, twice or thrice;

[0155] R 2 is hydrogen, halogen or (C1-C6)alkyl, wherein any of said (C1-C6)alkyl is optionally substituted once, twice or three times with halogen;

[0156] R 3 is hydrogen, halogen, (C1-C6)alkyl, wherein any of said (C1-C6)alkyl is optionally substituted once, twice or three times with halogen;

[0157] R 4 is hydrogen, halogen or (C1-C6) alkyl;

[0158] R 5 is hydrogen, halogen or (C1-C6) alkyl;

[0159] R 6is hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C4) alkoxy, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-NH((C1-C6) alkyl) -(C1-C6)alkyl)-OH, -(C1-C6)alkyl-NH((C1-C6)alkyl)-O-(C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl, -(C1-C6)alkyl-NHC(O)-((C1-C6)alkyl)- -(C1-C6)alkyl), -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1-C6)alkyl, -CN, -C(O)NH2, -NH2, -SO2((C1-C6)alkyl), -SO2-NH((C1-C6)alkyl), or aryl, wherein any of said (C1-C6)alkyl, (C3-C8)cycloalkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice, or three times with halogen;

[0160] R 7 is hydrogen, (C1-C6)alkyl, or -OH;

[0161] R 8 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy;

[0162] R 9 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy;

[0163] Each R 10 are independently hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, -NCH2, or -CHNH;

[0164] or R 1 and any R 10together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl;

[0165] Each R 11 are independently hydrogen or halogen;

[0166] R 12 is hydrogen or (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted once, twice or three times with halogen;

[0167] R 13 is hydrogen, (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl, wherein the (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen; and

[0168] Each R 14 independently halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -CN, -(C1-C6)-OH, -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -OH, (C1-C4)alkoxy, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl or 5-6 membered heteroaryl is further optionally substituted with one, two or three substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl or (C1-C4)alkoxy.

[0169] The present invention further relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0170]

[0171] in:

[0172] W is N or CH;

[0173] Each X 1 are independently N or CR 10 ;

[0174] X 2 N or CR 11 ;

[0175] Z 1 N or N +-O -

[0176] R 1 is hydrogen, halogen, (C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-aryl, 5- or 6-membered heteroaryl (C1-C4) Alkyl-, (C3-C8) cycloalkyl, (C2-C6) alkenyl, -(C2-C6) alkenyl-(C3-C8) cycloalkyl, -OH, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C1-C6) alkyl-aryl, -O-(C1-C6) alkyl-5-6 membered heteroaryl, -O-(C2-C6) alkenyl, -O-(C3-C 8) cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2H, -CO2(C1-C6)alkyl, -CO2(C3-C8)cycloalkyl, -O2C(C1-C6)alkyl, -O2C(C3-C8)cycloalkyl, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)((C1-C6)alkyl), aryl or 5-6 membered heteroaryl wherein any of the (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, -(C1-C6)alkyl-aryl, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-5-6-membered heteroaryl, -C(O)-aryl, aryl or 5-6-membered heteroaryl is optionally replaced by R 14 Replace once, twice or thrice;

[0177] R 2 is hydrogen, halogen, (C1-C6)alkyl, or -OH, wherein any of said (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen;

[0178] R 3 is hydrogen, halogen, (C1-C6)alkyl, or -OH, wherein any of said (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen;

[0179] R 4 is hydrogen, halogen or (C1-C6) alkyl;

[0180] R 5 is hydrogen, halogen or (C1-C6) alkyl;

[0181] R 6is hydrogen, halogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C4) alkoxy, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-O-(C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-NH((C1-C6) alkyl)-OH, -(C1-C6) alkyl-NH ((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl)-OH, -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-NH-(C3-C8) cycloalkyl, -(C1-C6) alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl- )alkyl-NHC(O)-((C1-C6)alkyl), -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1-C6)alkyl, -CN, -C(O)NH2, -C(O)NH(C1-C6)alkyl), -C(O)N(C1-C6)alkyl)(C1-C6)alkyl), -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)((C1-C6)alkyl), -SO2((C1-C6)alkyl) , -SO2-NH((C1-C6)alkyl), or aryl, wherein any of said (C1-C6)alkyl, (C3-C8)cycloalkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice, or three times with halogen;

[0182] R 7 is hydrogen, (C1-C6)alkyl, or -OH;

[0183] R 8 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy;

[0184] R 9 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy;

[0185] Each R 10are independently hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), (C2-C6)alkenyl, -O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)((C1-C6)alkyl), -NCH2, or -CHNH;

[0186] or R 1 and any R 10 together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl;

[0187] R 11 is hydrogen, halogen, (C1-C6)alkyl or (C2-C6)alkenyl;

[0188] or R 10 and R 11 together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl; and

[0189] Each R 14 independently halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -CN, -(C1-C6)-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -OH, (C1-C4)alkoxy, -O-(C3-C8)cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl or 5-6 membered heteroaryl is further optionally substituted with one, two or three substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl or (C1-C4)alkoxy.

[0190] The present invention further relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof:

[0191]

[0192] in:

[0193] W is N or CH;

[0194] Each X 1 are independently N or CR 10 ;

[0195] X 2 N or CR 11 ;

[0196] R 1 is hydrogen, halogen, (C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-aryl, 5- or 6-membered heteroaryl (C1-C4) Alkyl-, (C3-C8) cycloalkyl, (C2-C6) alkenyl, -(C2-C6) alkenyl-(C3-C8) cycloalkyl, -OH, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C1-C6) alkyl-aryl, -O-(C1-C6) alkyl-5-6 membered heteroaryl, -O-(C2-C6) alkenyl, -O-(C3-C 8) cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2H, -CO2(C1-C6)alkyl, -CO2(C3-C8)cycloalkyl, -O2C(C1-C6)alkyl, -O2C(C3-C8)cycloalkyl, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)((C1-C6)alkyl), aryl or 5-6 membered heteroaryl wherein any of the (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, -(C1-C6)alkyl-aryl, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-5-6-membered heteroaryl, -C(O)-aryl, aryl or 5-6-membered heteroaryl is optionally replaced by R 14 Replace once, twice or thrice;

[0197] R 2 is hydrogen, halogen, (C1-C6)alkyl, or -OH, wherein any of said (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen;

[0198] R 3is hydrogen, halogen, (C1-C6)alkyl, or -OH, wherein any of said (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen;

[0199] R 4 is hydrogen, halogen or (C1-C6) alkyl;

[0200] R 5 is hydrogen, halogen or (C1-C6) alkyl;

[0201] R 6 is hydrogen, halogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C4) alkoxy, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-O-(C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-NH((C1-C6) alkyl)-OH, -(C1-C6) alkyl-NH ((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl)-OH, -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-NH-(C3-C8) cycloalkyl, -(C1-C6) alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl- )alkyl-NHC(O)-((C1-C6)alkyl), -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1-C6)alkyl, -CN, -C(O)NH2, -C(O)NH(C1-C6)alkyl), -C(O)N(C1-C6)alkyl)(C1-C6)alkyl), -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)((C1-C6)alkyl), -SO2((C1-C6)alkyl) , -SO2-NH((C1-C6)alkyl), or aryl, wherein any of said (C1-C6)alkyl, (C3-C8)cycloalkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice, or three times with halogen;

[0202] R7 is hydrogen, (C1-C6)alkyl, or -OH;

[0203] R 8 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy;

[0204] R 9 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy;

[0205] Each R 10 are independently hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), (C2-C6)alkenyl, -O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)((C1-C6)alkyl), -NCH2, or -CHNH;

[0206] or R 1 and any R 10 together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl;

[0207] R 11 is hydrogen, halogen, (C1-C6)alkyl or (C2-C6)alkenyl;

[0208] or R 10 and R 11 together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl;

[0209] R 13 is hydrogen, (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl, wherein said (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl is optionally substituted once, twice, or three times with halogen; and

[0210] Each R 14 independently halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -CN, -(C1-C6)-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -OH, (C1-C4)alkoxy, -O-(C3-C8)cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl or 5-6 membered heteroaryl is further optionally substituted with one, two or three substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl or (C1-C4)alkoxy.

[0211] In some embodiments, the present invention relates to compounds of formula (I) to (V), wherein one X 1 is N and the other is CR 10 , where R 10 As defined above. In some embodiments, the present invention relates to compounds of formula (I) to (V), wherein one X 2 is N and the other is CR 11 , where R 11 As defined above. In some embodiments, the present invention relates to compounds of formula (I) to (V), wherein one X 1 is N and the other is CR 10 , an X 2 is N and the other is CR 11 , where R 10 and R 11 As defined above. For example, in the following formula (I) The group represented by

[0212]

[0213] where R 1 、R 10 and R 11 As defined above, and Indicates the binding site with the adjacent nitrogen atom.

[0214] Specific compounds of the present invention include:

[0215] (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0216] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0217] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0218] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0219] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0220] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-phenoxypyridin-2-yl)propanamide;

[0221] (S)-N-(5-benzylpyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0222] N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0223] (S)-N-(5-(cyclopentyloxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0224] (S)-N-(5-((E)-2-cyclopropylvinyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0225] (S)-N-(6-benzylpyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0226] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyridin-4-ylmethyl)pyridin-2-yl)propanamide;

[0227] (S)-N-(5-cyclopentylpyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0228] (S)-N-(5-cyclopropylpyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0229] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(m-tolyl)pyridin-2-yl)propanamide;

[0230] (S)-N-(2-cyclopropyloxazolo[4,5-b]pyridin-5-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0231] (S)-N-(5-cyclobutylpyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0232] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6-phenoxypyridazin-3-yl)propanamide;

[0233] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6-(o-tolyloxy)pyridazin-3-yl)propanamide;

[0234] N-(5-(2-cyclopropylethyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0235] (S)-N-(5-(benzyloxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0236] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-phenylpyridin-2-yl)propanamide;

[0237] N-(5-(cyclohexyloxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0238] (S)-N-(6-cyclopropylquinolin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0239] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-isopropoxypyridin-2-yl)propanamide;

[0240] N-(5-(cyclohexylmethyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0241] (S)-N-(5-(cyclopropylmethoxy)-3-fluoropyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0242] (S)-N-(5-(cyclopropylmethoxy)pyrazin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0243] N-(5-(cyclobutylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0244] N-(5-(1-cyclopropylethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0245] (S)-N-(6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0246] N-(5-(cyclopentylmethyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0247] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(isoquinolin-3-yl)propanamide;

[0248] (S)-N-(5-(cyclopropylmethoxy)pyrimidin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0249] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl)propanamide;

[0250] 6-((S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propionamido)cyclobutylnicotinate;

[0251] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(oxazol-2-ylmethoxy)pyridin-2-yl)propanamide;

[0252] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(4,5-difluoropyridin-2-yl)propanamide;

[0253] N-(1-(cyclopropylmethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0254] N-(5-(cyclopropylmethyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0255] N-(5-cyclohexylpyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0256] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6-methoxypyridazin-3-yl)propanamide;

[0257] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-methoxypyridin-2-yl)propanamide;

[0258] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyridin-3-ylmethyl)pyridin-2-yl)propanamide;

[0259] 6-((S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propionamido)cyclopentylnicotinate;

[0260] N-(5-(cyclopentylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0261] N-(5-(cyclopropyloxymethyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0262] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,2-difluoroethoxy)pyridin-2-yl)propanamide;

[0263] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(thiophen-2-yl)pyridin-2-yl)propanamide;

[0264] N-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0265] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(thiazol-2-ylmethyl)pyridin-2-yl)propanamide;

[0266] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(oxazol-2-ylmethyl)pyridin-2-yl)propanamide;

[0267] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(quinolin-2-yl)propanamide;

[0268] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)propanamide;

[0269] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(isoxazol-3-yl)pyridin-2-yl)propanamide;

[0270] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyridin-2-ylmethyl)pyridin-2-yl)propanamide hydrochloride;

[0271] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyridin-3-yloxy)pyridin-2-yl)propanamide;

[0272] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-phenoxypyrazin-2-yl)propanamide;

[0273] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyridin-2-yloxy)pyridin-2-yl)propanamide;

[0274] N-(6-(2-cyanophenoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0275] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6-(4-fluorophenoxy)pyridazin-3-yl)propanamide;

[0276] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyridin-4-yloxy)pyridin-2-yl)propanamide;

[0277] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((3-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide;

[0278] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide;

[0279] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((5-fluoropyridin-3-yl)oxy)pyridin-2-yl)propanamide;

[0280] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyrazin-2-yl)propanamide;

[0281] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide;

[0282] (S)-N-(5-cyclopropylpyrazin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0283] (S)-N-(6-(cyclobutylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0284] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((2-oxo-1,2-dihydropyridin-3-yl)oxy)pyridin-2-yl)propanamide;

[0285] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(spiro[3.3]hept-2-yloxy)pyridin-2-yl)propanamide;

[0286] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyrimidin-4-yloxy)pyridin-2-yl)propanamide;

[0287] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0288] (S)-N-(5-(cyclopropylmethoxy)-4-fluoropyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0289] N-(6-cyclopropyl-1,8-naphthyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0290] N-(5-cyclobutyloxypyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0291] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0292] (S)-N-(5-((Z)-2-cyclopropylvinyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0293] (S)-N-(5-chloropyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0294] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-isopropylpyridin-2-yl)propanamide;

[0295] 6-(2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propionamido)cyclopropylnicotinate;

[0296] (S)-N-(5-(cyclobutylmethyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0297] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propanamide;

[0298] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(3-fluoro-5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0299] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)-3-fluoropyridin-2-yl)propanamide;

[0300] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6-(neopentyloxy)pyridazin-3-yl)propanamide;

[0301] N-(5-((3-chloro-5-fluoropyridin-2-yl)oxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0302] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(3-fluoro-5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide;

[0303] N-(5-((3-cyano-5-fluoropyridin-2-yl)oxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0304] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6-(spiro[3.3]hept-2-yloxy)pyridazin-3-yl)propanamide;

[0305] N-(5-bromopyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0306] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((6-methoxypyridin-2-yl)oxy)pyridin-2-yl)propanamide;

[0307] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4,6-trifluorophenoxy)pyridin-2-yl)propanamide;

[0308] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4,5-trifluorophenoxy)pyridin-2-yl)propanamide;

[0309] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2-((dimethylamino)methyl)-4-fluorophenoxy)pyridin-2-yl)propanamide;

[0310] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2-fluoro-4-(2-methylthiazol-4-yl)phenoxy)pyridin-2-yl)propanamide;

[0311] (S)-N-(6-cyclobutyloxypyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0312] (S)-N-(6-(cyclopentyloxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0313] (S)-N-(5-(difluoro(4-fluorophenyl)methyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0314] (S)-2-((R)-4,4-difluoro-3-(5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0315] (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide;

[0316] (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)propanamide;

[0317] (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0318] (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)-4,4-difluoropiperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide;

[0319] (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0320] 4-((S)-1-((S)-1-((6-(cyclopropylmethoxy)pyridazin-3-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0321] 4-(4,4-difluoro-1-(1-oxo-1-((5-phenoxypyridin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0322] 4-((S)-1-((S)-1-((5-(cyclopropylmethoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0323] 4-((S)-1-((S)-1-((5-chloropyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0324] 4-((S)-4,4-difluoro-1-((S)-1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0325] 4-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0326] 4-((S)-4,4-difluoro-1-((S)-(1-((5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0327] 4-((S)-1-((S)-(1-((5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0328] 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0329] 4-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0330] 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(2,4,6-trifluorophenoxy)pyrazin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0331] 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(2,4,5-trifluorophenoxy)pyrazin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0332] 4-((S)-1-((S)-1-((5-(2,6-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0333] 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(2,3,4-trifluorophenoxy)pyrazin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0334] 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(2,4,6-trifluorophenoxy)pyridin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0335] 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(2,4,5-trifluorophenoxy)pyridin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0336] 4-((S)-4,4-difluoro-1-((S)-1-((5-((3-fluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0337] 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(pyridin-2-yloxy)pyridin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0338] 4-((S)-1-((S)-1-((5-(difluoro(4-fluorophenyl)methyl)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0339] 4-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluorobenzoyl)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0340] 4-((3S)-4,4-difluoro-1-(1-((5-((4-fluorophenyl)(hydroxy)methyl)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0341] 4-((S)-1-((S)-1-((5-(2,6-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0342] 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(2,3,4-trifluorophenoxy)pyridin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0343] 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0344] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)propanamide;

[0345] (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)propanamide;

[0346] (S)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0347] (S)-N-(5-chloropyridin-2-yl)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)propanamide;

[0348] (S)-N-(5-cyclopropylpyridin-2-yl)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)propanamide;

[0349] (S)-2-((S)-3-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)propanamide;

[0350] 2-(3-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-phenoxypyridin-2-yl)propanamide;

[0351] (S)-2-((S)-3-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide;

[0352] (S)-2-((S)-3-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide;

[0353] (S)-2-((S)-3-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0354] (S)-2-((R)-3-(5-amino-6-oxo-1,6-dihydropyridazin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0355] (S)-2-((R)-3-(5-amino-6-oxo-1,6-dihydropyridazin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide;

[0356] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)propanamide;

[0357] (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)propanamide;

[0358] (S)-N-(5-cyclopropylpyridin-2-yl)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)propanamide;

[0359] (S)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0360] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0361] (S)-2-((S)-4,4-difluoro-3-(6-oxo-5-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0362] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(5-(2-hydroxypropan-2-yl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0363] (S)-2-((S)-4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0364] (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-(4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0365] N-(5-chloropyridin-2-yl)-2-(4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0366] (S)-2-((S)-(4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0367] (S)-2-((S)-4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide;

[0368] (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0369] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0370] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((3S,4R)-(4-fluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0371] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((3S,4S)-(4-fluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0372] (S)-2-((3S,4R)-4-Fluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0373] (S)-2-((3S,4S)-4-Fluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0374] (S)-N-(5-fluoropyridin-2-yl)-2-((3S,5R)-3-methyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)propanamide;

[0375] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-methyl-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0376] N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-(3,3-difluoro-4-(6-oxo-1,6-dihydropyridin-3-yl)pyrrolidin-1-yl)propanamide;

[0377] 2-(3,3-difluoro-4-(6-oxo-1,6-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0378] (S)-N-(5-chloropyridin-2-yl)-2-((R)-(3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)propanamide;

[0379] (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0380] (S)-2-((S)-3-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide;

[0381] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-3-(6-oxo-4-(trifluoromethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0382] ((S)-2-((S)-3-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide;

[0383] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((R)-3-hydroxy-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0384] (S)-N-(5-chloropyridin-2-yl)-2-((3S,5S)-(3-methyl-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0385] (S)-N-(5-chloropyridin-2-yl)-2-((3R,5S)-(3-methyl-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0386] (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide;

[0387] (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide;

[0388] (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0389] (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0390] (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(6-oxo-5-phenyl-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0391] (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(5-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0392] 4-((S)-1-((S)-1-((5-chloropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0393] 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0394] 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0395] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-2-methylpropanamide;

[0396] (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0397] (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((R)-3-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)propanamide;

[0398] (S)-N-(5-chloropyridin-2-yl)-2-((R)-3-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)propanamide;

[0399] (2S)-2-(3-(5-amino-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0400] (2S)-2-(3-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0401] (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-(3-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide;

[0402] (2S)-2-(4,4-difluoro-3-(1-(2-(methylsulfonyl)ethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0403] (2S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-(4,4-difluoro-3-(1-(2-(methylsulfonyl)ethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0404] 2-(4,4-difluoro-3-(1-(2-(methylsulfonyl)ethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0405] (S)-2-((S)-(3-(1-(2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0406] (2S)-2-(4,4-difluoro-3-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0407] (S)-2-((S)-(3-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0408] 2-(4,4-difluoro-3-(6-oxo-1-(pyridin-2-ylmethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0409] 2-(4,4-difluoro-3-(6-oxo-1-(pyridin-4-ylmethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0410] 2-(4,4-difluoro-3-(1-(oxazol-2-ylmethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0411] (2S)-2-(4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0412] (2S)-2-(4,4-difluoro-3-(5-methyl-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0413] (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0414] 2-(3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-phenoxypyridin-2-yl)propanamide;

[0415] (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide;

[0416] (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0417] (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0418] (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyrazin-2-yl)propanamide;

[0419] (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-phenoxypyrazin-2-yl)propanamide;

[0420] (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide;

[0421] (S)-2-((S)-4,4-difluoro-3-(6-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0422] (S)-2-((S)-4,4-difluoro-3-(6-oxo-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0423] (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0424] (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0425] (2S)-2-(4,4-difluoro-3-(6-oxo-5-(2,2,2-trifluoro-1-hydroxyethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0426] (2S)-2-(4,4-difluoro-3-(6-oxo-5-(2,2,2-trifluoro-1-hydroxyethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0427] 2-(4,4-difluoro-3-(5-((methylsulfonyl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0428] (S)-2-((S)-4,4-difluoro-3-(5-((methylsulfonyl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0429] (S)-2-((S)-4,4-difluoro-3-(5-((methylsulfonyl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyrazin-2-yl)propanamide;

[0430] (S)-2-((S)-4,4-difluoro-3-(5-((methylsulfonyl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0431] 4-(4,4-difluoro-1-((S)-1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-methylpyridine 1-oxide;

[0432] 4-((R)-4,4-difluoro-1-((R)-1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-methylpyridine 1-oxide;

[0433] 4-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-methylpyridine 1-oxide;

[0434] 4-((S)-4,4-difluoro-1-((S)-1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-(2,2,2-trifluoroethyl)pyridine 1-oxide;

[0435] 4-((S)-1-((S)-1-((6-(cyclopropylmethoxy)pyridazin-3-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-(2,2,2-trifluoroethyl)pyridine 1-oxide;

[0436] (2S)-2-(3-(5-bromo-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide;

[0437] (2S)-2-(3-(5-(1-aminoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide;

[0438] (2S)-2-(3-(5-cyano-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide;

[0439] (2S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-(4,4-difluoro-3-(pyridin-4-yl)piperidin-1-yl)propanamide;

[0440] (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0441] 2-(4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0442] (S)-2-((S)-4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0443] (S)-2-((S)-4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide;

[0444] (S)-2-((S)-4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propanamide;

[0445] 2-(3-(5-((dimethylamino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0446] (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-3-(5-((dimethylamino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide;

[0447] (2S)-2-(3-(5-(1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0448] (S)-2-((S)-3-(5-((S)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0449] (S)-2-((S)-3-(5-((R)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0450] (S)-2-((S)-3-(5-((S)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0451] (S)-2-((S)-3-(5-((R)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0452] 2-(4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0453] 2-(4,4-difluoro-3-(5-(((2-hydroxyethyl)amino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0454] 2-(4,4-difluoro-3-(5-(((2-methoxyethyl)amino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0455] (S)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-((S)-3-(5-((4,4-difluoropiperidin-1-yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide;

[0456] (S)-2-((S)-3-(5-(((3,3-difluorocyclobutyl)amino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0457] (S)-2-((S)-4,4-difluoro-3-(6-oxo-5-(((2,2,2-trifluoroethyl)amino)methyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0458] (S)-2-((S)-4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0459] S)-2-((S)-4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propanamide;

[0460] (S)-2-((S)-3-(5-(acetylaminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0461] (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-(5-(methylsulfonyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide

[0462] (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-3-(5-(methylsulfonyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0463] (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-(5-(N-methylsulfamoyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0464] (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-3-(5-(N-methylsulfamoyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide;

[0465] (S)-2-((S)-3,3-difluoro-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0466] (R)-2-((R)-3,3-difluoro-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0467] 2-(3-(5-cyano-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide;

[0468] 2-(3-(5-cyano-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyrazin-2-yl)propanamide;

[0469] (S)-2-((S)-3-(5-cyano-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0470] 5-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

[0471] 5-(4,4-difluoro-1-(1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

[0472] 4-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide;

[0473] 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide;

[0474] 4-(4,4-difluoro-1-(1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine 1-oxide;

[0475] 4-(4,4-difluoro-1-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine 1-oxide;

[0476] 2-Carbamoyl-4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0477] 2-Carbamoyl-4-((S)-4,4-difluoro-1-((S)-1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0478] 2-Carbamoyl-4-(1-(1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0479] 4-(1-((S)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine-2-carboxamide;

[0480] 2-(Acetylaminomethyl)-4-(1-(1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0481] 2-(Acetylaminomethyl)-4-(4,4-difluoro-1-(1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0482] 2-(3-(2-(aminomethyl)pyridin-4-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0483] (2S)-2-(4,4-difluoro-3-(5-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0484] 3-(1-(1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine 1-oxide;

[0485] 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((6-oxo-1,6-dihydropyridin-2-yl)oxy)pyridin-2-yl)propanamide;

[0486] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(3,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0487] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluoro-2-methoxyphenoxy)pyridin-2-yl)propanamide;

[0488] (2S)-2-(3-(2-((3,3-difluoroazetidin-1-yl)methyl)pyridin-4-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0489] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluoro-2-(hydroxymethyl)phenoxy)pyridin-2-yl)propanamide;

[0490] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluoro-2-(hydroxymethyl)phenoxy)pyrazin-2-yl)propanamide;

[0491] 4-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluoro-2-(hydroxymethyl)phenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0492] 4-((3S)-4,4-difluoro-1-(1-((5-(4-fluoro-2-(hydroxymethyl)phenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide;

[0493] (R)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide;

[0494] (R)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide;

[0495] (R)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)-N-(5-fluoropyridin-2-yl)propanamide;

[0496] 2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide;

[0497] (R)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide;

[0498] (R)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide;

[0499] (R)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)-N-(5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide;

[0500] (R)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-((1S,3R)-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide;

[0501] (R)-N-(5((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)-2-((1S,3R)-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide;

[0502] N-(5-(4-fluorophenoxy)pyrazin-2-yl)-2-((3R)-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide;

[0503] (R)-N-(5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)-2-((1S,3R)-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide;

[0504] (R)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-((1S,3R)-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide;

[0505] 4-((1R,3S)-3-((R)-1-((5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)cyclohexyl)pyridine 1-oxide;

[0506] 4-((1R,3S)-3-((R)-1-((5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)cyclohexyl)pyridine 1-oxide;

[0507] 4-((1R,3S)-3-((R)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)cyclohexyl)pyridine 1-oxide;

[0508] 4-((1R,3S)-3-((S)-1-((5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)cyclohexyl)pyridine 1-oxide;

[0509] 4-((1R,5S)-5-((R)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-difluorocyclohexyl)pyridine 1-oxide;

[0510] 4-((1R,5S)-2,2-difluoro-5-((R)-1-((5-(4-fluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)cyclohexyl)pyridine 1-oxide;

[0511] 4-((1R,5S)-5-((R)-1-((5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-difluorocyclohexyl)pyridine 1-oxide;

[0512] 4-((1R,5S)-2,2-difluoro-5-((R)-1-((5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)cyclohexyl)pyridine 1-oxide; and

[0513] 4-((1R,5S)-5-((R)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-2,2-difluorocyclohexyl)pyridine 1-oxide;

[0514] or a pharmaceutically acceptable salt thereof.

[0515] In one embodiment, the compound of the invention is:

[0516] (R)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)acrylamide;

[0517] (S)-2-((S)-4,4-difluoro-3-(pyridin-4-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propanamide;

[0518] 4-((S)-1-((S)-1-((5-(2,4-difluoro-6-(hydroxymethyl)phenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0519] 4-((S)-1-((S)-1-((5-(2,4-difluoro-6-(hydroxymethyl)phenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide;

[0520] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluoro-6-(hydroxymethyl)phenoxy)pyrazin-2-yl)propanamide;

[0521] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluoro-6-(hydroxymethyl)phenoxy)pyridin-2-yl)propanamide;

[0522] or a pharmaceutically acceptable salt thereof.

[0523] In one embodiment, the compound of the invention is 4-((1R,5S)-5-((R)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-difluorocyclohexyl)pyridine 1-oxide or a pharmaceutically acceptable salt thereof.

[0524] In one embodiment, the compound of the invention is 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide.

[0525] In one embodiment, the compound of the invention is 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide or a pharmaceutically acceptable salt thereof.

[0526] It should be understood that this document relates to compounds of formula (I)-(IV) or pharmaceutically acceptable salts thereof. Thus, in one embodiment, the present invention relates to compounds of formula (I)-(IV). In another embodiment, the present invention relates to pharmaceutically acceptable salts of compounds of formula (I)-(IV). In another embodiment, the present invention relates to compounds of formula (I)-(IV) or pharmaceutically acceptable salts thereof.

[0527] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I)-(IV) (e.g., 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0528] Another aspect of the present invention relates to a method for treating a MrgX2-mediated disease or disorder in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound of Formula (I)-(IV) (e.g., 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0529] Another aspect of the present invention relates to a method for treating an MrgX2-mediated disease in a human in need thereof, wherein the disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic pruritus, drug-induced anaphylactoid reaction, metabolic syndrome, esophageal reflux, asthma, cough or migraine, chronic induced urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudoallergic reaction or contact urticaria. Another aspect of the present invention relates to a method for treating a MrgX2-mediated disease or disorder in a human in need thereof, wherein the disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic pruritus, drug-induced anaphylactoid reaction, metabolic syndrome, esophageal reflux, asthma, cough, or migraine. Another aspect of the present invention relates to a method for treating a MrgX2-mediated disease or disorder in a human in need thereof, wherein the disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.

[0530] Another aspect of the present invention relates to a method for treating chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic pruritus, drug-induced anaphylactoid reaction, metabolic syndrome, esophageal reflux, asthma, cough, or migraine. Another aspect of the present invention relates to a method for treating chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.

[0531] In another aspect, the present invention provides a compound of formula (I)-(IV) (e.g., 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide), or a pharmaceutically acceptable salt thereof, for use in therapy. In another aspect, a compound of formula (I)-(IV) (e.g., 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide), or a pharmaceutically acceptable salt thereof, for use in treating a MrgX2-mediated disease or disorder is provided. In another aspect, a compound of Formula (I)-(IV) (e.g., 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide) or a pharmaceutically acceptable salt thereof is provided for use in treating a MrgX2-mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic pruritus, drug-induced anaphylactoid reaction, metabolic syndrome, esophageal reflux, asthma, cough, or migraine. In another aspect, provided are compounds of formula (I)-(IV) (e.g., 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide) or pharmaceutically acceptable salts thereof for use in treating a MrgX2-mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain. In another aspect, provided are compounds of formula (I)-(IV) (e.g., 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide) or pharmaceutically acceptable salts thereof for use in treating chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic pruritus, drug-induced anaphylactoid reactions, metabolic syndrome, esophageal reflux, asthma, cough, or migraine.In another aspect, provided are compounds of formula (I)-(IV) (e.g., 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide) or pharmaceutically acceptable salts thereof for use in treating chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.

[0532] In another aspect, provided is a use of a compound of formula (I)-(IV) (e.g., 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a MrgX2-mediated disease or disorder. In another aspect, provided is a use of a compound of formula (I)-(IV) (e.g., 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a MrgX2-mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, mast cell In another aspect, compounds of formula (I)-(IV) are provided (e.g., 4-((S)-1-((S)-1-((5- Use of (2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a MrgX2-mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain or inflammatory pain.

[0533] In another aspect, provided is the use of a compound of formula (I)-(IV) (e.g., 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic pruritus, drug-induced anaphylactoid reaction, metabolic syndrome, esophageal reflux, asthma, cough, or migraine. In another aspect, provided is the use of a compound of formula (I)-(IV) (e.g., 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.

[0534] Because of their potential use in medicine, it will be appreciated that the salts of the compounds of formula (I)-(IV) are desirably pharmaceutically acceptable.

[0535] Pharmaceutically acceptable salts include those described in Berge, J. Pharm. Sci., 66, 1-19, (1977) or those listed in PHStahl and CGWermuth, eds., Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley-VCH / VHCA (2011) (see http: / / www.wiley.com / WileyCDA / WileyTitle / productCd-3906390519.html).

[0536] Suitable pharmaceutically acceptable salts may include acid or base addition salts.

[0537] Such base addition salts can be formed by reacting a compound of formula (I)-(IV) (e.g., containing 1H-tetrazole or other acidic functional groups) with a suitable base, optionally in a suitable solvent such as an organic solvent, to provide a salt which can be isolated by various methods including crystallization and filtration.

[0538] Such acid addition salts can be formed by reacting a compound of formula (I)-(IV) (e.g., containing a basic amine or other basic functional group) with a suitable acid, optionally in a suitable solvent such as an organic solvent, to provide a salt which can be isolated by various methods including crystallization and filtration.

[0539] Salts can be prepared in situ during the final separation and purification of compounds of formula (I)-(IV). If a basic compound of formula (I)-(IV) is isolated as a salt, the corresponding free base form of the compound can be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic base. Similarly, if a compound of formula (I)-(IV) containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of the compound can be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic acid.

[0540] It will be appreciated that if the compound of formula (I)-(IV) contains two or more basic moieties, the stoichiometry of the salt may include 1, 2 or more equivalents of acid. Such salts will contain 1, 2 or more acid counterions, for example, dihydrochloride.

[0541] Stoichiometric and non-stoichiometric forms of the pharmaceutically acceptable salts of the compounds of Formula (I)-(IV) are included within the scope of the present invention, including substoichiometric salts, for example, salts wherein the counterion contains more than one acidic proton.

[0542] Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camsylate, caprate, caproate, caprylate, cinnamate, citrate, cyclamates, digluconates, 2,5-dihydroxybenzoate, Disuccinate, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), esylate, formate, fumarate, galactonate (mucate), gentisate (2,5-dihydroxybenzoate), gluceptate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hexylresorcinate, hippurate , hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthalene-1,5-disulfonate (naphthalene disulfonate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicylic acid salt, pamoate (pamoate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, tosylate, pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoelate (8-chlorotheophylline), thiocyanate, triethiodide, undecanoate, undecenoate, and valerate.

[0543] Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS), arginine, phenethamine (N-benzylphenethylamine), benzathine (N,N'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, tert-butylamine, tromethamine (tris(hydroxymethyl)aminomethane), and zinc.

[0544] In one aspect of the present invention, there is provided the hydrochloride salt of 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide.

[0545] The compound of formula (I)-(IV) or its salt can exist in stereoisomeric form (for example, it contains one or more asymmetric carbon atoms).Single stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the present invention.Similarly, it should be understood that the compound of formula (I)-(IV) or salt can exist in the form of tautomers different from those shown in the formula, and these are also included within the scope of the present invention.It should be understood that the present invention includes all combinations and subsets of the specific groups defined above.The scope of the present invention includes mixtures of stereoisomers and purified enantiomers or mixtures enriched in enantiomers / diastereomers.

[0546] The present invention also includes isotopically labeled compounds, which are identical to the compounds shown in Formulas (I)-(IV) and their annexes, except that one or more atoms are replaced by an atom having an atomic mass or atomic number different from that usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 31 P. 32 P. 35 S.18 F. 36 Cl, 123 I and 125 I.

[0547] Compounds of the invention and pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Isotopically labeled compounds of the invention, for example, those into which a radioactive isotope such as 3 H, 14 C are used in drug and / or substrate tissue distribution assays. 3 H and carbon-14 14 C isotopes are particularly preferred due to their ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography). 125 I isotopes are particularly useful in SPECT (single photon emission computed tomography), all of which are used in brain imaging. 2 H substitution may provide some therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and is therefore preferred in some circumstances. Isotopically labeled compounds of formula (I)-(IV) of the present invention and subsequent compounds thereof can generally be prepared by carrying out the procedures described in the following schemes and / or examples, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0548] The present invention further provides a pharmaceutical composition (also referred to as a pharmaceutical formulation) comprising a compound of Formula (I)-(IV) or a pharmaceutically acceptable salt thereof and one or more excipients (also referred to as carriers and / or diluents in the pharmaceutical art). The excipient is acceptable in the sense that it is compatible with the other ingredients of the formulation and is not harmful to the recipient thereof (i.e., the patient).

[0549] Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected. In addition, suitable pharmaceutically acceptable excipients can be selected for the specific function they perform in the composition. For example, some pharmaceutically acceptable excipients are selected because they have the ability to promote the production of uniform dosage forms. Some pharmaceutically acceptable excipients are selected because they have the ability to promote the production of stable dosage forms. Some pharmaceutically acceptable excipients are selected because they have the ability to promote the compounds of the present invention to be carried or transported from one organ or part of the body to another organ or part of the body after administration to the patient. Some pharmaceutically acceptable excipients are selected because they have the ability to enhance patient compliance.

[0550] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavorings, taste masking agents, coloring agents, anti-caking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. Those skilled in the art will recognize that certain pharmaceutically acceptable excipients may serve more than one role and may serve other functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

[0551] The skilled person has the knowledge and skill in the art so that he or she can select suitable pharmaceutically acceptable excipients and use them in appropriate amounts for the present invention. In addition, there are many resources readily available to the skilled person that describe pharmaceutically acceptable excipients and can be used to select suitable pharmaceutically acceptable excipients. Examples include: Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0552] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0553] The pharmaceutical composition may be in the form of a unit dosage containing a predetermined amount of active ingredient per unit dose. Such unit dosage forms may contain a therapeutically effective dose of a compound of Formula (I)-(IV) or a salt thereof, or a portion thereof, such that the unit dosage form can be administered multiple times at a given time to achieve the desired therapeutically effective amount. Preferred unit dosage formulations are those containing a daily dose or subdose of the active ingredient as described above, or a suitable portion thereof. In addition, such pharmaceutical compositions may be prepared by any method known in the pharmaceutical art.

[0554] The pharmaceutical composition can be suitable for administration by any appropriate route, for example, oral (including buccal or sublingual), rectal, intranasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. Such compositions can be prepared by any method known in the pharmaceutical art, for example, by combining the active ingredient with an excipient.

[0555] When the pharmaceutical composition is suitable for oral administration, it can be a discrete unit such as a tablet or capsule; a powder or granules; a solution or suspension in an aqueous or non-aqueous liquid; an edible foam or whip; an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The compound of formula (I)-(IV) or a salt thereof or the pharmaceutical composition of the present invention can also be incorporated into candies, wafers and / or tongue tapes for administration as a "fast dissolve" drug.

[0556] For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water, etc.). Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly ground pharmaceutical carrier (e.g., an edible carbohydrate such as starch or mannitol). Flavoring agents, preservatives, dispersants, and coloring agents may also be present.

[0557] Capsules are prepared by preparing the powder mixture described above and filling it into a shaped gelatin or non-gelatin sheath. Before the filling operation, glidants and lubricants, such as colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol, may be added to the powder mixture. Disintegrants or solubilizers, such as agar, calcium carbonate, or sodium carbonate, may also be added to improve the availability of the drug when the capsule is ingested.

[0558] In addition, when needed or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be mixed in the mixture. Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth), sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax etc. The lubricant used in these dosage forms includes sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc. Disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum etc.

[0559] Tablets are prepared, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. The powder mixture is prepared by mixing a suitably ground compound of formula (I)-(IV) or a salt thereof with the following substances: a diluent or base as described above, and optionally a binder, such as carboxymethyl cellulose and alginate, gelatin, or polyvinyl pyrrolidone; a solution retardant such as paraffin; an absorption accelerator such as a quaternary salt; and / or an absorbent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting a binder such as syrup, starch paste, gum arabic, or a solution of a cellulose or polymeric material and passing it through a screen. As an alternative to granulation, the powder mixture can be run on a tablet press to produce incompletely formed pellets that are broken into granules. The granules can be lubricated to prevent adhesion to the tablet forming die by adding stearic acid, a stearate, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compound or salt of the invention can also be mixed with a particulate inert carrier and compressed directly into tablets without undergoing a granulation or pre-compression step. A clear, opaque protective coating consisting of a barrier layer of shellac, a coating of sugar or polymeric material, and a polishing coating of wax can be provided. Dyes can be added to these coatings to distinguish different dosages.

[0560] Oral liquids, such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given amount contains a predetermined amount of active ingredient. Syrups can be prepared as follows, and the compound of formula (I)-(IV) or its salt is dissolved in an aqueous solution of suitable seasoning, and elixirs are prepared using non-toxic alcohol vehicles. Suspensions can be prepared as follows, and the compound of the present invention or salt are dispersed in a non-toxic vehicle. Solubilizers and emulsifiers (such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavoring additives (such as peppermint oil), natural sweeteners, saccharin or other artificial sweeteners, etc. can also be added.

[0561] It should be understood that in addition to the ingredients particularly mentioned above, the pharmaceutical compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0562] When necessary, the pharmaceutical composition in dosage units for oral administration can be encapsulated in microcapsules. The preparation can also be prepared, for example, by coating or embedding particulate matter in polymers, waxes, etc. to achieve prolonged or sustained release.

[0563] Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or enemas.

[0564] Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

[0565] Pharmaceutical preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Pharmaceutical compositions may be present in unit dose or multi-dose containers (e.g., sealed ampoules and vials) and may be stored in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier (e.g., water) for injection immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.

[0566] According to another aspect of the present invention, there is provided a method for preparing a pharmaceutical composition, comprising mixing (or blending) a compound of formula (I)-(IV) or a salt thereof with at least one excipient.

[0567] The present invention also provides a method of treating mammals, particularly humans.

[0568] The pharmaceutical composition may be in the form of a unit dose containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of formula (I)-(IV), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient, or the pharmaceutical composition may be in the form of a unit dose containing a predetermined amount of active ingredient per unit dose. Preferred unit dose compositions are compositions containing a daily dose or subdose of the active ingredient, or an appropriate portion thereof, as described above. In addition, such pharmaceutical compositions may be prepared by any method known in the pharmaceutical art.

[0569] definition

[0570] The terms are used with their generally accepted meanings. The following definitions are intended to clarify, not to limit, the defined terms.

[0571] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched hydrocarbon moiety having a specified number of carbon atoms. The term "(C1-C6)alkyl" refers to an alkyl moiety containing from 1 to 6 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0572] "Alkoxy" refers to a group containing an alkyl group as defined above attached through an oxygen linking atom. The term "(C1-C4)alkoxy" refers to a straight or branched chain hydrocarbon group having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary "(C1-C4)alkoxy" groups useful in the present invention include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy.

[0573] When the term "alkyl" is used in combination with other substituents, such as "halo(C1-C4)alkyl," "aryl(C1-C4)alkyl-," or "(C1-C4)alkoxy(C1-C4)alkyl-," the term "alkyl" is intended to encompass divalent straight or branched hydrocarbon groups in which the point of attachment is through the alkyl portion. The term "halo(C1-C4)alkyl" is intended to represent a group having one or more halogen atoms, which may be the same or different, on one or more carbon atoms of an alkyl portion containing from 1 to 4 carbon atoms, which is a straight or branched carbon group. Examples of "halo(C1-C4)alkyl" groups for use in the present invention include, but are not limited to, -CF3 (trifluoromethyl), -CCl3 (trichloromethyl), 1,1-difluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl. Examples of "aryl(C1-C4)alkyl" or "phenyl(C1-C4)alkyl" groups used in the present invention include, but are not limited to, benzyl and phenethyl. Examples of "(C1-C4)alkoxy(C1-C4)alkyl-" groups used in the present invention include, but are not limited to, methoxymethyl, methoxyethyl, methoxyisopropyl, ethoxymethyl, ethoxyethyl, ethoxyisopropyl, isopropoxymethyl, isopropoxyethyl, isopropoxyisopropyl, tert-butoxymethyl, tert-butoxyethyl, and tert-butoxyisopropyl.

[0574] As used herein, the term "cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing a specified number of carbon atoms. The term "(C3-C8)cycloalkyl" refers to a non-aromatic, cyclic hydrocarbon ring containing 3 to 8 carbon atoms. Exemplary "(C3-C8)cycloalkyl" groups for use in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0575] As used herein, "4- to 6-membered heterocycloalkyl" represents a group or moiety comprising a non-aromatic monovalent monocyclic radical, which is saturated or partially unsaturated, containing 4, 5 or 6 ring atoms including one or two heteroatoms independently selected from oxygen, sulfur and nitrogen. Illustrative examples of 4- to 6-membered heterocycloalkyl groups useful in the present invention include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, 1,4-oxathianyl, 1,4-dithianyl, and 1,4-dithianyl.

[0576] "Aryl" refers to an optionally substituted monocyclic, fused bicyclic, or fused tricyclic group having 6 to 14 carbon atoms and having at least one aromatic ring that conforms to Hückel's rule. Examples of "aryl" are phenyl, naphthyl, indenyl, dihydroindenyl, anthracenyl, phenanthrenyl, and the like.

[0577] "Heteroaryl" refers to a group or moiety comprising an aromatic monovalent monocyclic or bicyclic group containing from 5 to 10 ring atoms, including from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term also includes bicyclic heterocyclic-aryl compounds containing an aryl ring portion fused to a heterocycloalkyl ring portion, containing from 5 to 10 ring atoms, including from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups useful in the present invention include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothiophenyl, indolizinyl, indolyl, isoindolyl, di ... Examples of 5-membered "heteroaryl" groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, and isothiazolyl. Examples of 6-membered "heteroaryl" groups include oxo-pyridyl, pyridyl, pyridazinyl, pyrazinyl, and pyrimidinyl. Examples of 6,6-fused "heteroaryl" groups include quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl. Examples of 6,5-fused "heteroaryl" groups include benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, indolizinyl, indolyl, isoindolyl, and indazolyl.

[0578] The "5 or 6 yuan heteroaryl" used in this application refers to a group or part comprising an aromatic, monovalent monocyclic group containing 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The selected 5 yuan heteroaryl group contains a nitrogen, oxygen or sulfur ring heteroatom and optionally contains 1, 2 or 3 additional nitrogen ring atoms. The selected 6 yuan heteroaryl group contains 1, 2 or 3 nitrogen ring heteroatoms. Illustrative examples of 5 or 6 yuan heteroaryl groups of the present invention include but are not limited to furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl and triazinyl.

[0579] The terms "halogen" and "halo" refer to fluoro, chloro, bromo, or iodo substituents. "Hydroxy" refers to the group -OH.

[0580] As used herein, the term "optionally" means that the subsequently described event or events may or may not occur, and includes both the event or events that occur and the event or events that do not occur.

[0581] "Pharmaceutically acceptable" refers to those compounds (including salts), materials, compositions and dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0582] As used herein, the term "treating" refers to alleviating a particular condition, eliminating or alleviating one or more symptoms of the condition, slowing or eliminating the progression of the condition, and delaying the recurrence of the condition in a previously afflicted or diagnosed patient or subject.

[0583] As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that elicits the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.

[0584] The term "therapeutically effective amount" means any amount that improves the treatment, cure, or relief of a disease, disorder, or side effect, or reduces the rate of progression of a disease or disorder, as compared to a corresponding subject not receiving the amount. The term also includes within its scope amounts that effectively enhance normal physiological function. When used in therapy, a therapeutically effective amount of a compound of formula (I)-(IV) and a salt thereof can be administered as a raw chemical. In addition, the active ingredient can be present as a pharmaceutical composition.

[0585] Compound preparation

[0586] abbreviation

[0587] Ag2CO3 silver carbonate

[0588] AIBN Azobisisobutyronitrile

[0589] aq water-based

[0590] BH3·THF Borane tetrahydrofuran complex

[0591] BnBr benzyl bromide

[0592] BOC or t-BOC or Boc tert-butoxycarbonyl

[0593] BOC-anhydride or Boc-anhydride di-tert-butyl dicarbonate

[0594] CBZ-Cl or Cbz-Cl Benzyl chloroformate

[0595] C18 column octadecylsilane column

[0596] CDCl3 or chloroform-d deuterated chloroform

[0597] CD3OD or methanol-d4 deuterated methanol

[0598] CHCl3 chloroform

[0599] CH2Cl2 dichloromethane

[0600] (C6H 11 )3P Tricyclohexylphosphine

[0601] CPME Cyclopentyl Methyl Ether

[0602] Cs2CO3 cesium carbonate

[0603] CsF cesium fluoride

[0604] CuI Copper(I) iodide

[0605] CyJohnPhos (2-Biphenyl)dicyclohexylphosphine

[0606] DAST Diethylaminosulfur trifluoride

[0607] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0608] DCC N,N′-dicyclohexylcarbodiimide

[0609] DCM dichloromethane

[0610] DIAD Diisopropyl azodicarboxylate

[0611] DIBAL-H or DIBAL diisobutylaluminum hydride

[0612] Dichloromethane-d2 deuterated dichloromethane

[0613] DMA dimethylacetamide

[0614] DME dimethoxyethane

[0615] DMF N,N-dimethylformamide

[0616] DIPEA or DIEA N,N-diisopropylethylamine

[0617] DMAP 4-dimethylaminopyridine

[0618] DMSO dimethyl sulfoxide

[0619] DMSO-d6 hexadeuterated dimethyl sulfoxide

[0620] dppf 1,1'-bis(diphenylphosphino)ferrocene

[0621] eq equivalent

[0622] EtOAc

[0623] ES electrospray mass spectrometry

[0624] Et3N triethylamine

[0625] EtOH

[0626] Et2O or ether

[0627] FA Formic acid

[0628] Fe

[0629] h or hr hours

[0630] hex hexane

[0631] H2 Hydrogen

[0632] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo

[0633] [4,5-b]pyridinium 3-oxide hexafluorophosphate

[0634] HBF4PCy3 tricyclohexylphosphonium tetrafluoroborate

[0635] HBr hydrobromic acid

[0636] HCl

[0637] H2NBoc tert-butyl carbamate

[0638] 1H NMR proton nuclear magnetic resonance

[0639] H2O water

[0640] HOAc acetic acid

[0641] HPLC high-performance liquid chromatography

[0642] IPA Isopropyl alcohol

[0643] K2CO3 potassium carbonate

[0644] KHCO3 potassium bicarbonate

[0645] KI Potassium iodide

[0646] K3PO4 potassium phosphate

[0647] LCMS or LC / MS liquid chromatography-mass spectrometry

[0648] LDA lithium diisopropylamide

[0649] LHMDS Lithium Hexamethyldisilazide

[0650] LiAlH4 lithium aluminum hydride

[0651] LiBH4 lithium borohydride

[0652] LiCl lithium chloride

[0653] LiF lithium fluoride

[0654] LiOH lithium hydroxide

[0655] m-CPBA m-Chloroperbenzoic acid

[0656] MDAP quality control automated purification

[0657] MeCN or CH3CN

[0658] or ACN or AcCN acetonitrile

[0659] MeI or CH3I iodomethane

[0660] MeOH methanol

[0661] 2-Me-THF 2-Methyltetrahydrofuran

[0662] MgSO4 magnesium sulfate

[0663] min

[0664] MS

[0665] MTBE methyl tert-butyl ether

[0666] m / z mass-to-charge ratio

[0667] N2 nitrogen

[0668] Na Sodium

[0669] NaBH4 sodium borohydride

[0670] NaBO3 sodium perborate

[0671] Na2CO3 sodium carbonate

[0672] NaH sodium hydride

[0673] NaHCO3 sodium bicarbonate

[0674] NaHSO3 sodium bisulfite

[0675] NaI sodium iodide

[0676] NaN3 sodium azide

[0677] NaOAc or AcONa sodium acetate

[0678] NaOH sodium hydroxide

[0679] NaOMe sodium methoxide

[0680] Na2S2O3 sodium thiosulfate

[0681] Na2SO4 sodium sulfate

[0682] NBS N-bromosuccinimide

[0683] n-BuLi n-butyllithium

[0684] N2H4 hydrazine

[0685] NH3 ammonia

[0686] NH4Cl ammonium chloride

[0687] NH4HCO3 ammonium bicarbonate

[0688] NH4OH ammonium hydroxide

[0689] NH2OH-HCl

[0690] or H2NOH-HCl Hydroxylamine hydrochloride

[0691] NiBr2 Nickel(II) Bromide

[0692] NiCl2(dme) Nickel(II) chloride ethylene glycol dimethyl ether complex

[0693] Oxone potassium peroxymonosulfate

[0694] Pd / C or Pd-C Palladium Carbon

[0695] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0696] Pd2(dba)3CHCl3 tris(dibenzylideneacetone)dipalladium(0)chloroform adduct

[0697] Pd2(dba)3CH2Cl2 tris(dibenzylideneacetone)dipalladium(0)-dichloromethane adduct

[0698] Pd(dppf)Cl2 or PdCl2(dppf) [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0699] Pd(dtbpf)Cl2 or PdCl2(dtbpf) [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)

[0700] Pd(OAc)2 Palladium acetate

[0701] Pd(OH)2 / C Palladium hydroxide / carbon

[0702] Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0)

[0703] PE or petroleum ether petroleum ether

[0704] PPh3 triphenylphosphine

[0705] POCl3 phosphorus oxychloride

[0706] ppm parts per million

[0707] prep

[0708] PTFE polytetrafluoroethylene

[0709] Raney-Ni Raney nickel

[0710] rt room temperature or retention time

[0711] sat. or sat'd saturated

[0712] SFC Supercritical Fluid Chromatography

[0713] TBAF Tetra-n-butylammonium fluoride

[0714] TBS-Cl tert-Butyldimethylsilyl chloride

[0715] TBSOTf tert-Butyldimethylsilyl trifluoromethanesulfonate

[0716] TBTU (1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-

[0717] Dimethylmethaniminium tetrafluoroborate

[0718] t-BuOK Potassium tert-butoxide

[0719] t-BuONa Sodium tert-butoxide

[0720] t-BuONO tert-Butyl nitrite

[0721] (t-Bu)3P tri-tert-butylphosphine

[0722] TEA triethylamine

[0723] TFA trifluoroacetic acid

[0724] THF Tetrahydrofuran

[0725] TLC thin layer chromatography

[0726] TMS-Cl Trimethylsilyl chloride

[0727] TMS-CN Cyanotrimethylsilane

[0728] TMSI trimethylsilyl iodide

[0729] T3P Propanephosphonic Anhydride

[0730] UPLC ultra-performance liquid chromatography

[0731] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0732] XantPhos Pd G3 [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-

[0733] [amino-1,1′-biphenyl]palladium(II) methanesulfonate

[0734] XPhos or X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0735] XtalFluor-E (diethylamino)difluorosulfonium tetrafluoroborate

[0736] Zn

[0737] experiment

[0738] The following guidelines apply to all experimental procedures described herein. Unless otherwise noted, all reactions were performed under positive nitrogen pressure. The temperatures specified are external (i.e., bath temperatures) and are approximate. Liquids sensitive to air and moisture were transferred by syringe. Reagents were used as received. Solvents used were those marked as "anhydrous" by their suppliers. The molar concentrations of reagents in solutions are approximate and were not titrated against the corresponding standards before use. Unless otherwise noted, all reactions were stirred with a stirring bar. Unless otherwise noted, heating was performed using a heating bath containing silicone oil. Reactions were performed using a 400 nm HPLC-MS / MS instrument equipped with a 400 nm HPLC-MS / MS instrument. Microwave EXP vials (0.2–20 mL) with septa and caps Initiator 2.0, performed with microwave irradiation (0–400 W, 2.45 GHz). The irradiation level used (i.e., high, normal, low) was based on the manufacturer's instructions, depending on the solvent and ionic charge. Cooling to below -70°C was performed using dry ice / acetone or dry ice / 2-propanol. Magnesium sulfate and sodium sulfate, used as desiccants, were anhydrous grades and used interchangeably. Solvent removal described as "under vacuum" or "under reduced pressure" was accomplished by rotary evaporation.

[0739] Preparative normal phase silica gel chromatography was performed using a RediSep or Teledyne Gold Silica Gel Column (4g-330g) CombiFlash Companion instrument or instrument equipped with SF25 silica gel column (4g–300g) IF280 instrument or equipped with HP silica gel column (10g–100g) SP1 instrument, unless otherwise specified. Unless otherwise noted, reverse phase HPLC purification was performed using a YMC-pack column (ODS-A 75x30 mm) as the solid phase. Unless otherwise noted, a mobile phase of 25 mL / min A (CH3CN-0.1% TFA): B (water-0.1% TFA) was used, with a 10-80% gradient of A (10 min) and UV detection at 214 nM.

[0740] API 150 single quadrupole mass spectrometer (PE Sciex, Thornhill, Ontario, Canada) is under positive ion detection mode, uses electrospray ionization to operate.The atomizing gas is produced from zero air generator (Balston Inc., Haverhill, MA, USA) and delivers with 65psi, and described air curtain gas (curtain gas) is the high purity nitrogen that delivers from Dewar liquid nitrogen container with 50psi.The voltage being applied to the electrospray needle is 4.8kV.Cell mouth (orifice) is set at 25V and mass spectrometer scans with the speed of 0.5 scan / second, and it uses the stride mass of 0.2amu and collects distribution data.

[0741] 1 H-NMR spectra were recorded at 250 MHz or 400 MHz using AVANCE 400 MHz instrument, equipped with ACD Spect Manager v.10 for reprocessing. Multiplicities are indicated as follows: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sxt = sextet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, and br = broad signal. J represents the NMR coupling constant measured in Hertz.

[0742] LCMS method :

[0743] LC / MS method 1: was performed on a Shimadzu LCMS-2020Xselect CSH C18 column (50 mm x 3.0 mm id 2.5 μm packing diameter) eluted with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B) using the following elution gradient 0.01-3.60 min: 30% to 70% B, 3.60-4.40 min to 95% B, 5.10-5.20 min to 5% B, at a flow rate of 1.2 mL / min at 45°C.

[0744] LC / MS Method 2: UPLC was performed on an Acquity UPLC CSH C18 column (30 mm x 2.1 mm id 1.7 μm packing diameter) eluted with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B) using the following elution gradient from 0 to 1.85 minutes: 1% to 100% B, 1.9 to 2.0 minutes, 100% B, at a flow rate of 1.3 mL / minute at 45° C. Mass spectra were recorded on a Waters Acquity QDa mass spectrometer detector using alternating scan positive and negative mode electrospray ionization with a scan range of 100 to 1000 AMU and a target sample frequency of 8 Hz.

[0745] LC / MS Method 3: UPLC was performed on an Acquity UPLC CSH C18 column (30 mm x 2.1 mm id 1.7 μm packing diameter) eluted with 10 mM ammonium bicarbonate in water adjusted to pH 10 with 25% ammonium hydroxide solution (solvent A) and acetonitrile (solvent B) using the following elution gradient from 0 to 1.85 minutes: 0% to 100% B, 1.9 to 2.0 minutes, 100% B, at a flow rate of 1.3 mL / minute at 45° C. Mass spectra were recorded on a Waters Acquity QDa mass spectrometer detector using alternating scan positive and negative modes.

[0746] LC / MS Method 4: was performed on a Shimadzu LCMS-2020 Ascentis CSH C18 column (50 mm x 3.0 mm id 2.7 μm packing diameter) eluted with 0.05% TFA in water (solvent A) and 0.05% TFA in acetonitrile (solvent B) using the following elution gradient from 0.01 to 1.10 minutes: 5% to 95% B, 1.80-1.90 to 5% B, at a flow rate of 1.5 mL / minute at 40°C.

[0747] LC / MS Method 5: UPLC was performed on an Acquity UPLC CSH C18 column (30 mm x 2.1 mm id 1.7 μm packing diameter) eluted with 0.1% TFA in water (solvent A) and 0.1% TFA in acetonitrile (solvent B) using the following elution gradient from 0 to 1.85 minutes: 1% to 100% B, 1.9 to 2.0 minutes, 100% B, at a flow rate of 1.3 mL / minute at 45° C. Mass spectra were recorded on a Waters Acquity QDa mass spectrometer detector using alternating scan positive and negative mode electrospray ionization with a scan range of 100 to 1000 AMU and a target sample frequency of 8 Hz.

[0748] LC / MS Method 6: was performed on an Ascentis Express C18 column (50 mm x 3.0 mm id 2.7 μm packing diameter) eluting with water / 0.05% TFA (solvent A) and acetonitrile / 0.05% TFA (solvent B) using the following elution gradient: 0.01-2.00 min: 5% to 100% B, 2.80-2.90 min to 5% B, at a flow rate of 1.5 mL / min at 40°C.

[0749] LC / MS Method 7: was performed on a Kinetex 2.6um EVO C18 100A column (50mm x 3.0mm id2.6μm packing diameter) eluting with water / 5mM NH4HCO3 (solvent A) and acetonitrile (solvent B) using the following elution gradient: 0.01-3.40 minutes: 25% to 65% B, to 4.00 minutes to 95% B, 5.00-5.30 minutes to 10% B, with a flow rate of 1.2mL / minute at 40°C.

[0750] LC / MS Method 8: was performed on a Poroshell HPH-18 column (50 mm x 3.0 mm id 2.7 μm packing diameter) eluted with 6.5 mM NH4HCO3 + NH3 H2O (solvent A) and acetonitrile (solvent B) using the following elution gradient: 0.01-2.00 min: 10% to 95% B, 2.60-2.75 min to 10% B, at a flow rate of 1.2 mL / min at 40°C.

[0751] LC / MS Method 9: was performed on an Ascentis Express C18 column (50 mm x 3.0 mm id 2.7 μm packing diameter) eluting with water / 0.05% TFA (solvent A) and acetonitrile / 0.05% TFA (solvent B) using the following elution gradient: 0.01-2.00 min: 5% to 95% B, 2.60-2.75 min to 5% B, at a flow rate of 1.5 mL / min at 40°C.

[0752] LC / MS Method 10: was performed on a Kinetex 2.6um EVO C18 100A column (50mm x 3.0mm id2.6μm packing diameter) eluting with water / 5mM NH4HCO3 (solvent A) and acetonitrile (solvent B) using the following elution gradient: 0.01-2.10 minutes: 10% to 95% B, 2.70-2.75 minutes to 10% B, with a flow rate of 1.2mL / minute at 40°C.

[0753] LC / MS Method 11: The column used was an Ascentis Express C18, 2.7 μm, 3.0×50 mm. A linear gradient was applied starting at 95% A (A: water-0.05% TFA) and ending at 95% B (B: acetonitrile-0.05% TFA) over 2.70 minutes, for a total run time of 3.00 minutes. The column temperature was 40°C, and the flow rate was 1.50 mL / min.

[0754] LC / MS Method 12: The column used was an Ascentis Express C18, 2.7 μm, 3.0×50 mm. A linear gradient was applied starting at 95% A (A: water / 0.05% TFA) and ending at 95% B (B: acetonitrile / 0.05% TFA) over 2.60 minutes, for a total run time of 3.00 minutes. The column temperature was 40° C., and the flow rate was 1.50 mL / min.

[0755] LC / MS Method 13: The column used was an Ascentis Express C18, 2.7 μm, 3.0×50 mm. A linear gradient was applied starting with 95% A (A: water / 0.05% TFA) and ending with 100% B (B: acetonitrile / 0.05% TFA) over 2.80 minutes, for a total run time of 3.00 minutes. The column temperature was 40° C., and the flow rate was 1.50 mL / min.

[0756] LC / MS Method 14: The column used was a Kinetex 2.6 μm, 3.0×50 mm. A linear gradient was applied starting at 90% A (A: water-5 mM NH₄HCO₃) and ending at 95% B (B: acetonitrile) over 2.70 minutes, for a total run time of 3.00 minutes. The column temperature was 40°C, and the flow rate was 1.20 mL / min.

[0757] LC / MS Method 15: The column used was a Kinetex 2.6 μm EVO C18 100A, 2.6 μm, 3.0 × 50 mm. A linear gradient was applied starting at 90% A (A: water-5 mM NH4HCO3) and ending at 95% B (B: acetonitrile) over 2.70 minutes, for a total run time of 2.90 minutes. The column temperature was 40°C, and the flow rate was 1.20 mL / min.

[0758] LC / MS Method 16: The column used was a Kinetex 2.6 μm EVO C18 100A, 2.6 μm, 3.0 × 50 mm. A linear gradient was applied starting at 90% A (A: water-5 mM NH4HCO3) and ending at 95% B (B: acetonitrile) over 4.90 minutes, for a total run time of 5.30 minutes. The column temperature was 40°C, and the flow rate was 1.20 mL / min.

[0759] LC / MS Method 17: The column used was a Poroshell HPH-C18, 2.7 μm, 3.0×50 mm. A linear gradient was applied starting at 90% A (A: 6.5 mM NH₄HCO₃ + NH₃H₂O) and ending at 95% B (B: acetonitrile) over 2.60 minutes, for a total run time of 3.00 minutes. The column temperature was 40°C, and the flow rate was 1.20 mL / min.

[0760] LC / MS Method 18: The column used was a Kinetex 2.6 μm EVO C18 100A, 2.6 μm, 3.0×50 mm. A linear gradient was applied starting at 90% A (A: water-5 mM NH₄HCO₃) and ending at 95% B (B: acetonitrile) over 5.00 minutes, for a total run time of 5.60 minutes. The column temperature was 40°C, and the flow rate was 1.20 mL / min.

[0761] LC / MS Method 19: The column used was a CORTECS C18, 2.7 μm, 2.1×50 mm. A linear gradient was applied starting with 95% A (A: water / 0.05% TFA) and ending with 100% B (B: acetonitrile / 0.05% TFA) over 2.80 minutes, for a total run time of 3.00 minutes. The column temperature was 40° C., and the flow rate was 1.00 mL / min.

[0762] LC / MS Method 20: The column used was an Xselect CSH C18, 2.5 μm, 3.0×50 mm. A linear gradient was applied starting at 95% A (A: water / 0.1% FA) and ending at 95% B (B: acetonitrile / 0.1% FA) over 2.70 minutes, for a total run time of 3.00 minutes. The column temperature was 40° C., and the flow rate was 1.20 mL / min.

[0763] LC / MS Method 21: The column used was a Poroshell HPH-C18, 2.7 μm, 3.0×50 mm. A linear gradient was applied starting at 10% A (A: 6.5 mM NH₄HCO₃ + NH₃H₂O) and ending at 95% B (B: acetonitrile) over 2.00 minutes, followed by an elution gradient from 95 to 10% B between 2.60 and 2.75 minutes, for a total run time of 3.00 minutes. The column temperature was 40°C, and the flow rate was 1.20 mL / min.

[0764] LC / MS Method 22: The column used was a Poroshell HPH-C18, 2.7 μm, 3.0×50 mm. A linear gradient was applied starting at 90% A (A: 6.5 mM NH₄HCO₃ + NH₃H₂O) and ending at 95% B (B: acetonitrile) over 4.70 minutes, for a total run time of 5.00 minutes. The column temperature was 45°C, and the flow rate was 1.20 mL / min.

[0765] LC / MS Method 23: The column used was a Kinetex 2.6 μm EVO C18 100A, 2.6 μm, 3.0 × 50 mm. A linear gradient was applied starting at 90% A (A: water-5 mM NH4HCO3) and ending at 95% B (B: acetonitrile) over 5.20 minutes, for a total run time of 5.60 minutes. The column temperature was 40°C, and the flow rate was 1.20 mL / min.

[0766] LC / MS Method 24: The column used was an Ascentis Express C18, 2.7 μm, 3.0×50 mm. A linear gradient was applied starting at 95% A (A: water / 0.05% TFA) and ending at 95% B (B: acetonitrile / 0.05% TFA) over 5.00 minutes, for a total run time of 5.30 minutes. The column temperature was 40° C., and the flow rate was 1.50 mL / min.

[0767] LC / MS Method 25: The column used was a Poroshell HPH-C18, 2.7 μm, 3.0 × 50 mm. A linear gradient was applied starting at 90% A (A: water - 6.5 mM NH4HCO3 + NH3H2O) and ending at 95% B (B: acetonitrile) over 2.70 minutes, for a total run time of 3.00 minutes. The column temperature was 40°C, and the flow rate was 1.50 mL / min.

[0768] LC / MS Method 26: The column used was a CORTECS C18, 2.7 μm, 2.1×50 mm. A linear gradient was applied starting with 95% A (A: water / 0.05% TFA) and ending with 100% B (B: acetonitrile / 0.05% TFA) over 4.40 minutes, for a total run time of 5.00 minutes. The column temperature was 40° C., and the flow rate was 1.00 mL / min.

[0769] LC / MS Method 27: The column used was an Xselect CSH C18, 2.5 μm, 3.0×50 mm. A linear gradient was applied starting at 95% A (A: water / 0.1% FA) and ending at 100% B (B: acetonitrile / 0.1% FA) over 2.70 minutes, for a total run time of 3.00 minutes. The column temperature was 40° C., and the flow rate was 1.20 mL / min.

[0770] LC / MS Method 28: The column used was a Kinetex XB-C18, 2.6 μm, 3.0×50 mm. A linear gradient was applied starting with 95% A (A: water / 0.1% FA) and ending with 100% B (B: acetonitrile / 0.1% FA) over 2.60 minutes, for a total run time of 3.00 minutes. The column temperature was 40° C., and the flow rate was 1.20 mL / min.

[0771] LC / MS Method 29: was performed on a Kinetex 2.6um EVO C18 100A column (50mm x 3.0mm id2.6μm packing diameter) eluting with water / 5mM NH4HCO3 (solvent A) and acetonitrile (solvent B) using the following elution gradient: 0.01-1.10 minutes: 10% to 95% B, 1.80-1.85 minutes to 10% B, with a flow rate of 1.2mL / minute at 40°C.

[0772] LC / MS method 30: was performed on a Poroshell HPH-C18 column (50 mm x 3.0 mm id 2.7 μm packing diameter) eluted with 6.5 mM NH4HCO3 + NH3H2O ​​(solvent A) and acetonitrile (solvent B) using the following elution gradient: 0.01-1.10 min: 10% to 95% B, 1.80-1.90 min to 10% B, with a flow rate of 1.2 mL / min at 40°C.

[0773] LC / MS Method 31: was performed on a CORTECS C18 column (50 mm x 2.1 mm id 2.7 μm packing diameter) eluting with water / 0.05% TFA (solvent A) and ACN / 0.05% TFA (solvent B) using the following elution gradient: 0.01-1.10 min: 5% to 100% B, 1.80-1.90 min to 5% B, at a flow rate of 1.0 mL / min at 40°C.

[0774] LC / MS Method 32: The column used was a Kinetex XB-C18, 2.6 μm, 3.0×50 mm. Elution was performed with water / 0.1% FA (solvent A) and ACN / 0.1% FA (solvent B) using the following elution gradient: 0.01-1.10 min: 5% to 100% B, 1.70-1.75 min to 5% B, at a flow rate of 1.0 mL / min at 40° C.

[0775] LC / MS method 33: was performed on a Shimadzu LCMS-2020 Ascentis Express C18 column (50 mm x 3.0 mm i.d. 2.7 μm packing diameter) eluted with 0.05% TFA in water (solvent A) and 0.05% TFA in acetonitrile (solvent B) using the following elution gradient from 0.01 to 1.10 minutes: 5% to 100% B, 1.80-1.90 to 5% B, at a flow rate of 1.5 mL / minute at 40°C.

[0776] LC / MS method 34: was performed on a Kinetex 2.6um EVO C18 100A column (50mm x 3.0mm id2.6μm packing diameter) eluting with water / 5mM NH4HCO3 (solvent A) and acetonitrile (solvent B) using the following elution gradient: 0.01-1.10 minutes: 10% to 95% B, 1.80-1.85 minutes to 10% B, with a flow rate of 1.2mL / minute at 40°C.

[0777] LC / MS method 35: was performed on a Kinetex 2.6um EVO C18 100A column (50mm x 3.0mm id2.6μm packing diameter) eluting with water / 0.1% FA (solvent A) and acetonitrile / 0.1% FA (solvent B) using the following elution gradient: 0.01-2.10 minutes: 5% to 95% B, 2.70-2.75 minutes to 5% B, with a flow rate of 1.2mL / minute at 40°C.

[0778] LC / MS method 36: was performed on an Xselect CSH C18 column (50 mm x 3.0 mm id 2.5 μm packing diameter) eluting with water / 0.1% FA (solvent A) and acetonitrile / 0.1% FA (solvent B) using the following elution gradient: 0.01-1.10 min: 5% to 100% B, 1.70-1.75 min to 5% B, at a flow rate of 1.2 mL / min at 40°C.

[0779] LC / MS Method 37: The column used was a Kinetex XB-C18, 1.7 μm, 2.1×30 mm. Elution was performed with water / 0.05% TFA (solvent A) and ACN / 0.0.5% TFA (solvent B) using the following elution gradient: 0.01-0.60 min: 5% to 95% B, 1.00-1.05 min to 5% B, at a flow rate of 1.0 mL / min at 40° C.

[0780] LC / MS method 38: was performed on a Titank C18 column (50 mm x 3.0 mm id 3.0 μm packing diameter) eluting with water / 5 mM NH4HCO3 (solvent A) and acetonitrile (solvent B) using the following elution gradient: 0.01-1.20 min: 10% to 95% B, 1.70-1.75 min to 10% B, at a flow rate of 1.2 mL / min at 40°C.

[0781] LC / MS Method 39: was performed on a HALO 2.0um C18 90A column (30mm x 3.0mm id 2.0μm packing diameter) eluting with water / 0.1% FA (solvent A) and acetonitrile / 0.1% FA (solvent B) using the following elution gradient: 0.01-0.45 minutes: 5% to 95% B, 0.80-0.85 minutes to 5% B, with a flow rate of 1.5mL / minute at 40°C.

[0782] intermediates

[0783] Intermediate 1

[0784] 2-Bromo-N-(5-fluoropyridin-2-yl)propionamide

[0785]

[0786] A mixture of 2-bromopropionic acid (16.3 g, 107.2 mmol, 1.2 eq), DCM (200 mL), DCC (27.6 g, 134.0 mmol, 1.5 eq) and 5-fluoropyridin-2-amine (10.0 g, 89.3 mmol, 1.0 eq) was stirred at 25° C. for 2.0 h, filtered, concentrated, and dissolved in DCM (50 ml). Silica (100-200 mesh, 60.0 g) was added, and the mixture was concentrated and loaded onto a silica gel column (330 g, 100-200 mesh). Eluents were ethyl acetate / petroleum ether (1 / 9) to give 2-bromo-N-(5-fluoropyridin-2-yl)propanamide (20.0 g, purity: 90%, yield: 90%) as a yellow oil. LCMS: (ES, m / z): 247 [M+H] + . 1 H NMR: (400MHz, CD3OD) δ8.22 (d, J=3.2Hz, 1H), 8.18-8.15 (m, 1H), 7.64-7.59 (m, 1H), 4.76-4.69 (m, 1H), 1.84 (d, J=6.8Hz, 3H).

[0787] Intermediates 2-13 were synthesized in a similar manner from commercially available aromatic amines.

[0788]

[0789]

[0790]

[0791]

[0792] Intermediate 14

[0793] 2-Bromo-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propionamide

[0794]

[0795] Step 1

[0796] Na (1.96 g, 85.22 mmol, 1.1 eq) was added portionwise to cyclopropylmethanol (78.14 g, 1.09 mol, 14.0 eq), and the mixture was stirred at room temperature. After 30 minutes, 6-chloropyridazine-3-amine (10.00 g, 77.52 mmol, 1.0 eq) was added. The reaction was purged with nitrogen and stirred at 130 ° C. After 12 h, the mixture was poured into ice water (800 mL) and extracted with ethyl acetate (800 mL x 3). The combined organic layers were washed with brine (1000 mL x 2), dried over sodium sulfate, concentrated, and purified by PREP-HPLC (column: C18 irregular 40-60 μm 60A 330 g) eluting with 5-40% AcCN in water (10 mmol / L, NH4HCO3) to give 6-(cyclopropylmethoxy)pyridazin-3-amine (10.5 g, yield: 82%, purity: 93%) as a yellow solid. LCMS: (ES, m / z): 166 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ6.89-6.78 (m, 2H), 4.63 (s, 2H), 4.19 (d, J = 7.2Hz, 2H), 1.35-1.22 (m, 1H), 0.63-0.57 (m, 2H), 0.37-0.31 (m, 2H).

[0797] Step 2

[0798] To a solution of 6-(cyclopropylmethoxy)pyridazin-3-amine (5.00 g, 30.30 mmol, 1.0 eq) and 2-bromopropionic acid (6.91 g, 45.46 mmol, 1.5 eq) in DCM (150 mL) was added DMAP (1.11 g, 9.09 mmol, 0.3 eq) and DCC (12.48 g, 60.60 mmol, 2.0 eq). After 16 h, the solid was filtered off, the filtrate was concentrated, and the residue was applied to a silica gel column and eluted with 0-15% ethyl acetate in petroleum ether to give 2-bromo-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide (4.8 g, yield: 53%, purity: 95%) as a yellow oil. LCMS: (ES, m / z): 300 [M+H] + . 1H NMR: (400MHz, CDCl3) δ11.55 (br, 1H), 8.60 (d, J=9.6Hz, 1H), 7.13 (d, J=9.6Hz, 1H), 5.48-5.41 (m, 1H), 4.31 (d, J=7.2Hz, 2H), 1.92 (d, J=7.2Hz, 3H), 1.75-1.67 (m, 1H), 0.71-0.68 (m, 2H), 0.42-0.37 (m, 2H).

[0799] Intermediates 15-21 were synthesized in a similar manner, with 19 and 20 being derived from aryl bromides and 16 using t-BuOK as the base.

[0800]

[0801]

[0802]

[0803] Intermediate 22

[0804] 2-Bromo-N-(5-(cyclopropylmethoxy)pyridin-2-yl)propionamide

[0805]

[0806] Step 1

[0807] To a solution of 6-nitropyridin-3-ol (1.00 g, 7.14 mmol) in DMF (15 mL) was added (bromomethyl)cyclopropane (1.156 g, 8.57 mmol) and KCO (1.973 g, 14.28 mmol) at 25°C. After 8 h, water (100 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, concentrated, and purified over silica (80 g) eluting with 0-50% EtOAc in petroleum ether to give 5-(cyclopropylmethoxy)-2-nitropyridine (1.25 g, 5.79 mmol, purity: 90%, yield: 81%) as a yellow solid. LCMS: (ES, m / z): 195 [M+H] + , RT = 0.938 min, LC / MS method 4. 1 H NMR: (400MHz, CDCl3) δ 8.26-8.29 (m, 2H), 7.38-7.41 (m, 1H), 4.00 (d, J = 8Hz, 2H), 1.27-1.39 (m, 1H), 0.72-0.77 (m, 2H), 0.42-0.46 (m, 2H).

[0808] Step 2

[0809] A mixture of 5-(cyclopropylmethoxy)-2-nitropyridine (6.6 g, 34.0 mmol, 1.0 eq), MeOH (60.0 mL) and Pd / C (0.6 g, 10%) was evacuated and purged three times with nitrogen, then with hydrogen. The reaction was stirred at 25° C. under a hydrogen (balloon) atmosphere for 2 h, filtered and concentrated to give crude 5-(cyclopropylmethoxy)pyridin-2-amine (5.8 g) as a yellow solid, which was used without purification. LCMS: (ES, m / z): 165 [M+H] + .

[0810] Step 3

[0811] To a solution of 5-(cyclopropylmethoxy)pyridin-2-amine (0.50 g, 3.05 mmol, 1.0 eq) and 2-bromopropionic acid (0.7 g, 4.57 mmol, 1.5 eq) in DCM (10 mL) was added DCC (0.94 g, 4.57 mmol, 1.5 eq) in one portion at 25°C. After 2 h, the reaction was filtered, concentrated, and purified by preparative TLC using ethyl acetate: petroleum ether (1:10) to give 2-bromo-N-(5-(cyclopropylmethoxy)pyridin-2-yl)propanamide (0.9 g, yield: 53%, purity: 95%) as a white solid. LCMS: (ES, m / z): 299 [M+H] + . 1 H NMR: (300MHz, CD3OD) δ8.02-7.99 (m, 2H), 8.03-8.01 (m, 1H), 4.76-4.69 (m, 1H), 3.90 (d, J= 6.9Hz, 2H), 1.84 (d, J=6.9Hz, 3H), 1.32-1.28 (m, 1H), 0.69-0.62 (m, 2H), 0.41-0.35 (m, 2H).

[0812] Intermediates 23-32, 28-29, 31-32 were synthesized in a similar manner from alkyl halides using cesium carbonate as base and iron / ammonium chloride as reducing agents; 31 using iron / ammonium chloride as reducing agents.

[0813]

[0814]

[0815]

[0816] Intermediate 33

[0817] (E)-2-Bromo-N-(5-(2-cyclopropylvinyl)pyridin-2-yl)propionamide

[0818]

[0819] Step 1

[0820] A mixture of 5-bromo-2-nitropyridine (400 mg, 1.97 mmol, 1.0 eq), (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (458 mg, 2.36 mmol, 1.2 eq), Pd(OAc) (45 mg, 0.2 mmol, 0.1 eq), PPh (516 mg, 1.97 mmol, 1.0 eq), KCO (816 mg, 5.91 mmol, 3.0 eq) and DME / HO (8 mL, 1 / 1) was purged with nitrogen three times and stirred at 85° C. After 12 h, the reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were dried over Na2SO4, concentrated, and purified on silica gel using ethyl acetate:petroleum ether (1:3) as eluent to afford (E)-5-(2-cyclopropylvinyl)-2-nitropyridine (280 mg, purity: 92%, yield: 69%) as a yellow oil. LCMS: (ES, m / z): 191 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ8.52 (d, J=2.3Hz, 1H), 8.20 (d, J=8.5Hz, 1H), 7.89 (dd, J=8.5, 2.3Hz, 1H), 6.57 (d , J=15.8Hz, 1H), 6.02 (dd, J=15.8, 9.3Hz, 1H), 1.73-1.65 (m, 1H), 1.03-0.95 (m, 2H), 0.70-0.64 (m, 2H).

[0821] Step 2

[0822] To a solution of (E)-5-(2-cyclopropylvinyl)-2-nitropyridine (270 mg, 1.42 mmol, 1.0 eq) and NHCl (753 mg, 14.2 mmol, 10.0 eq) in MeOH / H0 (40 mL, 3 / 1) was added Fe (795 mg, 14.2 mmol, 10.0 eq) in one portion, and the mixture was stirred at 60°C. After 2 h, the reaction was filtered, concentrated, and purified on silica gel eluting with EtOAc:petroleum ether (1:1) to give (E)-5-(2-cyclopropylvinyl)pyridin-2-amine (200 mg) as a yellow oil. LCMS: (ES, m / z): 161 [M+H]+ . 1 H NMR: (300MHz, DMSO-d6) δ7.82 (d, J=2.4Hz, 1H), 7.44 (dd, J=8.6, 2.4Hz, 1H), 6.38 (d, J=8.6Hz, 1H), 6.29 (dd, J=15. 9, 8.8Hz, 1H), 5.91 (s, 2H), 5.56 (dd, J=15.9, 8.8Hz, 1H), 1.55-1.45 (m, 1H), 0.78-0.70 (m, 2H), 0.47-0.40 (m, 2H).

[0823] Step 3

[0824] A mixture of 2-bromopropionic acid (133 mg, 0.875 mmol, 1.0 eq), DCC (217 mg, 1.05 mmol, 1.2 eq) and (E)-5-(2-cyclopropylvinyl)pyridin-2-amine (140 mg, 0.875 mmol, 1.0 eq) in DCM (5 mL) was stirred at 25 ° C. After 12 h, the mixture was quenched with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were dried over Na2SO4, concentrated and purified on silica gel using ethyl acetate: petroleum ether (1:4) as eluent to give (E)-2-bromo-N-(5-(2-cyclopropylvinyl)pyridin-2-yl)propanamide (150 mg, yield: 58%, purity: 90%) as a yellow solid. LCMS: (ES, m / z): 295 [M + H] + . 1 H NMR: (400MHz, DMSO-d6) δ10.85 (s, 1H), 8.30 (d, J = 2.4Hz, 1H), 8.00 (d, J = 8.7Hz, 1H), 7.83 (dd, J = 8.6, 2.5Hz, 1H), 6.45 (d, J = 16.0Hz, 1H), 5.91 (dd, J=15.9, 9.2Hz, 1H), 4.92-4.81 (m, 1H), 1.74 (d, J=6.7Hz, 3H), 1.63-1.55 (m, 1H), 0.88-0.75 (m, 2H), 0.58-0.47 (m, 2H).

[0825] Intermediate 34

[0826] 2-Bromo-N-(6-methyl-[2,3'-bipyridyl]-6'-yl)propionamide

[0827]

[0828] Step 1

[0829] A mixture of 2-bromo-6-methylpyridine (600 mg, 3.49 mmol, 1.0 eq), (6-aminopyridin-3-yl)boronic acid (626 mg, 4.53 mmol, 1.3 eq), Pd(dppf)Cl (285 mg, 0.35 mmol, 0.1 eq) and KCO (963 mg, 6.98 mmol, 2.0 eq) in DMF / H0 (12 mL, 2 / 1) was purged with nitrogen three times and stirred at 80° C. After 1 h, the reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were dried over Na2SO4, concentrated, and purified on silica gel eluting with a solution of MeOH in DCM (1-30%) to give 6-methyl-[2,3'-bipyridyl]-6'-amine (620 mg, purity: 98%, yield: 96%) as a yellow solid. LCMS: (ES, m / z): 186 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ8.64 (d, J=2.4Hz, 1H), 8.06 (dd, J=8.6, 2.5Hz, 1H), 7.70-7 .55 (m, 2H), 7.08 (d, J=7.4Hz, 1H), 6.51 (d, J=8.7Hz, 1H), 6.23 (s, 2H), 2.49 (s, 3H).

[0830] Step 2

[0831] To a solution of 2-bromopropionic acid (263 mg, 1.72 mmol, 1.1 eq), DCC (484 mg, 2.35 mmol, 1.5 eq), and DMAP (19.0 mg, 0.15 mmol, 0.1 eq) in DCM (5 mL) was added 6-methyl-[2,3'-bipyridyl]-6'-amine (290 mg, 1.56 mmol, 1.0 eq). After 2 h, water (100 mL) was added, and the mixture was extracted with EtOAc (100 mL x 3). The combined organic phases were dried over Na2SO4, concentrated, and purified on silica gel using ethyl acetate:petroleum ether (1:3) as the eluent to give 2-bromo-N-(6-methyl-[2,3'-bipyridyl]-6'-yl)propanamide (342 mg, 68% yield, 69% purity) as a yellow solid. LCMS: (ES, m / z): 320 [M+H] +. (400MHz, DMSO-d6) δ11.07 (s, 1H), 9.05 (dd, J=2.5, 0.8Hz, 1H), 8.48 (dd, J=8.7, 2.4Hz, 1H), 8.19 (d, J=8.7Hz , 1H), 7.85-7.75 (m, 2H), 7.25 (dd, J=7.1, 1.4Hz, 1H), 4.96-4.87 (m, 1H), 2.55 (s, 3H), 1.77 (d, J=6.7Hz, 3H).

[0832] Intermediates 35-39 (35 using cesium carbonate in THF; 36 using sodium bicarbonate and Pd(PPh3)4 in dioxane / water; 37 using K3PO4 and Pd(dtbpf)Cl2 in THF / water; 38 using sodium carbonate and Pd(PPh3)4 in EtOH / water; 39 boronate) were synthesized in a similar manner from alkyl and aryl halides.

[0833]

[0834]

[0835]

[0836] Intermediate 40

[0837] 2-Bromo-N-(5-cyclopentylpyridin-2-yl)propionamide

[0838]

[0839] Step 1

[0840] A mixture of 5-bromopyridin-2-amine (2.0 g, 11.63 mmol, 1.0 eq), cyclopentenylboronic acid (1.7 g, 15.12 mmol, 1.3 eq), Pd(dppf)Cl (900 mg, 1.2 mmol, 0.1 eq) and KCO (3.3 g, 23.26 mmol, 2.0 eq) in DMF (20 mL) and HO (10 mL) was purged three times with nitrogen and stirred at 80°C. After 1 h, the reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over NaSO, concentrated, and purified on silica gel using ethyl acetate: petroleum ether (2:5) as eluent to give 5-cyclopentenylpyridin-2-amine (1.7 g, purity: 99%, yield: 91%) as a yellow solid. LCMS: (ES, m / z): 161 [M+H] + . 1H NMR: (400MHz, DMSO-d6) δ7.94 (s, 1H), 7.51 (dd, J=8.7, 2.4Hz, 1H), 6.40 (d, J=8.7H z, 1H), 5.99-5.93 (m, 3H), 2.60-2.52 (m, 2H), 2.44-2.36 (m, 2H), 1.96-1.94 (m, 2H).

[0841] Step 2

[0842] A mixture of 5-cyclopentenylpyridin-2-amine (1.70 g, 10.56 mmol, 1.0 eq), Pd / C (500 mg, 10%) and MeOH (40 mL) was evacuated and purged with nitrogen three times, then purged with hydrogen. The reaction was stirred at 25 ° C. under a hydrogen (balloon) atmosphere for 1 h, filtered, concentrated and purified on silica gel, eluting with EtOAc: petroleum ether (1: 1) to give 5-cyclopentylpyridin-2-amine (1.6 g, purity: 85%, yield: 93%) as a yellow solid. LCMS: (ES, m / z): 163 [M + H] + . 1 H NMR: (300MHz, DMSO-d6) δ7.75 (d, J=2.4Hz, 1H), 7.24 (dd, J=8.4, 2.4Hz, 1H), 6.37 (d, J=8.7Hz, 1H), 5.61(s, 2H), 2.82-2.70(m, 1H), 1.95-1.84(m, 2H), 1.75-1.50(m, 4H), 1.45-1.30(m, 2H).

[0843] Step 3

[0844] A mixture of 5-cyclopentylpyridin-2-amine (300m, g, 1.85mmol, 1.0eq), 2-bromopropionic acid (282mg, 1.85mmol, 1.0eq), DCC (458mg, 2.22mmol, 1.2eq) and DMAP (23mg, 0.2mmol, 0.1eq) in DCM (10mL) was stirred at room temperature. After 2h, the mixture was quenched with water (50mL) and extracted with DCM (50mL x 3). The combined organic phases were dried over Na2SO4, concentrated and purified on silica gel using ethyl acetate: petroleum ether (1:10) to give 2-bromo-N-(5-cyclopentylpyridin-2-yl)propionamide (260mg, yield: 47%, purity: 97%) as a yellow solid. LCMS: (ES, m / z): 297[M+H] + . 1H NMR: (300MHz, DMSO-d6) δ10.75 (br, 1H), 8.24-8.19 (m, 1H), 8.00-7.92 (m, 1H), 7.72-7. 62 (m, 1H), 4.90-4.80 (m, 1H), 3.02-2.90 (m, 1H), 2.10-1.90 (m, 2H), 1.85-1.40 (m, 9H).

[0845] Intermediate 41 was synthesized in a similar manner.

[0846]

[0847] Intermediate 42

[0848] 2-Bromo-N-(5-(cyclopropylmethoxy)-3-fluoropyridin-2-yl)propionamide

[0849]

[0850] Step 1

[0851] To a solution of 5-bromo-3-fluoropyridin-2-amine (5.00 g, 26.3 mmol, 1.0 eq) in dioxane (60 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (10.0 g, 39.5 mmol, 1.5 eq), potassium carbonate (7.75 g, 78.9 mmol, 3.0 eq) and Pd(dppf)Cl2 (1.95 g, 2.63 mmol, 0.1 eq). The reaction was purged with nitrogen three times and stirred at 80°C. After 15 h, the reaction was purified directly by preparative HPLC (column: C18, 330 g) eluting with 0-10% AcCN in water (0.05% TFA) to give (6-amino-5-fluoropyridin-3-yl)boronic acid (3.6 g, yield: 88%, purity: 70%) as a light yellow solid. LCMS: (ES, m / z): 157 [M+H] + . 1 H NMR: (300MHz, DMSO-d6) δ7.71-7.66(m, 1H), 7.57-7.47(m, 1H), 6.45(s, 2H), 3.59(s, 2H).

[0852] Step 2

[0853] To a solution of (6-amino-5-fluoropyridin-3-yl)boronic acid (3.6 g, 23.1 mmol, 1.0 eq) in THF (40 mL) and water (40 mL) was added NaBO 4H O (10.7 g, 69.2 mmol, 3.0 eq). After 1 h, the reaction was directly purified by preparative HPLC (column: C18, 330 g) eluting with 0-10% AcCN in water (with 0.05% NH 4 HCO 3 ) to give 6-amino-5-fluoropyridin-3-ol (1.6 g, yield: 64%, purity: 80%) as a brown solid. LCMS: (ES, m / z): 129 [M + H] + . 1 HNMR: (300MHz, CD3OD) δppm 7.42 (d, J=2.4Hz, 1H), 6.98-6.94 (m, 1H).

[0854] Step 3

[0855] To a solution of 6-amino-5-fluoropyridin-3-ol (1.35 g, 10.5 mmol, 1.0 eq) in DMF (20 mL) was added potassium carbonate (4.37 g, 31.6 mmol, 3.0 eq) and (bromomethyl)cyclopropane (1.41 g, 10.5 mmol, 1.0 eq), and the mixture was heated to 80 ° C. After 15 h, the reaction was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×150 mL), dried over sodium sulfate, concentrated, and purified on silica gel eluting with MeOH:DCM (1:10) to give 5-(cyclopropylmethoxy)-3-fluoropyridin-2-amine (600 mg, yield: 31%, purity: 90%) as a brown solid. LCMS: (ES, m / z): 183 [M+H] + . 1 H NMR: (300MHz, CD3OD) δppm 7.51 (d, J=2.7Hz, 1H), 7.16-7.11 (m, 1H), 3.79 (d, J=6.9Hz, 2H), 1.28-1.15 (m, 1H), 0.64-0.56 (m, 2H), 0.36-0.29 (m, 2H).

[0856] Step 4

[0857] To a solution of 5-(cyclopropylmethoxy)-3-fluoropyridin-2-amine (600 mg, 3.30 mmol, 1.0 eq) in DCM (10 mL) was added DCC (1.02 g, 4.95 mmol, 1.5 eq) and 2-bromopropionic acid (757 mg, 4.95 mmol, 1.5 eq). After 2 h, the reaction was filtered, concentrated, and purified on silica gel using ethyl acetate: petroleum ether (1:3) as the eluent to give 2-bromo-N-(5-(cyclopropylmethoxy)-3-fluoropyridin-2-yl)propanamide (830 mg, 80% yield, 90% purity) as a white solid. LCMS: (ES, m / z): 317 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ10.38 (s, 1H), 8.00 (d, J=2.7Hz, 1H), 7.53-7.49 (m, 1H), 4.79-4.69 (m, 1H), 3.95-3.90 (m, 2H), 1.73 (d, J=6.9Hz, 3H), 1.26-1.21 (m, 1H), 0.62-0.54 (m, 2H), 0.36-0.31 (m, 2H).

[0858] Intermediate 43 was synthesized in a similar manner.

[0859]

[0860] Intermediate 44

[0861] 2-Bromo-N-(6-cyclopropyl-1,8-naphthyridin-2-yl)propionamide

[0862]

[0863] Step 1

[0864] A mixture of 6-bromo-1,8-naphthyridin-2-amine (840 mg, 3.77 mmol, 1.0 eq), cyclopropylboronic acid (650 mg, 7.54 mmol, 2.0 eq), palladium acetate (170 mg, 0.75 mmol, 0.2 eq), tricyclohexylphosphine (211 mg, 0.75 mmol, 0.2 eq, 10% in n-hexane), potassium phosphate (2.4 g, 11.31 mmol, 3 eq), water (1 mL) and toluene (20 mL) was purged with nitrogen three times and stirred at 100° C. After 16 h, the reaction was quenched with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic phases were dried over Na2SO4, concentrated, and purified on silica gel using MeOH:DCM (1:10) as eluent to give 6-cyclopropyl-1,8-naphthyridin-2-amine (200 mg, purity: 69%, yield: 28%) as a yellow solid. LCMS: (ES, m / z): 186 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ8.54 (d, J=2.4Hz, 1H), 7.84 (d, J=8.7Hz, 1H), 7.66 (d, J=2.4Hz, 1H), 6.78 (d, J=8.7Hz, 1H), 6.68 (s, 2H), 2.06-1.97 (m, 1H), 1.06-0.91 (m, 2H), 0.86-0.70 (m, 2H).

[0865] Step 2

[0866] A mixture of 2-bromopropionic acid (166 mg, 1.08 mmol, 1 eq), dicyclohexylcarbodiimide (450 mg, 2.16 mmol, 2 eq) and 6-cyclopropyl-1,8-naphthyridin-2-amine (200 mg, 1.08 mmol, 1.0 eq) in dichloromethane (10 mL) was stirred at 25° C. for 2 h. The reaction was filtered, concentrated, and purified on silica gel eluting with DCM:MeOH (10:1) to give 2-bromo-N-(6-cyclopropyl-1,8-naphthyridin-2-yl)propanamide (300 mg, yield: 87%, purity: 69%) as a yellow oil. LCMS: (ES, m / z): 320 [M+H] + . (400MHz, DMSO-d6) δ11.42 (s, 1H), 8.87 (d, J=2.7Hz, 1H), 8.54-8.25 (m, 2H), 8.02 (d, J= 2.7Hz, 1H), 4.94-4.92(m, 1H), 2.16-2.13(m, 1H), 1.80-1.60(m, 5H), 1.34-1.14(m, 2H).

[0867] Intermediate 45 was synthesized in a similar manner.

[0868]

[0869] Intermediate 46

[0870] 2-Bromo-N-(5-cyclobutylpyridin-2-yl)propionamide

[0871]

[0872] Step 1

[0873] A mixture of tert-butyl (5-bromopyridin-2-yl)carbamate (14 g, 51 mmol, 1.0 eq, pyridine-2,6-bis(carboximidamide) (660 mg, 4.1 mmol, 0.08 eq), NiCl2(dme) (890 mg, 4.1 mmol, 0.08 eq), NaI (3 g, 20.2 mmol, 0.40 eq), bromocyclobutane (16.4 g, 121.4 mmol, 2.4 eq), Zn (10.2 g, 162 mmol, 3.2 eq) and TFA (923 mg, 8.1 mmol, 0.16 eq)) in DMA (120 mL) was purged with nitrogen three times and stirred at 60° C. After 12 h, the reaction was quenched with water (500 mL) and extracted with EtOAc (500 mL×3). The combined organic phases were washed with brine (2 x 500 mL), dried over Na2SO4, concentrated, and purified on silica gel eluting with EtOAc:petroleum ether (1:1) to give tert-butyl (5-cyclobutylpyridin-2-yl)carbamate (4.3 g, yield: 34%) as a yellow solid. LCMS: (ES, m / z): 249 [M+H] + . 1 H NMR: (300MHz, DMSO-d6) δ9.65 (s, 1H), 8.10 (d, J = 2.4Hz, 1H), 7.73 (d, J = 8.4Hz, 1H), 7.65 (d d, J=8.4, 2.4Hz, 1H), 3.51-3.42 (m, 1H), 2.31-2.25 (m, 2H), 2.15-1.47 (m, 4H), 1.45 (s, 9H).

[0874] Step 2 Tert-butyl 5-cyclobutylpyridin-2-ylcarbamate (1.5 g, 6 mmol, 1.0 eq) was stirred in HCl (4 M in dioxane, 10 mL) at 28 ° C. After 2 h, the reaction was concentrated and 2-bromopropionic acid (1.38 g, 9.0 mmol, 1.5 eq), DCC (2.48 g, 12.1 mmol, 2.0 eq), DMAP (147 mg, 1.2 mmol, 0.2 eq) and dichloromethane (20 mL) were added. After 2 h, the reaction was quenched with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic phases were dried over Na2SO4, concentrated and purified on silica gel, eluting with EtOAc: petroleum ether (1: 1) to give 2-bromo-N-(5-cyclobutylpyridin-2-yl)propionamide (650 mg, yield: 45%) as a yellow solid. LCMS: (ES, m / z): 283 [M+H] + . (300MHz, DMSO-d6) δ10.80 (s, 1H), 8.21 (d, J = 2.4Hz, 1H), 8.05 (d, J = 8.4Hz, 1H), 7.74 (dd, J = 8.6, 2.5Hz, 1H), 4.94-4.70 ( m, 1H), 3.58-3.46 (m, 1H), 2.35-2.29 (m, 2H), 2.21-2.07 (m, 1H), 2.06-1.97 (m, 1H), 1.95-1.79 (m, 1H), 1.76-1.70 (m, 4H).

[0875] Intermediate 47

[0876] (Z)-2-Bromo-N-(5-(2-cyclopropylvinyl)pyridin-2-yl)propionamide

[0877]

[0878] Step 1

[0879] To a solution of 5-bromo-2-nitropyridine (2.01 g, 10.00 mmol, 1.00 eq) in degassed DMF (20 mL) was added bis(triphenylphosphine)palladium(II) dichloride (420 mg, 0.60 mmol, 0.06 eq), copper(I) iodide (95 mg, 0.50 mmol, 0.05 eq), diisopropylamine (5.06 g, 50.00 mmol, 5.00 eq) and ethynylcyclopropane (0.99 g, 15.00 mmol, 1.50 eq). The mixture was stirred at 75° C. for 45 minutes, poured into water (200 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with brine (400 mL), dried over sodium sulfate, concentrated, and purified on silica gel eluting with ethyl acetate in petroleum ether (0-10% over 30 min) to give 5-(cyclopropylethynyl)-2-nitropyridine (1.3 g, yield: 69%, purity: 97%) as a yellow solid. LCMS: (ES, m / z): 189 [M+H] + . 1 H NMR: (300MHz, CDCl3) δ8.58 (d, J=1.8Hz, 1H), 8.20 (d, J=8.4Hz, 1H), 7.94 (dd, J=2.1, 8.4Hz, 1H), 1.59-1.50 (m, 1H), 1.03-0.91 (m, 4H).

[0880] Step 2

[0881] To a solution of 5-(cyclopropylethynyl)-2-nitropyridine (560 mg, 2.98 mmol, 1.0 eq) in methanol (8 mL) and water (2 mL) was added Fe (1.00 g, 17.85 mmol, 6.0 eq) and NHCl (322 mg, 5.75 mmol, 2.0 eq), and the reaction was stirred at 50 ° C for 24 h. The solid was filtered off and the filtrate was concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate: petroleum ether (0-35% in 30 min) to give 5-(cyclopropylethynyl)pyridin-2-amine (220 mg, yield: 47%, purity: 96%) as a yellow solid. LCMS: (ES, m / z): 159 [M + H] + . 1 H NMR: (300MHz, DMSO-d6)δppm 7.91 (d, J=1.8Hz, 1H), 7.32 (dd, J=2.4, 8.4Hz, 1H), 6.35 (dd, J=0.6, 8.7Hz, 1H), 6.22(s, 2H), 1.53-1.44(m, 1H), 0.87-0.80(m, 2H), 0.69-0.64(m, 2H).

[0882] Step 3

[0883] A mixture of 5-(cyclopropylethynyl)pyridin-2-amine (200 mg, 1.27 mmol, 1.0 eq) and Lindela catalyst (100 mg) in ethyl acetate (5 mL) was evacuated and purged three times with nitrogen, then purged with hydrogen. The mixture was stirred for 1.5 h in a hydrogen atmosphere. The reaction was filtered, concentrated and purified on a silica gel column using ethyl acetate: petroleum ether (1: 3) to give (Z)-5-(2-cyclopropylvinyl)pyridin-2-amine (120 mg, yield: 59%, purity: 76%) as a white solid. LCMS: (ES, m / z): 161 [M+H] + . 1 H NMR: (400MHz, DMSO-d6)δppm 7.96 (d, J=2.4Hz, 1H), 7.51 (dd, J=2.4, 8.4Hz, 1H), 6.43 (d, J=8.4Hz, 1H), 6.10 (d, J=7.6Hz, 1H), 5 .96 (s, 2H), 4.94 (dd, J=8.8, 11.6Hz, 1H), 1.79-1.69 (m, 1H), 0.83-0.78 (m, 2H), 0.42-0.36 (m, 2H).

[0884] Step 4

[0885] To a solution of (Z)-5-(2-cyclopropylvinyl)pyridin-2-amine (120 mg, 0.75 mmol, 1.0 eq) in dichloromethane (2 mL) was added 2-bromopropionic acid (114 mg, 0.75 mmol, 1.0 eq) and DCC (230 mg, 1.13 mmol, 1.5 eq). The reaction was stirred for 24 h, poured into water (100 mL), filtered and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, dried over sodium sulfate, concentrated and purified by preparative TLC (ethyl acetate: petroleum ether, 1:5) to give (Z)-2-bromo-N-(5-(2-cyclopropylvinyl)pyridin-2-yl)propanamide (86 mg, yield: 39%, purity: 90%) as a yellow solid. LCMS: (ES, m / z): 295 [M+H] + . 1H NMR: (300MHz, CD3OD) δ8.38 (d, J=2.4Hz, 1H), 8.08 (d, J=8.8Hz, 1H), 7.89 (dd, J=2.4, 8.0Hz, 1H), 6.30 (d, J=11.6Hz, 1H), 5.23 (dd, J=10.0, 11.6Hz, 1H), 4.78-4.71 (m, 1H), 2.26-2.15 (m, 1H), 1.85 (d, J=6.8Hz, 3H), 0.83-0.78 (m, 2H), 0.42-0.36 (m, 2H).

[0886] Intermediate 48 was synthesized in a similar manner using Pd / C as a catalyst during the hydrogenation.

[0887]

[0888] Intermediate 49

[0889] 2-Bromo-N-(2-cyclopropyloxazolo[4,5-b]pyridin-5-yl)propionamide

[0890]

[0891] Step 1

[0892] To a solution of TBTU (0.308 g, 0.96 mmol, 1.2 eq) and TEA (0.23 g, 2.23 mmol, 2.8 eq) in DMF (5 mL) was added 2-amino-6-bromopyridin-3-ol (150 mg, 0.80 mmol, 1.0 eq) and cyclopropanecarboxylic acid (69 mg, 0.80 mmol, 1.0 eq). The mixture was stirred at 25 ° C for 15 h, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over Na2SO4, concentrated and purified on a silica gel column using ethyl acetate: petroleum ether (1:10) as eluent to give cyclopropanecarboxylic acid 2-amino-6-bromopyridin-3-yl ester (160 mg, purity: 87%, yield: 80%) as a light yellow oil. LCMS: (ES, m / z): 257 [M + H] + . 1 H NMR: (300MHz, CD3OD) δ7.18 (d, J=8.1Hz, 1H), 6.76 (d, J=8.1Hz, 1H), 2.02-1.94 (m, 1H), 1.14-1.08 (m, 4H).

[0893] Step 2

[0894] Cyclopropanecarboxylic acid 2-amino-6-bromopyridin-3-yl ester (1.5 g, 5.88 mmol, 1.0 eq), THF (15 mL) and Burgess reagent (6.99 g, 29.4 mmol, 5.0 eq) were stirred at 130 ° C. under microwave for 1.0 h in a sealed tube. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over Na2SO4, concentrated and purified on a silica gel column using ethyl acetate: petroleum ether (1:20) as eluent to give 5-bromo-2-cyclopropyloxazolo[4,5-b]pyridine (0.24 g, purity: 80%, yield: 17%) as a light yellow solid. LCMS: (ES, m / z): 239 [M + H] + . 1 H NMR: (300MHz, CD3OD) δppm 7.89 (d, J=12.4Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 2.35-2.30 (m, 1H), 1.35-1.31 (m, 4H).

[0895] Step 3

[0896] To a solution of 5-bromo-2-cyclopropyloxazolo[4,5-b]pyridine (280 mg, 1.18 mmol, 1.0 eq) in EtOH (7 mL) was added H O (3 mL), N,N'-dimethylethylenediamine (31 mg, 0.35 mmol, 0.3 eq), sodium ascorbate (117 mg, 0.59 mmol, 0.5 eq), NaN (85 mg, 1.30 mmol, 1.1 eq) and CuI (45 mg, 0.24 mmol, 0.2 eq). The mixture was stirred at 25 ° C. for 2 h, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over Na2SO4, concentrated, and purified on a silica gel column using methanol: dichloromethane (1:20) as eluent to give 2-cyclopropyloxazolo[4,5-b]pyridin-5-amine (90 mg, purity: 80%) as a light yellow oil. LCMS: (ES, m / z): 176 [M+H] + . 1 H NMR: (400MHz, CD3OD) δppm 7.63 (d, J=8.7Hz, 1H), 6.52-6.49 (m, 1H), 2.25-2.20 (m, 1H), 1.26-1.20 (m, 4H).

[0897] Step 4

[0898] To a solution of 2-cyclopropyloxazolo[4,5-b]pyridin-5-amine (100 mg, 0.57 mmol, 1.0 eq) in DCM (8 mL) was added 2-bromopropionic acid (95 mg, 0.63 mmol, 1.1 eq), DCC (141 mg, 0.68 mmol, 1.2 eq) and DMAP (7.0 mg, 0.057 mmol, 0.1 eq). The mixture was stirred for 2 h, quenched with water (50 mL) and extracted with DCM (50 mL x 2). The organic phases were combined, dried over Na2SO4, concentrated and purified on a silica gel column using ethyl acetate: petroleum ether (1:10) as eluent to give 2-bromo-N-(2-cyclopropyloxazolo[4,5-b]pyridin-5-yl)propionamide (170 mg, purity: 90%, yield: 96%) as a white solid. LCMS: (ES, m / z): 310 [M+H] + . 1 H NMR: (300MHz, CD3OD) δ8.18-8.15 (m, 1H), 7.95 (d, J=9.2Hz, 1H), 4.79-4.74 (m, 1 H), 2.33-2.30(m, 1H), 1.90-1.82(m, 3H), 1.40-1.30(m, 2H), 1.20-1.12(m, 2H).

[0899] Intermediate 50

[0900] 2-Bromo-N-(5-(cyclohexylmethyl)pyridin-2-yl)propionamide

[0901]

[0902] Step 1

[0903] To tert-butyl (5-bromopyridin-2-yl)carbamate (2 g, 7.32 mmol, 1.0 eq) in THF (50 mL) was added n-butyl lithium (8.79 mL, 21.97 mmol, 3.0 eq, 2.5 M in hexane) dropwise at -78 ° C. over 15 min. After 30 minutes, cyclohexanecarboxaldehyde (1.232 g, 10.98 mmol, 1.5 eq) was added dropwise, and the resulting mixture was warmed to room temperature. After 2 h, the reaction was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, concentrated, and purified on a silica gel column eluted with ethyl acetate in petroleum ether (0-40% in 15 min) to give tert-butyl (5-(cyclohexyl(hydroxy)methyl)pyridin-2-yl)carbamate (1.57 g, purity: 95%, yield: 67%) as a white solid. LCMS: (ES, m / z): 307 [M+H] +, retention time 1.135 minutes, LCMS method 36. 1 H NMR: (400MHz, DMSO-d6) δ9.69 (s, 1H), 8.10 (d, J = 2.2Hz, 1H), 7.73 (d, J = 8.5Hz, 1H), 7.63-7.57 (m, 1H), 5.12 (d, J = 4.4Hz, 1H), 4 .27-4.18 (m, 1H), 1.89-1.79 (m, 1H), 1.73-1.54 (m, 3H), 1.47 (s, 9H), 1.45-1.27 (m, 2H), 1.21-1.01 (m, 3H), 0.99-0.81 (m, 2H).

[0904] Step 2

[0905] To a solution of tert-butyl (5-(cyclohexyl(hydroxy)methyl)pyridin-2-yl)carbamate (1.57 g, 5.12 mmol, 1.0 eq) in triethylsilane (7 mL, 43.8 mmol, 8.6 eq) was added 2,2,2-trifluoroacetic acid (7 mL, 94 mmol, 18.4 eq) at 0°C, and the resulting mixture was stirred at room temperature. After 15 h, the reaction was concentrated, and the residue was poured into ice water (100 mL) and extracted with ethyl acetate (80 mL x 3). The organic phase was washed with saturated aqueous NaHCO3 (100 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified on a silica gel column eluted with ethyl acetate in petroleum ether (0-55% in 10 min) to give 5-(cyclohexylmethyl)pyridin-2-amine (360 mg, purity: 95%, yield: 35%) as a white solid. LCMS: (ES, m / z): 191 [M+H] + , retention time 1.155 minutes, LCMS method 30. (400 MHz, DMSO-d6) δ 7.67 (d, J = 2.4 Hz, 1H), 7.19-7.12 (m, 1H), 6.37 (d, J = 8.4 Hz, 1H), 5.64 (s, 2H), 2.25 (d, J = 7.0 Hz, 2H), 1.72-1.51 (m, 5H), 1.41-1.29 (m, 1H), 1.24-1.04 (m, 3H), 0.95-0.75 (m, 2H).

[0906] Step 3

[0907] To a solution of 5-(cyclohexylmethyl)pyridin-2-amine (200 mg, 1.05 mmol, 1.0 eq) in DCM (10 mL) was added 2-bromopropionic acid (193 mg, 1.26 mmol, 1.2 eq), DCC (434 mg, 2.10 mmol, 2.0 eq) and DMAP (12.84 mg, 0.11 mmol, 0.1 eq). The reaction was stirred for 2 h, filtered, concentrated and purified on a silica gel column using ethyl acetate in petroleum ether (0-16% in 10 min) to give 2-bromo-N-(5-(cyclohexylmethyl)pyridin-2-yl)propanamide (340 mg, purity: 93%, yield: 92%) as a white solid. LCMS: (ES, m / z): 325 [M+H] + , retention time 1.385 minutes, LCMS method 30. 1 HNMR (400MHz, DMSO-d6) δ10.79 (s, 1H), 8.13 (d, J = 2.3Hz, 1H), 7.99 (d, J = 8.5Hz, 1H), 7.65-7.58 (m, 1H), 4.91-4.81 (m, 1H) , 2.44 (d, J=7.0Hz, 2H), 1.74 (d, J=6.7Hz, 3H), 1.69-1.54 (m, 5H), 1.54-1.42 (m, 1H), 1.20-1.08 (m, 3H), 0.99-0.81 (m, 2H).

[0908] Intermediates 51-53 were synthesized in a similar manner.

[0909]

[0910]

[0911] Intermediate 54

[0912] 2-Bromo-N-(6-phenoxypyridazin-3-yl)propionamide

[0913]

[0914] Step 1

[0915] To a solution of 6-chloropyridazin-3-amine (1.00 g, 7.75 mmol, 1.0 eq) in acetonitrile (10 mL) was added phenol (1.82 g, 19.38 mmol, 2.5 eq) followed by a solution of sodium hydroxide (0.93 g, 23.25 mmol, 3.0 eq) in water (5 mL). The resulting mixture was stirred at 120 ° C. for 3 days, poured into water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic extracts were dried over sodium sulfate, concentrated and purified on a silica gel column eluted with petroleum ether in ethyl acetate (0-50% in 30 min) to give 6-phenoxypyridazin-3-amine (400 mg, yield: 28%, purity: 85%) as a yellow oil. LCMS: (ES, m / z): 188 [M + H] + . 1 H NMR: (300MHz, CDCl3) δ7.42-7.36(m, 2H), 7.25-7.14(m, 3H), 7.06-6.95(m, 2H), 4.94(br, 2H).

[0916] Step 2

[0917] To a solution of 6-phenoxypyridazin-3-amine (400 mg, 2.14 mmol, 1.0 eq) and 2-bromopropionic acid (389 mg, 2.56 mmol, 1.2 eq) in DCM (10 mL) was added DCC (881 mg, 4.28 mmol, 2.0 eq) and DMAP (26 mg, 0.21 mmol, 0.1 eq). After 1 h, the reaction was filtered, concentrated, and purified on a silica gel column eluted with ethyl acetate in petroleum ether (0-30%) to give 2-bromo-N-(6-phenoxypyridazin-3-yl)propanamide (300 mg, yield: 44%, purity: 95%) as a yellow solid. LCMS: (ES, m / z): 322 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ11.51 (S, 1H), 8.71 (d, J=9.6Hz, 1H), 7.51-7.45 (m, 2H) , 7.36-7.30 (m, 2H), 7.24-7.21 (m, 2H), 4.99-4.93 (m, 1H), 1.61 (d, J=6.6Hz, 3H).

[0918] Intermediates 55-64 were synthesized in a similar manner, in some cases using cesium carbonate, CuI and dimethylglycine in dioxane in step 1.

[0919]

[0920]

[0921]

[0922] Intermediate 65

[0923] (R)-2-Bromo-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propionamide

[0924]

[0925] Step 1

[0926] A mixture of 5-bromopyrazin-2-amine (33.0 g, 190 mmol), 2,4-difluorophenol (29.6 g, 228 mmol), dimethylglycine (3.91 g, 37.9 mmol), cesium carbonate (93.0 g, 284 mmol) and copper (I) iodide (7.22 g, 37.9 mmol) in dioxane (600 mL) was heated at 110 ° C. After 2 h, the mixture was concentrated, diluted with EtOAc, washed with saturated aqueous sodium carbonate solution (2 x 100 mL) and brine (1 x 100 mL), dried over magnesium sulfate, filtered and concentrated. The resulting residue was dissolved in MeCN (200 mL), water (500 mL) was added, and the mixture was stirred at room temperature for 1 h. The resulting solid precipitate was collected by filtration, dissolved in EtOAc, concentrated onto silica gel and purified by column chromatography eluting with 0-100% ethyl acetate in heptane to afford 17.0 g (purity: 100%, yield: 40%) of 5-(2,4-difluorophenoxy)pyrazin-2-amine as a white solid. LCMS rt = 0.72 min, Method 5, (ES, m / z) 224 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δppm 7.92 (d, J=1.5Hz, 1H), 7.45-7.38 (m, 2H), 7.28 (td, J=9.2, 5.6Hz, 1H), 7.13-7.05 (m, 1H), 6.16 (s, 2H).

[0927] Step 2

[0928] A mixture of 5-(2,4-difluorophenoxy)pyrazin-2-amine (40 g, 179 mmol), (R)-2-bromopropionic acid (32.9 g, 215 mmol) and silver nitrate (4.57 g, 26.9 mmol) in DCM (700 mL) was treated with DCC (44.4 g, 215 mmol) in portions using a cooling water bath to maintain the temperature between 15 and 20° C. The resulting mixture was stirred at room temperature overnight, filtered and loaded onto a silica gel column, eluted with 5-40% ethyl acetate in heptane to give a yellow solid, which was triturated with heptane to give 43 g (purity: 97%, yield: 67%) of (R)-2-bromo-N-(5-((5-chloropyridin-2-yl)oxy)pyridin-2-yl)propanamide as a light yellow solid. LCMS (ES, m / z) 358 [M+H] + , rt = 1.03 min, Method 5. Analytical chiral HPLC (Chiral IG 150 x 4.6 mm, 70:30 EtOH:heptane): 3.43 min (desired product, major isomer) and 4.35 min (minor isomer), %ee = 92%. 1 H NMR: (400MHz, DMSO-d6) δ11.16 (s, 1H), 8.80 (d, J = 1.0Hz, 1H), 8.47 (d, J = 1.5Hz, 1H) , 7.58-7.36 (m, 2H), 7.28-7.06 (m, 1H), 4.86 (q, J=6.8Hz, 1H), 1.75 (d, J=6.8Hz, 3H).

[0929] Intermediate 66

[0930] 6-(2-bromopropionamido) cyclopentyl nicotinate

[0931]

[0932] Step 1

[0933] To a solution of 6-nitronicotinic acid (1.00 g, 5.95 mmol, 1.0 eq) in DCM (30 mL) was added oxalyl chloride (1.50 g, 11.90 mmol, 2.0 eq) and DMF (5 drops) at 0°C. The reaction was stirred at room temperature for 30 minutes and concentrated to give 6-nitronicotinyl chloride. A solution of cyclopentanol (1.00 g, 11.62 mmol, 2.0 eq) and triethylamine (18.0 g, 17.85 mmol, 3.0 eq) in DCM (40 mL) was stirred at 0°C and a solution of 6-nitronicotinyl chloride in dichloromethane (20 mL) was added dropwise. The reaction was stirred at room temperature for 2 h, poured into water (200 mL) and extracted with dichloromethane (200 mL x 3). The combined organic extracts were washed with brine (500 mL), dried over sodium sulfate, concentrated and purified on a silica gel column eluting with ethyl acetate in petroleum ether (0-30%) to give cyclopentyl 6-nitronicotinate (430 mg, yield: 28%, purity: 100%) as a white solid. 1 H NMR: (400MHz, CDCl3) δ9.20 (d, J=2.0Hz, 1H), 8.62 (d, J=2.4, 8.4Hz, 1H), 8.32 (d, J=8. 4Hz, 1H), 5.53-5.49 (m, 1H), 2.09-1.99 (m, 2H), 1.94-1.80 (m, 4H), 1.77-1.70 (m, 2H).

[0934] Step 2

[0935] To a solution of 6-nitronicotinic acid cyclopentyl ester (300 mg, 1.27 mmol, 1.0 eq) in EtOH (30 mL) and water (5 mL) was added Fe (356 mg, 6.36 mmol, 5.0 eq) and NHCl (343 mg, 6.36 mmol, 5.0 eq). The reaction was stirred at 80 ° C for 2 h, filtered and concentrated to give 6-aminonicotinic acid cyclopentyl ester (250 mg, yield: 95%, purity: 98%) as a white solid, which was used without purification. LCMS: (ES, m / z): 207 [M + H] + . 1 H NMR: (300MHz, CDCl3) δ8.50 (d, J=3.6Hz, 1H), 7.95 (d, J=2.0, 8.8Hz, 1H), 6.61 (d, J=8. 8Hz, 1H), 5.36-5.32(m, 1H), 2.01-1.93(m, 2H), 1.84-1.79(m, 4H), 1.73-1.65(m, 2H).

[0936] Step 3

[0937] To a solution of 2-bromopropionic acid (369 mg, 2.42 mmol, 2.0 eq) in DCM (30 mL) was added DCC (500 mg, 2.42 mmol, 2.0 eq), DMAP (15 mg, 0.12 mmol, 0.1 eq) and 6-aminonicotinate cyclopentyl ester (250 mg, 1.21 mmol, 1.0 eq). After 16 h, the reaction was filtered, concentrated, and purified by preparative TLC (ethyl acetate: petroleum ether = 1: 5) to give 6-(2-bromopropionamido)nicotinate cyclopentyl ester (290 mg, yield: 70%, purity: 97%) as a white solid. LCMS: (ES, m / z): 341 [M + H] + . 1 H NMR: (400MHz, CD3OD) δ8.92-8.89(m, 1H), 8.34-8.25(m, 2H), 5.47-5.32(m, 1H), 4.65-4.54 (m, 1H), 1.97 (d, J=6.9Hz, 3H), 1.93-1.79 (m, 4H), 1.75-1.66 (m, 4H).

[0938] Intermediates 67-68 were synthesized in a similar manner.

[0939]

[0940] Intermediate 69

[0941] 2-Bromo-N-(5-(1-cyclopropylethoxy)pyridin-2-yl)propionamide

[0942]

[0943] Step 1

[0944] To a solution of 5-fluoro-2-nitropyridine (500 mg, 3.52 mmol, 1.0 eq) and 1-cyclopropylethanol (546 mg, 6.34 mmol, 1.8 eq) in DMF (10 mL) was added cesium carbonate (2.29 g, 7.04 mmol, 2.0 eq) and the reaction was heated to 80 ° C. After 2 h, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined extracts were dried over sodium sulfate, concentrated and purified on a silica gel column eluted with ethyl acetate: petroleum ether (1: 3) to give 5- (1-cyclopropylethoxy) -2-nitropyridine (400 mg, yield: 55%, purity: 84%) as a yellow oil. LCMS: (ES, m / z): 209 [M + H] + . 1HNMR: (400MHz, DMSO-d6) δ8.31-8.29(m, 2H), 7.71(d, J=2.8, 8.8Hz, 1H), 4.33-4.26(m , 1H), 1.36 (d, J=6.0Hz, 3H), 1.21-1.14 (m, 1H), 0.57-0.52 (m, 2H), 0.43-0.32 (m, 2H).

[0945] Step 2

[0946] To a solution of 5-(1-cyclopropylethoxy)-2-nitropyridine (380 mg, 1.83 mmol, 1.0 eq) in methanol (8 mL) and water (2 mL) was added Fe (1.23 g, 21.92 mmol, 12.0 eq) and NHCl (198 mg, 3.65 mmol, 2.0 eq), and the mixture was heated to 80° C. After 3 h, the reaction was filtered, concentrated, and purified on a silica gel column eluted with ethyl acetate: petroleum ether (1:1) to give 5-(1-cyclopropylethoxy)pyridin-2-amine (250 mg, yield: 78%, purity: 97%) as a yellow solid. LCMS: (ES, m / z): 179 [M+H] + . 1 H NMR: (300MHz, DMSO-d6) δ7.59 (d, J=2.7Hz, 1H), 7.06 (dd, J=2.7, 8.7Hz, 1H), 6.36 (d, J=9.0Hz, 1H), 5.45 ( s, 2H), 3.59-3.50 (m, 1H), 1.20 (d, J=6.0Hz, 3H), 0.98-0.90 (m, 1H), 0.44-0.41 (m, 2H), 0.26-0.18 (m, 2H).

[0947] Step 3

[0948] To a solution of 5-(1-cyclopropylethoxy)pyridin-2-amine (230 mg, 1.28 mmol, 1.0 eq) in DCM (5 mL) was added 2-bromopropionic acid (200 mg, 1.3 mmol, 1.0 eq), DMAP (16.0 mg, 0.13 mmol, 0.1 eq) and DCC (320 mg, 1.55 mmol, 1.2 eq). After 2 h, the mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic extracts were dried over sodium sulfate, concentrated and purified on a silica gel column eluted with ethyl acetate: petroleum ether (1:4) to give 2-bromo-N-(5-(1-cyclopropylethoxy)pyridin-2-yl)propanamide (280 mg, yield: 70%, purity: 86%) as a yellow solid. LCMS: (ES, m / z): 313 [M+H]+ . 1 H NMR: (400MHz, CD3OD) δ7.98-7.95 (m, 2H), 7.38 (dd, J=3.0, 9.3Hz, 1H), 4.74-4.67 (m, 1H), 3.93-3.84 (m, 1 H), 1.81 (d, J=6.6Hz, 3H), 1.36 (d, J=6.0Hz, 3H), 1.12-1.04 (m, 1H), 0.56-0.51 (m, 2H), 0.37-0.26 (m, 2H).

[0949] Intermediates 70-82, 70, 71 and 74-76 (nitro reduction by Pd / C-catalyzed hydrogenation) were synthesized in a similar manner from 5-halogeno-2-nitropyridines.

[0950]

[0951]

[0952]

[0953]

[0954] Intermediate 83

[0955] 2-Bromo-N-(6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)propionamide

[0956]

[0957] Step 1

[0958] A mixture of 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride (200 mg, 1.047 mmol, 1.0 eq), cyclopropylboronic acid (180 mg, 2.094 mmol, 2.0 eq), 2,2'-bipyridine (164 mg, 1.047 mmol, 1.0 eq), diacetoxycopper (190 mg, 1.047 mmol, 1.0 eq), and NaCO (333 mg, 3.14 mmol, 3.0 eq) in 1,2-dichloroethane (20 mL) was evacuated and purged with nitrogen three times, then stirred at 70°C. After 2 h, the reaction was filtered and concentrated. The residue was diluted with 25% NH3·H2O (100 mL, aq.) and extracted with ethyl acetate (100 mL x 2). The combined extracts were washed with water (100 mL), dried over sodium sulfate, concentrated, and purified on a silica gel column eluted with ethyl acetate: petroleum ether (1:1) to give 2-chloro-6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (280 mg, purity: 90%) as a brown solid. LCMS: (ES, m / z): 195 [M+H] + , retention time 0.952 minutes, LCMS method 34. 1 H NMR: (300MHz, DMSO-d6) δ7.70 (d, J=8.1Hz, 1H), 7.31 (d, J=8.1Hz, 1H), 3.96 (d, J=8.7Hz, 4H), 2.09-2.06 (m, 1H), 0.52-0.36 (m, 4H).

[0959] Step 2

[0960] A mixture of 2-chloro-6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (800 mg, 4.11 mmol, 1.0 eq), X-phos (392 mg, 0.822 mmol, 0.2 eq), H2N Boc (962 mg, 8.22 mmol, 2.0 eq), Cs2CO3 (2.68 g, 8.22 mmol, 2.0 eq) and Pd(OAc)2 (92 mg, 0.411 mmol, 0.1 eq) in dioxane (10 mL) was evacuated and purged with nitrogen three times, then stirred at 90°C. After 3 h, the reaction was filtered and concentrated. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The organic extract was dried over sodium sulfate, concentrated, and purified on a silica gel column using ethyl acetate:petroleum ether (1:3) as the eluent to afford 500 mg (90% purity, 64% yield) of tert-butyl (6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)carbamate as a yellow solid. LCMS: (ES, m / z): 276 [M+H] + . 1 H NMR: (300MHz, DMSO-d6) δ9.65 (s, 1H), 7.61-7.53 (m, 2H), 3.92 (s, 2H), 3.84 (s, 2H), 2.08-2.03 (m, 1H), 1.44 (s, 9H), 0.51-0.34 (m, 4H).

[0961] Step 3

[0962] A mixture of tert-butyl (6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)carbamate (500 mg, 1.816 mmol 1.0 eq), dichloromethane (12 mL) and TFA (3 mL) was stirred at room temperature for 2 h and concentrated. The residue was diluted with water (100 mL) and washed with dichloromethane (100 mL). The aqueous phase was separated and adjusted to pH 7-8 with saturated NaHCO3 aqueous solution and extracted with methanol: dichloromethane (100 mL×3, 1:10). The combined organic phases were dried over Na2SO4 and concentrated to give 6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-amine 260 mg (purity: 95%) as a brown solid, which was used without further purification. LCMS: (ES, m / z): 176 [M+H] + , retention time 0.726 minutes, LCMS method 30. 1H NMR: (400MHz, DMSO-d6)δppm 7.21 (d, J=8.0Hz, 1H), 6.23 (d, J=8.0Hz, 1H), 5.75 (s, 2H), 3.82 (s, 2H), 3.75 (s, 2H), 2.07-1.97 (m, 1H), 0.48-0.34 (m, 4H).

[0963] Step 4

[0964] A mixture of 6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-amine (260 mg, 1.484 mmol, 1.0 eq), 2-bromopropionic acid (340 mg, 2.226 mmol, 1.5 eq), DCC (459 mg, 2.226 mmol, 1.5 eq) and DMAP (18 mg, 0.148 mmol, 0.1 eq) in DCM (10 mL) was stirred for 2 h, filtered, and concentrated. The residue was dissolved in DMF (5 mL) and purified by reverse phase chromatography (C18 spherical column, 100A) eluting with 0-40% AcCN in water (10 mM NH4HCO3) to give 2-bromo-N-(6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)propanamide (310 mg, purity: 95%, yield: 66.7%) as a yellow oil. LCMS: (ES, m / z): 310 [M+H] + , retention time 1.007 minutes, LCMS method 34. 1 H NMR: (300MHz, DMSO-d6) δ10.88 (s, 1H), 7.93 (d, J=8.4Hz, 1H), 7.67 (d, J=8.4Hz, 1H), 4.88-4 .81 (m, 1H), 4.10-3.96 (m, 4H), 2.20-2.16 (m, 1H), 1.74 (d, J=6.7Hz, 3H), 0.54-0.43 (m, 4H).

[0965] Intermediate 84

[0966] 2-Bromo-N-(5-(cyclopropylmethoxy)pyrimidin-2-yl)propionamide

[0967]

[0968] Step 1

[0969] To a solution of 2-chloropyrimidin-5-ol (1.00 g, 7.69 mmol, 1.0 eq) in DMF (10 mL) was added potassium carbonate (2.13 g, 15.38 mmol, 2.0 eq) and (bromomethyl)cyclopropane (2.06 g, 15.38 mmol, 2.0 eq), and the resulting mixture was stirred at 50 ° C for 2 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate in petroleum ether (0-25%, 30 min) as an eluent to give 2-chloro-5-(cyclopropylmethoxy)pyrimidine (1.35 g, yield: 95%, purity: 97%) as a white solid. LCMS: (ES, m / z): 185 [M + H] + . 1 H NMR: (400MHz, DMSO-d6) δ 8.53 (s, 2H), 4.00 (d, J = 7.2Hz, 2H), 1.31-1.18 (m, 1H), 0.63-0.58 (m, 2H), 0.37-0.34 (m, 2H).

[0970] Step 2

[0971] In a sealed tube, 2-chloro-5-(cyclopropylmethoxy)pyrimidine (1.20 g, 6.53 mmol, 1.0 eq) and NH3-H2O (10 mL, 25%) were stirred at 150°C for 3 h. The reaction was concentrated and purified on a silica gel column using methanol in dichloromethane (0-10%, 30 min) to give 5-(cyclopropylmethoxy)pyrimidin-2-amine (900 mg, 94% yield, 83.5% purity) as a white solid. LCMS: (ES, m / z): 166 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ 8.03 (s, 2H), 6.17 (s, 2H), 3.77 (d, J = 7.6Hz, 2H), 1.20-1.12 (m, 1H), 0.57-0.53 (m, 2H), 0.30-0.26 (m, 2H).

[0972] Step 3

[0973] To a solution of 2-bromopropionic acid (185 mg, 1.21 mmol, 1.0 eq) in dichloromethane (5 mL) was added DCC (300 mg, 1.45 mmol, 1.2 eq) followed by 5-(cyclopropylmethoxy)pyrimidin-2-amine (200 mg, 1.21 mmol, 1.0 eq). The resulting mixture was stirred for 12 h, poured into water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over sodium sulfate, concentrated and purified by preparative TLC (ethyl acetate: petroleum ether = 1:2) to give 2-bromo-N-(5-(cyclopropylmethoxy)pyrimidin-2-yl)propanamide (130 mg, yield: 36%, purity: 90%) as a yellow solid. LCMS: (ES, m / z): 300 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ10.81 (s, 1H), 8.45 (s, 2H), 4.95-4.89 (m, 1H), 3.96 (d, J=7.2H z, 2H), 1.72 (d, J=6.8Hz, 3H), 1.65-1.58 (m, 1H), 0.61-0.57 (m, 2H), 0.37-0.34 (m, 2H).

[0974] Intermediate 85

[0975] 2-Bromo-N-(1-(cyclopropylmethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)propanamide

[0976]

[0977] Step 1

[0978] A mixture of 1H-pyrazolo[3,4-c]pyridin-5-amine (1 g, 7.46 mmol, 1.0 eq), (bromomethyl)cyclopropane (900 mg, 6.72 mmol, 0.9 eq) and Cs2CO3 (4.86 g, 14.9 mmol, 2.0 eq) in DMF (20 mL) was stirred at 28 ° C for 1 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over Na2SO4, concentrated and purified on a silica gel column eluted with ethyl acetate: petroleum ether (1:4) to give 1-(cyclopropylmethyl)-1H-pyrazolo[3,4-c]pyridin-5-amine (250 mg, purity: 96%, yield: 17%) as a brown solid. LCMS: (ES, m / z): 189 [M+H] + . 1H NMR: (300MHz, DMSO-d6) δ8.65 (s, 1H), 7.79 (d, J = 0.6Hz, 1H), 6.58 (d, J = 1.2Hz, 1H), 5. 41 (br, 2H), 4.24 (d, J=6.9Hz, 2H), 1.32-1.11 (m, 1H), 0.52-0.38 (m, 2H), 0.36 (m, 2H).

[0979] Step 2

[0980] A mixture of 2-bromopropionic acid (243 mg, 1.60 mmol, 1.5 eq), DCC (437 mg, 2.12 mmol, 2.0 eq), DMAP (26 mg, 0.21 mmol, 0.2 eq), and 1-(cyclopropylmethyl)-1H-pyrazolo[3,4-c]pyridin-5-amine (200 mg, 1.06 mmol, 1.0 eq) in dichloromethane (20 mL) was stirred at 28° C. for 2 h. The reaction was concentrated and purified on a silica gel column eluted with ethyl acetate:petroleum ether (1:1) to give 2-bromo-N-(1-(cyclopropylmethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)propanamide (150 mg, purity: 87%, yield: 43%) as a yellow solid. LCMS: (ES, m / z): 323 [M+H] + . (400MHz, DMSO-d6) δ10.71 (s, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 7.96 (s, 1H), 4.96-4.91 (m, 1H), 4.36 (d, J=5.4Hz, 2H), 1.76 (d, J=5.1Hz, 3H), 1.32-1.11 (m, 1H), 0.64-0.55 (m, 2H), 0.50-0.46 (m, 2H).

[0981] Intermediate 86 was synthesized in a similar manner.

[0982]

[0983] Intermediate 87

[0984] 2-Bromo-N-(5-(cyclopropyloxymethyl)pyridin-2-yl)propionamide

[0985]

[0986] Step 1

[0987] To a solution of tert-butyl (5-(hydroxymethyl)pyridin-2-yl)carbamate (2.00 g, 8.93 mmol, 1.0 eq) in THF (50 mL) at 0°C was added DIEA (6.91 g, 53.57 mmol, 6.0 eq) followed by the dropwise addition of methanesulfonyl chloride (3.05 g, 26.79 mmol, 3.0 eq). The resulting mixture was stirred at 0°C for 30 minutes, then allowed to warm to room temperature and stirred for 2 hours. The reaction was poured into water (150 mL) and extracted with ethyl acetate (150 mL x 3). The combined extracts were dried over sodium sulfate, concentrated, and purified by reverse phase column (C18 silica gel 80 g) eluting with 5-50% AcCN in water (10 mM NH4HCO3) to give tert-butyl (5-(chloromethyl)pyridin-2-yl)carbamate (1.58 g, yield: 73%, purity: 99.6%) as a yellow solid. LCMS: (ES, m / z): 243 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ 8.37 (s, 1H), 8.31 (d, J=2.4Hz, 1H), 8.01 (d, J=8.8Hz, 1H), 7.73 (dd, J=2.4, 8.4Hz, 1H), 4.57 (s, 2H), 1.57 (s, 9H).

[0988] Step 2

[0989] To a solution of cyclopropanol (1.05 g, 18.10 mmol, 3.5 eq) in acetonitrile (60 mL) was added cesium carbonate (5.00 g, 15.34 mmol, 3.0 eq) and tert-butyl (5-(chloromethyl)pyridin-2-yl)carbamate (1.25 g, 5.16 mmol, 1.0 eq). The resulting mixture was stirred for 2 h, concentrated, and purified on a silica gel column using ethyl acetate in petroleum ether (0-50% over 30 min) to give tert-butyl (5-(cyclopropyloxymethyl)pyridin-2-yl)carbamate (168 mg, 12% yield, 99% purity) as a yellow solid. LCMS: (ES, m / z): 265 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ8.26 (d, J=2.0Hz, 1H) 8.16 (s, 1H), 7.97 (d, J=8.4Hz, 1H), 7.68 (dd, J=2.4 , 8.8Hz, 1H), 4.51 (s, 2H), 3.36-3.32 (m, 1H), 1.56 (s, 9H), 0.66-0.63 (m, 2H), 0.54-0.49 (m, 2H).

[0990] Step 3

[0991] Tert-butyl (5-(cyclopropyloxymethyl)pyridin-2-yl)carbamate (168 mg, 0.64 mmol, 1.0 eq) was dissolved in HCl (10 mL, 4 M in dioxane) and the resulting mixture was stirred at room temperature for 2 h. The reaction was concentrated to give crude 5-(cyclopropyloxymethyl)pyridin-2-amine (198 mg) as a yellow oil, which was used without purification. LCMS: (ES, m / z): 165 [M+H] + .

[0992] Step 4

[0993] To a solution of 5-(cyclopropyloxymethyl)pyridin-2-amine (198 mg, 1.21 mmol, 1.0 eq) and 2-bromopropionic acid (367 mg, 2.41 mmol, 2.0 eq) in DCM (10 mL) was added DCC (748 mg, 3.63 mmol, 3.0 eq) and DMAP (15 mg, 0.12 mmol, 0.1 eq). The resulting mixture was stirred for 1 h, filtered, concentrated, and purified on a silica gel column using ethyl acetate in petroleum ether (0-30% over 15 min) to give 2-bromo-N-(5-(cyclopropyloxymethyl)pyridin-2-yl)propanamide (66 mg, yield: 18%, purity: 96%) as a yellow oil. LCMS: (ES, m / z): 299 [M+H] + . 1 H NMR: (300MHz, CD3OD) δ8.30 (s, 1H) 8.12-8.09 (m, 1H), 7.82-7.77 (m, 1H), 4.78-4.6 8(m, 1H), 4.57(s, 2H), 3.43-3.37(m, 1H), 1.84(d, J=6.6Hz, 3H), 0.65-0.50(m, 4H).

[0994] Intermediate 88

[0995] 2-Bromo-N-(5-(oxazol-2-ylmethyl)pyridin-2-yl)propionamide

[0996]

[0997] Step 1

[0998] A mixture of methyl 2-(6-chloropyridin-3-yl)acetate (5.1 g, 27.56 mmol, 1.0 eq) and NH 3 (7 M in methanol, 50 mL) was stirred at 25 ° C. for 16 h, concentrated, diluted with water (100 mL), and extracted with ethyl acetate (100 mL×3). The combined organic extracts were dried over sodium sulfate and concentrated to give crude 2-(6-chloropyridin-3-yl)acetamide (4.6 g, purity: 93%, yield: 98%) as a yellow solid, which was used without purification. LCMS: (ES, m / z): 171 [M+H] + . 1 H NMR: (300MHz, DMSO-d6) δ 8.27 (d, J=2.4Hz, 1H), 7.74 (dd, J=8.1, 2.4Hz, 1H), 7.57 (s, 2H), 7.46 (d, J=8.1Hz, 1H), 3.45 (s, 2H).

[0999] Step 2

[1000] A mixture of 2-(6-chloropyridin-3-yl)acetamide (1.6 g, 9.41 mmol, 1.0 eq), Eaton's reagent (14.4 g, 56.47 mmol, 6 eq) and 1,3-dioxol-2-one (1.61 g, 18.82 mmol, 2 eq) was evacuated and purged with nitrogen three times, and the reaction was stirred at 100 ° C. After 16 h, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined extracts were dried over sodium sulfate, concentrated, and purified on a silica gel column eluted with dichloromethane:methanol (10:1) to give 2-((6-chloropyridin-3-yl)methyl)oxazole (490 mg, purity: 88%, yield: 26%) as a yellow oil. LCMS: (ES, m / z): 195 [M+H] + . 1 H NMR: (400MHz, DMSO-d6)δppm 8.39 (d, J=2.4Hz, 1H), 8.05 (d, J=0.9Hz, 1H), 7.81 (dd, J=11.2, 3.6Hz, 1H), 7.50 (d, J=11.2Hz, 1H), 7.15 (d, J=0.9Hz, 1H), 4.23 (s, 2H).

[1001] Step 3

[1002] To a solution of 2-((6-chloropyridin-3-yl)methyl)oxazole (480 mg, 2.47 mmol, 1 eq) and tert-butyl carbamate (348 mg, 2.97 mmol, 1.2 eq) in dioxane (5 ml) was added CsCO (2.01 g, 6.17 mmol, 2.5 eq), Pd(OAc) (28 mg, 0.12 mmol, 0.05 eq) and X-Phos (118 mg, 0.247 mmol, 0.1 eq). The flask was evacuated and purged with nitrogen three times, and the mixture was stirred at 90 ° C for 2 h. The solvent was removed under reduced pressure, and the residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic extracts were dried over sodium sulfate, concentrated, and purified on a silica gel column using ethyl acetate:petroleum ether (1:1) as the eluent to give tert-butyl (5-(oxazol-2-ylmethyl)pyridin-2-yl)carbamate (360 mg, purity: 80%, yield = 53%) as a yellow solid. LCMS: (ES, m / z): 276 [M+H] + . 1 H NMR: (300MHz, DMSO-d6)δppm 9.77 (s, 1H), 8.18 (d, J = 2.4Hz, 1H), 8.03 (d, J = 1.2Hz, 1H), 7.76 (d, J = 8.4Hz, 1H ), 7.65 (dd, J=8.4, 2.4Hz, 1H), 7.14 (d, J=1.2Hz, 1H), 4.11 (s, 2H), 1.47 (s, 9H).

[1003] Step 4

[1004] A mixture of tert-butyl (5-(oxazol-2-ylmethyl)pyridin-2-yl)carbamate (360 mg, 1.31 mmol, 1 eq) and trifluoroacetic acid (1 mL) in dichloromethane (5 mL) was stirred at 25 ° C. for 3 h. The mixture was concentrated and diluted with water (100 mL), and the pH of the solution was adjusted to 7-8 with NaHCO 3. The solution was extracted with ethyl acetate (100 mL×3), and the extract was dried over sodium sulfate, concentrated, and purified on a silica gel column eluted with dichloromethane: methanol (10:1) to give 5-(oxazol-2-ylmethyl)pyridin-2-amine (130 mg, purity: 80%, yield: 56%) as a yellow solid. LCMS: (ES, m / z): 176 [M+H] + . 1H NMR: (300MHz, DMSO-d6)δppm 8.00 (d, J=0.9Hz, 1H), 7.82 (d, J=2.4Hz, 1H), 7.27 (dd, J=8.4, 2.4Hz, 1H), 7.11 (d, J=0.9Hz, 1H), 6.40 (d, J=8.4Hz, 1H), 5.85 (s, 2H), 3.92 (s, 2H).

[1005] Step 5

[1006] A mixture of 2-bromopropionic acid (108 mg, 0.71 mmol, 1 eq), DCC (368 mg, 1.78 mmol, 2.5 eq), DMAP (9 mg, 0.071 mmol, 0.1 eq) and 5-(oxazol-2-ylmethyl)pyridin-2-amine (125 mg, 0.71 mmol, 1 eq) in dichloromethane (2 mL) was stirred at 25 ° C. for 2 h and then filtered. The filtrate was concentrated and purified on a silica gel column eluted with ethyl acetate: petroleum ether (1:1) to give 2-bromo-N-(5-(oxazol-2-ylmethyl)pyridin-2-yl)propanamide (170 mg, purity: 90%, yield: 77%) as a yellow solid. LCMS: (ES, m / z): 310 [M + H] + . 1 H NMR: (300MHz, DMSO-d6)δppm 10.90 (s, 1H), 8.30 (d, J = 2.4Hz, 1H), 8.09-8.00 (m, 2H), 7.75 (dd, J = 8.4, 2 .4Hz, 1H), 7.15(s, 1H), 4.90-4.84(m, 1H), 4.17(s, 2H), 1.78-1.66(m, 3H).

[1007] Intermediate 89

[1008] 2-Bromo-N-(5-(isoxazol-3-yl)pyridin-2-yl)propanamide

[1009]

[1010] Step 1

[1011] To a solution of 6-aminopyridine-3-carboxaldehyde (2.5g, 20.5mmol, 1.0eq) in THF (20mL), di-tert-butyl dicarbonate (9.8g, 45mmol, 2.2eq), triethylamine (6.2g, 61.5mmol, 3.0eq) and 4-dimethylaminopyridine (0.25g, 2mmol, 0.1eq) were added. The resulting mixture was stirred at room temperature for 16h, concentrated and distributed between dichloromethane and water. The aqueous layer was extracted again with dichloromethane (200mL x 2), and the combined extracts were dried over sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate: petroleum ether (1:2) to obtain tert-butyl N-[(tert-butoxy) carbonyl]-N-(5-formylpyridin-2-yl)carbamate (2.7g, purity: 90%, yield: 41%), which was a yellow oil.

[1012] LCMS: (ES, m / z): 323 [M+H] + . 1 H NMR: (400MHz, CDCl3-d) δppm 10.08 (s, 1H), 8.88 (d, J=2.4Hz, 1H), 8.22 (dd, J=8.8, 2.4Hz, 1H), 7.68 (d, J=8.8Hz, 1H), 1.53 (s, 18H).

[1013] Step 2

[1014] A mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-(5-formylpyridin-2-yl)carbamate (2.0 g, 6.2 mmol, 1.0 eq), AcONa (306 mg, 3.7 mmol, 0.6 eq) and H2NOH-HCl (515 mg, 7.4 mmol, 1.2 eq) in methanol:water (10 mL, 1:1) was stirred at 25 ° C for 1 h and poured into water (200 mL). The resulting solid was collected by filtration and dried to give tert-butyl N-[(tert-butoxy)carbonyl]-N-{5-[(1E)-(hydroxyimino)methyl]pyridin-2-yl}carbamate (1.7 g, purity: 95%, yield: 77%) as a white solid, which was used without further purification. LCMS: (ES, m / z): 195 [M + H] + . 1 H NMR: (400MHz, DMSO-d6) δppm 11.57 (s, 1H), 8.60 (d, J=2.4Hz, 1H), 8.23 ​​(dd, J=8.4, 2.4Hz, 1H), 8.12-8.06 (m, 1H), 7.43 (d, J=8.4Hz, 1H), 1.41 (s, 18H).

[1015] Step 3

[1016] To a solution of tert-butyl N-[(tert-butoxy)carbonyl]-N-{5-[(1E)-(hydroxyimino)methyl]pyridin-2-yl}carbamate (1.5 g, 4.45 mmol, 1.0 eq) in DMF (10 mL) was added N-chlorosuccinimide (710 mg, 5.34 mmol, 1.2 eq) and the reaction was stirred at 30° C. After 30 minutes, diethyl ether (90 mL) was added and the reaction was cooled to −5° C. Triethylamine (30 mL) was added, followed by ethynyltrimethylsilane (35 mL). After 1 h, the reaction was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (100 mL×3). The combined extracts were dried over sodium sulfate, concentrated and purified on a silica gel column eluting with ethyl acetate:petroleum ether (1:1) to give tert-butyl N-[(tert-butoxy)carbonyl]-N-{5-[5-(trimethylsilyl)-1,2-oxazol-3-yl]pyridin-2-yl}carbamate (1.8 g, purity: 95%, yield: 91%) as a white solid.

[1017] LCMS: (ES, m / z): 434 [M+H] + . 1 H NMR: (300MHz, CDCl3) δppm 8.89 (d, J=2.4Hz, 1H), 8.23 ​​(dd, J=8.4, 2.4Hz, 1H), 7.40 (dd, J=8.4, 0.9Hz, 1H), 6.80 (s, 1H), 1.48 (s, 18H), 0.42 (s, 9H).

[1018] Step 4

[1019] A mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-{5-[5-(trimethylsilyl)-1,2-oxazol-3-yl]pyridin-2-yl}carbamate (1 g, 2.3 mmol, 1 eq), methanol (20 mL) and potassium carbonate (316 mg, 2.3 mmol, 1 eq) was stirred at 40 ° C. After 1 h, the reaction was concentrated, diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined extracts were dried over sodium sulfate, concentrated and purified on a silica gel column, eluting with ethyl acetate: petroleum ether (1:1) to give tert-butyl N-[(tert-butoxy)carbonyl]-N-[5-(1,2-oxazol-3-yl)pyridin-2-yl]carbamate (400 mg, purity: 80%, yield: 48%) as a white solid. LCMS: (ES, m / z): 362 [M+H] + . 1H NMR: (300MHz, CDCl3) δppm 8.74 (s, 1H), 8.50 (d, J=1.8Hz, 1H), 8.20 (s, 1H), 8.18-8.07 (m, 1H), 6.68 (d, J=1.8Hz, 1H), 1.58 (s, 18H).

[1020] Step 5

[1021] A solution of tert-butyl N-[(tert-butoxy)carbonyl]-N-[5-(1,2-oxazol-3-yl)pyridin-2-yl]carbamate (500 mg, 1.38 mmol, 1 eq) in dichloromethane (10 mL) and trifluoroacetic acid (2 mL) was stirred for 2 h, concentrated and diluted with water (100 mL). The pH of the reaction was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (100 mL×3). The combined extracts were dried over sodium sulfate, concentrated and purified on a silica gel column eluted with methanol: dichloromethane (1:5) to give 5-(isoxazol-3-yl)pyridin-2-amine (200 mg, purity: 97%, yield = 89%) as a yellow solid. LCMS: (ES, m / z): 162 [M+H] + . 1 H NMR: (300MHz, DMSO-d6)δppm 8.90 (d, J=1.8Hz, 1H), 8.44 (d, J=2.5Hz, 1H), 7.85 (dd, J=8.6, 2.5Hz, 1H), 7.03 (d, J=1.8Hz, 1H), 6.58-6.46 (m, 1H), 6.42 (s, 2H).

[1022] Step 6

[1023] To a mixture of 5-(isoxazol-3-yl)pyridin-2-amine (200 mg, 1.24 mmol, 1 eq) and 2-bromopropionic acid (190 mg, 1.24 mmol, 1.0 eq) in dichloromethane (4 mL) was added dicyclohexylcarbodiimide (512 mg, 2.48 mmol, 2 eq) and 4-dimethylaminopyridine (30 mg, 0.248 mmol, 0.1 eq). The reaction was stirred for 4 h, filtered through a pad of celite, filtered, concentrated, and purified on a silica gel column eluted with ethyl acetate: petroleum ether (1:1) to give 2-bromo-N-(5-(isoxazol-3-yl)pyridin-2-yl)propanamide (330 mg, purity: 90%, yield: 90%) as a yellow oil. LCMS: (ES, m / z): 296 [M+H] + . 1H NMR: (300MHz, DMSO-d6) δppm 11.15 (s, 1H), 9.06 (d, J=1.8Hz, 1H), 8.90-8.89 (m 1H), 8.34 (dd, J=8.7, 2.4Hz, 1H), 8.23 ​​(d, J=8.7Hz, 1H), 7.24 (d, J=1.8Hz, 1H), 4.91 (m, 1H), 1.77 (d, J=6.6Hz, 3H).

[1024] Intermediate 90

[1025] N-(6-Benzylpyridazin-3-yl)-2-bromopropionamide

[1026]

[1027] Step 1

[1028] To a solution of 6-chloropyridazin-3-amine (258 mg, 2.0 mmol, 1.0 eq) in dioxane (2 mL) was added benzylzinc (II) bromide (6.0 mL, 3.0 mmol, 1.5 eq) and Pd (PPh 3 ) 4 (230 mg, 0.2 mmol, 0.1 eq), and the flask was evacuated and purged with nitrogen three times. The reaction was stirred at 80° C. under microwave for 1 h, filtered, concentrated, and purified by preparative TLC (ethyl acetate: petroleum ether = 1: 2) to give 6-benzylpyridazin-3-amine (130 mg, purity: 98%) as a white solid. LCMS: (ES, m / z): 186 [M + H] + . 1 H NMR: (300MHz, CDCl3) δ7.34-7.22 (m, 5H), 7.04 (d, J=9.0Hz, 1H), 6.73 (d, J=9.3Hz, 1H), 4.92 (br, 2H), 4.20 (s, 2H).

[1029] Step 2

[1030] A mixture of 6-benzylpyridazin-3-amine (100 mg, 0.54 mmol, 1.0 eq), 2-bromopropionic acid (91 mg, 0.59 mmol, 1.1 eq), DCC (134 mg, 0.65 mmol, 1.2 eq) and DMAP (66.0 mg, 0.54 mmol, 0.1 eq) in DCM (3.0 mL) was stirred for 1 h, filtered, concentrated, and purified by preparative TLC (ethyl acetate: petroleum ether = 1:2) to give N-(6-benzylpyridazin-3-yl)-2-bromopropionamide (140 mg, purity: 94%, yield: 77%) as a white solid. LCMS: (ES, m / z): 320 [M + H] +. (400MHz, DMSO-d6) δ11.46 (br, 1H), 8.23 ​​(d, J = 9.0Hz, 1H), 7.60 (d, J = 9.0Hz, 1 H), 7.34-7.22 (m, 5H), 4.93-4.87 (m, 1H), 4.25 (s, 2H), 1.75 (d, J=6.6Hz, 3H).

[1031] Intermediate 91

[1032] 2-Bromo-N-(5-(pyridin-4-ylmethyl)pyridin-2-yl)propionamide

[1033]

[1034] Step 1

[1035] Tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (1.00 g, 3.13 mmol, 1 eq), HBr salt of 4-(bromomethyl)pyridine (791 mg, 3.13 mmol, 1 eq), Pd(dppf)Cl2 (229 mg, 0.31 mmol, 0.1 eq) and Cs2CO3 (3.06, 9.38 mmol) were added to the mixture. A mixture of 1,3 eq) in THF (10 mL) and water (5 mL) was evacuated and purged with nitrogen three times, then stirred at 80° C. for 6 h, concentrated, and purified by C18 (120 g) column chromatography eluting with 0-80% AcCN in water (0.05%, TFA) to give tert-butyl (5-(pyridin-4-ylmethyl)pyridin-2-yl)carbamate (200 mg, yield: 24%, purity: 63%) as a yellow oil. LCMS: (ES, m / z): 286 [M+H] + . 1 HNMR: (300MHz, CDCl3) δ 8.62-8.49 (m, 2H), 7.69-7.37 (m, 4H), 7.22-7.11 (m, 1H), 3.97 (s, 2H), 1.54 (s, 9H).

[1036] Step 2

[1037] Tert-butyl (5-(pyridin-4-ylmethyl)pyridin-2-yl)carbamate (200 mg, 0.70 mmol, 1 eq), DCM (10 mL) and TFA (3 mL) were stirred for 3 h, concentrated, and purified by C18 (120 g) column chromatography eluting with 0-50% AcCN in water (10 mmol / L, NH4HCO3) to give 5-(pyridin-4-ylmethyl)pyridin-2-amine (110 mg, yield: 85%, purity: 100%) as a red oil. LCMS: (ES, m / z): 186 [M+H] + . 1 H NMR: (300MHz, CD3OD) δ 8.90-8.75 (m, 2H), 8.15-7.80 (m, 4H), 7.14-6.95 (m, 1H), 4.34 (s, 2H).

[1038] Step 3

[1039] To a solution of 2-bromopropionic acid (91 mg, 0.59 mmol, 1.0 eq) in DCM (10 mL) was added DCC (245 mg, 1.19 mmol, 2.0 eq), DMAP (14.51 mg, 0.12 mmol, 0.2 eq) and 5-(pyridin-4-ylmethyl)pyridin-2-amine (110 mg, 0.59 mmol, 1.0 eq). After 16 h, the reaction was adsorbed onto silica and purified by silica column (40 g), eluting with 0-100% ethyl acetate-petroleum ether to afford 2-bromo-N-(5-(pyridin-4-ylmethyl)pyridin-2-yl)propanamide (120 mg, 58.7% yield, 93% purity) as a white solid. LCMS: (ES, m / z): 320 [M+H] + , retention time 0.669 minutes, LCMS method 36. 1 H NMR: (400MHz, CDCl3)δppm 8.62(s, 1H), 8.60-8.54(m, 2H), 8.22-8.15(m, 2H), 7.59-7.53(m, 1H), 7.1 9 (d, J=5.7Hz, 2H), 4.57-4.52 (m, 1H), 4.02 (s, 2H), 1.98 (d, J=6.8Hz, 3H).

[1040] Intermediate 92

[1041] 2-Bromo-N-(5-(pyridin-2-ylmethyl)pyridin-2-yl)propionamide

[1042]

[1043] Step 1

[1044] To methyl 2-(pyridin-2-yl)acetate (1.51 g, 10.0 mmol, 1 eq) and H2O (0.19 g, 10.5 mmol, 1.05 eq) was added a solution of t-BuOK (1.18 g, 10.5 mmol, 1.05 eq) in EtOH (10 mL) at 60°C over 10 min. After 3 h, the reaction was concentrated in vacuo and ether (20 mL) was added. The resulting solid was collected by filtration to give potassium 2-(pyridin-2-yl)acetate (1.6 g, yield: 91%, purity: 100%) as a white solid, which was used without purification. LCMS: (ES, m / z): 138 [M+H-39+H] + . 1 H NMR: (400MHz, DMSO-d6) δ 8.35-8.33 (m, 1H), 7.60-7.56 (m, 1H), 7.30-7.27 (m, 1H), 7.09-7.06 (m, 1H), 3.49 (s, 2H).

[1045] Step 2

[1046] To a 25 mL sealed tube was added a solution of potassium 2-(pyridin-2-yl)acetate (517 mg, 2.96 mmol, 1.2 eq) in 1,3,5-trimethylbenzene (10 mL), 5-bromo-2-nitropyridine (500 mg, 2.46 mmol, 1.0 eq), Pd2(dba)3 (113 mg, 0.12 mmol, 0.05 eq) and Xantphos (86 mg, 0.15 mmol, 0.06 eq), and the mixture was evacuated and purged with nitrogen three times, then stirred overnight at 150° C. The reaction was cooled to room temperature, and MeOH (10 mL) was added. The mixture was filtered, concentrated and purified by C18 (120 g) column chromatography eluting with AcCN in water (0.05%, TFA) to give 2-nitro-5-(pyridin-2-ylmethyl)pyridine (120 mg, yield: 23%, purity: 100%) as a yellow oil. LCMS: (ES, m / z): 216 [M+H] + . 1 H NMR: (400MHz, CDCl3) δppm8.67-8.60 (m, 1H), 8.56 (d, J=2.2Hz, 1H), 8.21 (d, J=8.2Hz, 1H), 8.01 (d d, J=8.3Hz, 2.3Hz, 1H), 7.88-7.86 (m, 1H), 7.43-7.37 (m, 1H), 7.35 (d, J=7.9Hz, 1H), 4.40 (s, 2H).

[1047] Step 3

[1048] To a mixture of 2-nitro-5-(pyridin-2-ylmethyl)pyridine (120 mg, 0.56 mmol, 1 eq), MeOH (5 mL) and Pd / C (10%, 24 mg) was bubbled H at room temperature for 2 h. The reaction was filtered and concentrated to give 5-(pyridin-2-ylmethyl)pyridin-2-amine (120 mg, yield: (crude), purity: 97%) as a yellow oil, which was used without purification. LCMS: (ES, m / z): 186 [M+H] + . 1 H NMR: (400MHz, CD3OD)δppm 8.56 (d, J=5.1Hz, 1H), 7.99-7.97 (m, 1H), 7.87 (dd, J=9.2Hz, 2.2Hz, 1H), 7.80-7.7 8 (m, 1H), 7.52 (d, J=7.9Hz, 1H), 7.49-7.42 (m, 1H), 7.02-6.95 (m, 1H), 4.14 (s, 2H).

[1049] Step 4

[1050] A mixture of 2-bromopropionic acid (119 mg, 0.78 mmol, 1.2 eq), DCC (267 mg, 1.30 mmol, 2 eq), DMAP (16 mg, 0.13 mmol, 0.2 eq) and 5-(pyridin-2-ylmethyl)pyridin-2-amine (120 mg, 0.65 mmol, 1 eq) in DCM (10 mL) was stirred at room temperature overnight, filtered, concentrated, and purified by preparative TLC using ethyl acetate:petroleum ether (1:3) to give 2-bromo-N-(5-(pyridin-2-ylmethyl)pyridin-2-yl)propanamide (50 mg, yield: 24%, purity: 74%) as a white solid. LCMS: (ES, m / z): 320 [M+H] + . 1 H NMR: (300MHz, CD3OD)δppm 8.00 (d, J=0.9Hz, 1H), 7.82 (d, J=2.4Hz, 1H), 7.27 (dd, J=8.4, 2.4Hz, 1H), 7.11 (d, J=0.9Hz, 1H), 6.40 (d, J=8.4Hz, 1H), 5.85 (s, 2H), 3.92 (s, 2H).

[1051] Intermediate 93

[1052] 2-Bromo-N-(5-(pyridin-2-yloxy)pyridin-2-yl)propionamide

[1053]

[1054] Step 1

[1055] 2-Chloropyridine (0.644mL, 6.81mmol), 6-aminopyridine-3-ol (0.5g, 4.54mmol) and cesium carbonate (3.70g, 11.35mmol) are stirred at 120°C in DMSO (6mL). After 18h, the mixture is slowly dripped into water (60mL), stored in a refrigerator over the weekend, and then extracted with EtOAc (4x100mL). The combined organic layer is washed with brine (2x50mL), dried over sodium sulfate, concentrated and purified by flash chromatography (silica 40g Gold column), eluted with 0-20% MeOH in DCM to obtain 5-(pyridin-2-yloxy)pyridine-2-amine (460mg, 2.334mmol, purity: 95%, recovery: 51%) as an orange solid. LCMS (m / z) 188 (M+H) + , retention time: 0.23 minutes, LC / MS method 2. 1 H NMR: (400MHz, DMSO-d6) δ8.10 (dd, J=4.89, 1.47Hz, 1H), 7.80 (ddd, J=8.31, 7.34, 1.96Hz, 1H), 7.74 (d, J=2.45Hz, 1H), 7.22 ( dd, J=8.80, 2.93Hz, 1H), 7.07 (ddd, J=7.34, 4.89, 0.98Hz, 1H), 6.96 (d, J=8.31Hz, 1H), 6.49 (d, J=8.80Hz, 1H), 5.82 (s, 2H).

[1056] Step 2

[1057] To a solution of 5-(pyridin-2-yloxy)pyridin-2-amine (0.46 g, 2.457 mmol) and 2-bromopropionic acid (0.243 mL, 2.70 mmol) in DCM (15 mL) at 0°C was added DCC (0.608 g, 2.95 mmol) and the reaction was allowed to warm to room temperature. After 18 h, the reaction was filtered, concentrated, and purified by column chromatography (24 g Gold), eluting with 0-100% EtOAc in heptane to provide 2-bromo-N-(5-(pyridin-2-yloxy)pyridin-2-yl)propanamide (790 mg, 2.33 mmol, purity: 95%, recovery: 95%) as a yellow solid. LCMS (m / z) 322 (M+H) + , retention time: 0.82 minutes, LC / MS method 2. 1H NMR: (400MHz, DMSO-d6) δ10.91 (s, 1H) 8.19-8.30 (m, 1H), 8.09-8.18 (m, 2H), 7.88 (ddd, J=8.44, 6.72, 1.9 6Hz, 1H), 7.67 (dd, J=8.80, 2.93Hz, 1H), 7.07-7.21 (m, 2H), 4.89 (q, J=6.68Hz, 1H) 1.76 (d, J=6.85Hz, 3H).

[1058] Intermediates 94-96 were synthesized in a similar manner with the addition of 0.2 eq of CuI and dimethylglycine in dioxane in the chloride displacement.

[1059]

[1060] Intermediate 97

[1061] 2-Bromo-N-(6-(2-cyanophenoxy)pyridazin-3-yl)propionamide

[1062]

[1063] Step 1

[1064] A solution of 3,6-dichloropyridazine (5 g, 33.6 mmol), 2-hydroxybenzonitrile (4.40 g, 36.9 mmol) and potassium carbonate (6.96 g, 50.3 mmol) in DMF (35 mL) was stirred at 80 ° C for 18 h. The reaction was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc (2x100 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, concentrated and purified by column chromatography (ISCO 220 g Gold), eluting with 0-13% MeOH in DCM to provide 2- ((6-chloropyridazine-3-yl) oxy) benzonitrile (7.348 g, 30.1 mmol, purity: 95%, recovery: 90%) as a white solid. LCMS (m / z) 232 (M + H) + , retention time: 0.73 minutes, LC / MS method 2. 1 H NMR: (400MHz, DMSO-d6) δ8.07 (d, J=9.29Hz, 1H), 7.99 (dd, J=7.82, 1.47Hz, 1H), 7.80-7.88 (m, 2H), 7.48-7.58 (m, 2H).

[1065] Step 2

[1066] To a nitrogen-purged microwave vial containing 2-((6-chloropyridazin-3-yl)oxy)benzonitrile (250 mg, 1.079 mmol), Pd(dba)(49.4 mg, 0.054 mmol), Xantphos (31.2 mg, 0.054 mmol) and cesium carbonate (879 mg, 2.70 mmol) was added dioxane (5 mL) followed by diphenylformimine (0.181 mL, 1.079 mmol). The reaction was microwave-heated to 120°C for 30 minutes and then heated to 150°C for 16 h. The mixture was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water and brine, dried over sodium sulfate, concentrated and purified by column chromatography (ISCO 24g Gold) eluting with 0-100% EtOAc in heptane to afford 2-((6-((diphenylmethylene)amino)pyridazin-3-yl)oxy)benzonitrile (115 mg, 0.183 mmol, purity: 60%, recovery: 17%) as a brownish orange solid. LCMS (m / z) 377 (M+H) + , retention time: 1.16 minutes, LC / MS method 3. 1 H NMR: (400MHz, DMSO-d6) δ8.35-8.48 (m, 2H), 7.80 (d, J=2.93Hz, 1H), 7.28 (dd, J=8.80, 2.93Hz, 1H), 6.82-6.93 (m, 2H), 6.53 (d, J=8.80Hz, 1H), 6.00 (s, 2H).

[1067] Step 3

[1068] To a solution of 2-((6-((diphenylmethylene)amino)pyridazin-3-yl)oxy)benzonitrile (115 mg, 0.306 mmol) in MeOH (3 mL) was added 1 M aq HCl (3.00 mL). After several hours at room temperature, the reaction was extracted with DCM, and the aqueous layer was concentrated to afford crude 2-((6-((diphenylmethylene)amino)pyridazin-3-yl)oxy)benzonitrile (115 mg, 0.306 mmol, purity: 93%, recovery: 20%) as a light yellow solid, which was used without purification. LCMS (m / z) 213 (M+H) + , retention time: 0.56 minutes, LC / MS method 3.

[1069] Step 4

[1070] A solution of 2-((6-aminopyridazin-3-yl)oxy)benzonitrile (16 mg, 0.075 mmol), 2-bromopropionic acid (12.69 mg, 0.083 mmol) and DCC (18.67 mg, 0.090 mmol) in DCM (5 mL) was stirred over the weekend and then directly purified by flash chromatography (ISCO 220 g Gold) eluting with 0-60% EtOAc in heptane to afford 2-bromo-N-(6-(2-cyanophenoxy)pyridazin-3-yl)propanamide (10 mg, 0.027 mmol, purity: 95%, recovery: 36%) as a white solid. LCMS (m / z) 348 (M+H) + , retention time: 0.87 minutes, LC / MS method 3. 1 H NMR: (400MHz, CD3OD) δ8.59 (d, J=9.3Hz, 1H), 7.85 (dd, J=7.8, 1.5Hz, 1H), 7.78 (td, J=7.9, 1.7 Hz, 1H), 7.61 (d, J=9.8Hz, 1H), 7.40-7.50 (m, 2H), 4.77 (q, J=6.8Hz, 1H), 1.84 (d, J=6.8Hz, 3H).

[1071] Intermediate 98

[1072] 2-Bromo-N-(5-((3-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide

[1073]

[1074] Step 1

[1075] To a solution of 6-aminopyridin-3-ol (124 mg, 1.130 mmol) in sulfolane (1.5 mL) was added DIPEA (0.395 mL, 2.259 mmol) and 2,3-difluoropyridine (0.103 mL, 1.130 mmol) in a microwave vial. The mixture was irradiated at 180° C. for 12.5 h and purified to give 5-((3-fluoropyridin-2-yl)oxy)pyridin-2-amine (78 mg, 0.380 mmol, purity: 99%, recovery: 34%) as an off-white solid. LCMS (m / z) 206 (M+H) + , retention time: 0.59 minutes, LC / MS method 3. 1HNMR: (400MHz, CDCl3) δ8.03 (d, J=2.69Hz, 1H), 7.91 (dd, J=4.89, 1.71Hz, 1H), 7.48 (ddd, J=9.84, 8.01, 1.47Hz, 1 H), 7.37 (dd, J=8.80, 2.69Hz, 1H), 7.00 (ddd, J=7.89, 4.83, 3.18Hz, 1H), 6.59 (d, J=9.05Hz, 1H), 4.51 (br.s., 2H).

[1076] Step 2

[1077] To a solution of 5-((3-fluoropyridin-2-yl)oxy)pyridin-2-amine (78 mg, 0.380 mmol) and 2-bromopropionic acid (0.041 mL, 0.456 mmol) in DCM (2 mL) was added DCC (118 mg, 0.570 mmol) and DMAP (4.64 mg, 0.038 mmol). After 2.5 h, the reaction was filtered, concentrated, and purified by column chromatography (ISCO 12 g Gold) eluting with 0-30% EtOAc in heptane to provide 2-bromo-N-(5-((3-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide (105 mg, 0.309 mmol, purity: 99%, recovery: 81%) as a white solid. LCMS (m / z) 340 (M+H) + , retention time: 0.92 minutes, LC / MS method 3. 1 H NMR: (400MHz, CDCl3) δ8.70 (br.s., 1H), 8.30 (d, J=9.05Hz, 1H), 8.27 (d, J=2.69Hz, 1H), 7.91 (dd, J=4.89, 1.47Hz, 1H), 7.65 (dd, J=8.93, 2.81Hz, 1H), 7.53 (ddd, J=9.84, 8.01, 1.47Hz, 1H), 7.06 (ddd, J=7.89, 4.83, 3.18Hz, 1H), 4.56 (q, J=6.93Hz, 1H), 1.99 (d, J=7.09Hz, 3H).

[1078] Intermediates 99-102 (102 for fluoride displacement using Cs2CO3 in AcCN at 60°C) were synthesized in a similar manner.

[1079]

[1080] Intermediate 103

[1081] 2-Bromo-N-(5-(spiro[3.3]hept-2-yloxy)pyridin-2-yl)propanamide

[1082]

[1083] Step 1

[1084] To a solution of spiro[3.3]heptan-2-ol (500 mg, 4.46 mmol) and triphenylphosphine (780 mg, 2.97 mmol) in THF (10 mL) was added DIAD (0.578 mL, 2.97 mmol), followed by a solution of tert-butyl (5-hydroxypyridin-2-yl)carbamate (625 mg, 2.97 mmol) in THF (10 mL) 15 minutes later. After 18 h, additional triphenylphosphine (780 mg, 2.97 mmol) and DIAD (0.578 mL, 2.97 mmol) were added, and the reaction was degassed and backfilled with nitrogen. After 4 h, the reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc (2×), and the combined organic layers were washed with brine (2×), dried over MgSO 4 , concentrated, and purified by flash chromatography (Silica 40 g Gold column), eluting with 20-70% EtOAc in heptane to give tert-butyl (5-(spiro[3.3]hept-2-yloxy)pyridin-2-yl)carbamate. The purified product was stirred in a solution of HCl (3M, 10 mL, 30.0 mmol) in CMPE at room temperature for 18 h, then at 50° C. for 2 h, and concentrated. The residue was dissolved in EtOAc, neutralized with NaHCO 3 , washed with water and brine, dried over MgSO 4 , and concentrated to give 5-(spiro[3.3]hept-2-yloxy)pyridin-2-amine (159 mg, 0.778 mmol, purity: 99%, recovery: 26%). LCMS (m / z) 205 (M+H) + , retention time: 0.66 minutes, LC / MS method 5. 1 H NMR: (400 MHz, DMS)-d6) δ 7.46-7.59 (m, 1H), 7.00 (dd, J = 8.80, 2.93 Hz, 1H), 6.38 (d, J = 8.80 Hz, 1H), 5.43 (s, 2H), 4.41 (quintet, J = 6.97 Hz, 1H), 2.46 (ddd, J = 9.78, 6.85, 2.93 Hz, 2H), 2.00-2.04 (m, 1H), 1.90-1.97 (m, 4H), 1.75-1.84 (m, 2H).

[1085] Step 2

[1086] A solution of 5-(spiro[3.3]hept-2-yloxy)pyridin-2-amine (160 mg, 0.783 mmol), 2-bromopropionic acid (70 μL, 0.778 mmol) and DCC (162 mg, 0.783 mmol) in DMF (5.222 mL) was stirred for 18 h, poured into water, neutralized with sodium bicarbonate, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified by column chromatography (ISCO 40 g Gold), eluting with 0-80% EtOAc in heptane to provide 2-bromo-N-(5-(spiro[3.3]hept-2-yloxy)pyridin-2-yl)propanamide (80 mg, 0.236 mmol, purity: 96%, recovery: 30%) as a yellow oil. LCMS (m / z) 338 (M+H) + , retention time: 1.09 minutes, LC / MS method 5. 1 H NMR: (400 MHz, DMS)-d6) δ 10.49-10.90 (m, 1H), 7.88-8.04 (m, 2H), 7.35 (dd, J = 9.05, 3.18 Hz, 1H), 4.85 (q, J = 6.85 Hz, 1H), 4.63 (quintet, J = 6.85 Hz, 1H), 2.55-2.64 (m, 2H), 1.97-2.12 (m, 5H) 1.79-1.90 (m, 2H), 1.60-1.71 (m, 2H), 1.12-1.35 (m, 2H).

[1087] Intermediate 104

[1088] 2-Bromo-N-(5-(difluoro(4-fluorophenyl)methyl)pyridin-2-yl)propanamide

[1089]

[1090] Step 1

[1091] To a solution of dppf (1.056 g, 1.904 mmol), palladium(II) acetate (0.342 g, 1.523 mmol) and 6-chloronicotinic acid (4 g, 25.4 mmol) in THF (40 ml) was added a slurry of pivalic anhydride (7.79 mL, 38.1 mmol), water (1.143 mL, 63.5 mmol) and (4-fluorophenyl)boronic acid (5.33 g, 38.1 mmol) in THF (30 ml). The reaction was purged with N, stirred at 60° C. overnight, cooled to room temperature, concentrated, dissolved in DCM, concentrated with Isolute and loaded onto a silica column, eluted with 0-100% EtOAc in heptane to give 690 mg (11.53% yield) (6-chloropyridin-3-yl)(4-fluorophenyl)methanone as a white solid. LCMS: (ES, m / s): 236 [M+H] + . 1 H NMR: NMR(400MHz, chloroform-d)ppm 9.02 (d, J=1.71Hz, 1H), 8.77 (d, J=2.45Hz, 1H), 8.27 (dd, J=8.31, 2.45Hz, 1H), 8.10 (dd, J=8.19, 2.32Hz , 1H), 7.87 (dd, J=8.80, 5.38Hz, 2H), 7.49-7.55 (m, 1H), 7.45 (d, J=8.31Hz, 1H), 7.23 (t, J=8.56Hz, 2H).

[1092] Step 2

[1093] DAST (280 μl, 2.122 mmol) was added to a fluoropolymer bottle containing (6-chloropyridin-3-yl)(4-fluorophenyl)methanone (500 mg, 2.122 mmol). The resulting mixture was heated to 40° C. for 6 d, diluted with DCM, concentrated with Isolute and then loaded onto a silica column, eluted with 0-50% EtOAc in heptane to give 165 mg (0.640 mmol, 30.2% yield) of 2-chloro-5-(difluoro(4-fluorophenyl)methyl)pyridine as a brown oil. LCMS: (ES, m / s): 258 [M+H] + . 1 H NMR: NMR (400 MHz, chloroform-d) ppm 8.53 (d, J = 1.71 Hz, 1H), 7.78 (dd, J = 8.31, 2.45 Hz, 1H), 7.46-7.54 (m, 2H), 7.43 (d, J = 7.82 Hz, 1H), 7.10-7.21 (m, 2H).

[1094] Step 3

[1095] To a microwave reaction vial was added Pd2(dba)3 (62.6 mg, 0.068 mmol) and CyJohnPhos (47.9 mg, 0.137 mmol), followed by a solution of 2-chloro-5-(difluoro(4-fluorophenyl)methyl)pyridine (176 mg, 0.683 mmol) in dioxane (2 mL) and LHMDS (2.049 mL, 2.049 mmol, 1 M in THF). The reaction was degassed and purged with N2, stirred at 60°C for 24 h, and then stirred at room temperature over the weekend. The mixture was concentrated, diluted with DCM, concentrated with Isolute and then loaded onto a silica column and eluted with 0-40% EtOAc in heptane, then 20-100% 3:1 EtOAc:EtOH in heptane to give 5-(difluoro(4-fluorophenyl)methyl)pyridin-2-amine (121 mg, 0.508 mmol, 74.4% yield) as a brown solid. LCMS: (ES, m / s): 239 [M+H] + . 1 H NMR: (400 MHz, chloroform-d) ppm 8.12 (s, 1H), 7.47-7.58 (m, 3H), 7.14 (t, J = 8.56 Hz, 2H), 6.54 (d, J = 8.56 Hz, 1H), 4.77 (br. s., 2H).

[1096] Step 4

[1097] To the solution of DCC (146mg, 0.705mmol) in DCM (1.5ml), 2-bromopropionic acid (0.055ml, 0.611mmol) is added. After 15 minutes, 5-(difluoro-(4-fluorophenyl) methyl) pyridine-2-amine (112mg, 0.470mmol) in DCM (1.5ml) is added dropwise, then the DMAP of catalytic amount is added. The mixture is stirred for 2h, diluted with DCM, washed with saturated sodium bicarbonate solution, concentrated and loaded onto silica column (40g) with Isolute, eluted with the heptane solution of 0-50%EtOAc to obtain 140mg (0.375mmol, 80% yield) 2-bromo-N-(5-(difluoro-(4-fluorophenyl) methyl) pyridine-2-yl) propionamide, is colorless oil.LCMS (ES, m / s): 373[M+H] + , rt = 1.17 min, method 3. 1H NMR: NMR (400MHz, chloroform-d) ppm 8.71 (br.s., 1H), 8.44 (d, J=1.22Hz, 1H), 8.27 (d, J=8.56Hz, 1H), 7.84 (dd, J=8.80, 2. 20Hz, 1H,) 7.51 (dd, J=8.80, 5.14Hz, 2H), 7.15 (t, J=8.68Hz, 2H), 4.55 (q, J=6.93Hz, 1H), 1.98 (d, J=7.09Hz, 3H).

[1098] Intermediate 105

[1099] 2-Bromo-N-(5-(4-fluorobenzoyl)pyridin-2-yl)propionamide

[1100]

[1101] Step 1

[1102] To a solution of 6-aminonicotinic acid (1000 mg, 7.24 mmol), HATU (3303 mg, 8.69 mmol) and N,O-dimethylhydroxylamine hydrochloride (847 mg, 8.69 mmol) in DMF (15 mL) was added Hunig's base (2.53 mL, 14.48 mmol). The mixture was stirred overnight and then partitioned between water and EtOAc. The organic layer was washed with water (2×) and brine, dried over sodium sulfate, filtered, concentrated, and then concentrated again with DCM and Isolute before being loaded onto a silica column and eluted with 0-100% 3:1 EtOAc:EtOH in heptane to give 570 mg (3.15 mmol, 43.4% yield) of 6-amino-N-methoxy-N-methylnicotinamide as a colorless oil. LCMS: (ES, m / s): 182 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm 8.28 (d, J=2.45Hz, 1H), 7.71 (dd, J=8.80, 2.45Hz, 1H), 6.47 (dd, J=8.80, 0.98Hz, 1H), 3.55 (s, 3H) 3.21 (s, 3H).

[1103] Step 2

[1104] To a solution of DCC (370 mg, 1.793 mmol) in DCM (1.5 ml) was added 2-bromopropionic acid (0.140 ml, 1.556 mmol). After 15 minutes, a solution of 6-amino-N-methoxy-N-methylnicotinamide (260 mg, 1.435 mmol) in DCM (1.5 ml) was added dropwise, followed by a catalytic amount of DMAP. The reaction was stirred for 2 h, filtered through celite and concentrated with Isolute, then loaded onto a silica column and eluted with 0-75% 3:1 EtOAc:EtOH in heptane to give 90 mg (0.285 mmol, 19.84% yield) of 6-(2-bromopropionamido)-N-methoxy-N-methylnicotinamide as a clear oil. LCMS: (ES, m / s): 316, 318 [M+H] + . 1 H NMR: (400 MHz, chloroform-d) δ 9.39 (br. s., 1H), 8.73 (d, J = 1.71 Hz, 1H), 8.25-8.32 (m, 1H), 8.14-8.22 (m, 1H), 4.59 (q, J = 7.01 Hz, 1H), 3.58 (s, 3H) 3.41 (s, 3H), 1.95 (d, J = 7.09 Hz, 3H).

[1105] Step 3

[1106] To a solution of 6-(2-bromopropionamido)-N-methoxy-N-methylnicotinamide (84 mg, 0.266 mmol) in THF (2 mL) at 0° C. was added (4-fluorophenyl)magnesium bromide (0.664 mL, 0.664 mmol) dropwise over 30 min. After 3 h, additional (4-fluorophenyl)magnesium bromide was added, and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with saturated NH4Cl dropwise and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered, concentrated, diluted with DCM, concentrated with Isolute, and then loaded onto a silica column and eluted with 0-70% 3:1 EtOAc:EtOH in heptane to give 41 mg (0.117 mmol, 43.9% yield) of 2-bromo-N-(5-(4-fluorobenzoyl)pyridin-2-yl)propanamide as a white solid. LCMS (ES, m / s): 351 [M+H] + : rt = 1.03 min, method 3. 1H NMR: (400MHz, chloroform-d)δppm 8.85 (br.s., 1H), 8.75 (d, J=1.71Hz, 1H), 8.35 (d, J=8.56Hz, 1H), 8.20 (dd, J=8.68, 2.32Hz , 1H), 7.80-7.90 (m, 2H), 7.18-7.26 (m, 2H), 4.59 (q, J=7.09Hz, 1H), 2.00 (d, J=7.09Hz, 3H).

[1107] Intermediate 106

[1108] 2-Bromo-N-(5-((4-fluorophenyl)(hydroxy)methyl)pyridin-2-yl)propionamide

[1109]

[1110] Step 1

[1111] To a solution of 2-bromo-N-(5-(4-fluorobenzoyl)pyridin-2-yl)propanamide (38 mg, 0.108 mmol) in methanol (2 mL) was added sodium borohydride (4.09 mg, 0.108 mmol) at 0°C. The reaction was stirred at room temperature for 30 minutes, concentrated, diluted with DCM and concentrated with Isolute, then loaded onto a silica column and eluted with 3:1 EtOAc:EtOH in heptane to give (0.045 mmol, 41.9% yield) 2-bromo-N-(5-((4-fluorophenyl)(hydroxy)methyl)pyridin-2-yl)propanamide as a white solid. LCMS (ES, m / s): 351, 353 [M+H] + , rt = 0.90 min. , Method 3. 1 H NMR (400MHz, chloroform-d) δppm 8.81 (br.s., 1H), 8.32 (s, 1H), 8.17 (d, J=8.56Hz, 1H), 7.72 (dt, J=8.56, 1.96Hz, 1H), 7. 31-7.39 (m, 2H), 7.07 (t, J=8.68Hz, 2H), 4.52 (q, J=6.85Hz, 1H), 1.95 (d, J=7.09Hz, 3H).

[1112] Intermediate 107

[1113] 2-Bromo-N-(3-fluoro-5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide

[1114]

[1115] Step 1

[1116] A mixture of copper (I) iodide (0.258 g, 1.356 mmol), dimethylglycine (0.140 g, 1.356 mmol), cesium carbonate (3.31 g, 10.17 mmol), 6-chloro-5-fluoropyridine-3-ol (1 g, 6.78 mmol) and 2-bromo-5-fluoropyridine (1.431 g, 8.13 mmol) in dioxane (10 mL) was purged with nitrogen, evacuated (5X) and heated to 110° C. After 18 h, the reaction was cooled to room temperature, then distributed between EtOAc and salt solution. The two-phase mixture was filtered through diatomaceous earth, then separated. The aqueous layer was extracted with EtOAc (2x), and the combined organic layers were dried over sodium sulfate, concentrated, and purified by flash chromatography eluting with 0-80% ethyl acetate in heptane to afford 1.035 g (4.27 mmol, 62.9% yield) of 2-chloro-3-fluoro-5-((5-fluoropyridin-2-yl)oxy)pyridine as a white solid. LCMS (ES, m / s): 243.0. 1 H NMR (400MHz, DMSO-d6) δ 8.29 (d, J=2.4Hz, 1H), 8.21 (d, J=3.4Hz, 1H), 8.08 (dd, J=9.8, 2.4Hz, 1H), 7.98-7.88 (m, 1H), 7.31 (dd, J=9.0, 3.7Hz, 1H).

[1117] Step 2

[1118] A mixture of 2-chloro-3-fluoro-5-((5-fluoropyridin-2-yl)oxy)pyridine (400 mg, 1.649 mmol), cesium carbonate (1343 mg, 4.12 mmol) and (2,4-dimethoxyphenyl)methanamine (0.297 mL, 1.978 mmol) in dioxane (10 mL) was purged with N for 10 min. XantPhos Pd G3 (156 mg, 0.165 mmol) was added and the reaction was purged with N for 1 minute, heated at 80° C. for 19 h, stirred at room temperature over the weekend and poured into 1M HCl / ice and EtOAc and stirred for 15 min. The layers were separated and the aqueous layer was back-extracted with EtOAc. The combined organics were dried over magnesium sulfate, concentrated, and purified on a silica gel column eluting with 5-50% 3:1 EtOAc:EtOH (+2% NH4OH) in heptane to afford 538 mg (1.369 mmol, 83% yield) of N-(2,4-dimethoxybenzyl)-3-fluoro-5-((5-fluoropyridin-2-yl)oxy)pyridin-2-amine as a yellow liquid. LCMS (ES, m / s): 374.3 [M+H]. 1H NMR (400MHz, DMSO-d6) δ8.14-8.07 (m, 1H), 7.84-7.77 (m, 1H), 7.72-7.69 (m, 1H), 7.49-7.40 (m, 1H), 7.13-7.05 (m, 2H), 6.89-6.80 (m, 1H), 6.57-6.53 (m, 1H), 6.48-6.41 (m, 1H), 4.51-4.39 (m, 2H), 3.81 (s, 3H), 3.73 (s, 3H).

[1119] Step 3

[1120] A solution of N-(2,4-dimethoxybenzyl)-3-fluoro-5-((5-fluoropyridin-2-yl)oxy)pyridin-2-amine (535 mg, 1.433 mmol) in TFA (5.52 ml, 71.6 mmol) was stirred for 30 min; diluted with CHCl (about 50 ml); concentrated; azeotroped with CHCl; and stirred in CHCl (30 ml), NaHCO (sat), and water for 15 min. The layers were partitioned, and the aqueous layer was back-extracted with CHCl (30 ml). The combined organics were dried over magnesium sulfate, filtered, and concentrated to give 298 mg (1.202 mmol, 84% yield) of 3-fluoro-5-((5-fluoropyridin-2-yl)oxy)pyridin-2-amine, which was used without further purification. LCMS (ES, m / s): 224.1 [M+H]. 1 H NMR (400MHz, DMSO-d6) Shift 8.15-8.07 (m, 1H), 7.84-7.76 (m, 1H), 7.71-7.66 (m, 1H), 7.46-7.37 (m, 1H), 7.13-7.04 (m, 1H), 6.15 (s, 2H).

[1121] Step 4

[1122] To a solution of DCC (145 mg, 0.703 mmol) in DCM (5 ml) was added 2-bromopropionic acid (0.063 ml, 0.703 mmol) at 22° C. After 10 minutes, 3-fluoro-5-((5-fluoropyridin-2-yl)oxy)pyridin-2-amine (112 mg, 0.502 mmol) was added, followed by some DMAP crystals. The reaction was stirred at room temperature overnight, and more 2-bromopropionic acid (0.063 ml, 0.703 mmol) and DCC (105 mg) were added. The mixture was stirred overnight, diluted with DCM (15 ml), filtered, washed with NaHCO (sat'd), dried over MgSO, filtered, concentrated and purified on a silica gel column eluting with 5-65% EtOAc in heptane to give 123 mg (0.275 mmol, 54.7% yield) of 2-bromo-N-(3-fluoro-5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide. LCMS (ES, m / s): 358.1 [M+H]. 1 H NMR(400MHz, DMSO-d6)Shift 10.73-10.56 (m, 1H), 8.20 (dd, J=12.5, 2.7Hz, 2H), 7.98-7.78 (m, 2H), 7.27 (dd, J=9.0, 3.7Hz, 1H), 4.83-4.70 (m, 1H), 1.76 (d, J=6.8Hz, 3H).

[1123] Intermediate 108

[1124] (R)-2-Bromo-N-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenoxy)pyridin-2-yl)propanamide

[1125]

[1126] Step 1

[1127] To a solution of 4-fluoro-2-(hydroxymethyl)phenol (2 g, 14.07 mmol) and imidazole (1.437 g, 21.11 mmol) in DCM (35 mL) was added a solution of TBS-Cl (2.121 g, 14.07 mmol) in DCM (5.0 mL). After 2 h, the reaction was diluted with EtOAc (100 mL), washed with water (2 x 30 mL) and brine (30 mL), dried over NaSO, concentrated, and purified on a silica column (80 g) eluting with 0-20% EtOAc in heptane to give 2.95 g (11.51 mmol, 82% yield) of 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenol as a clear oil. LCMS: (ES, m / z): 255.2 [MH] + . 1 H NMR (400 MHz, chloroform-d) δ ppm 7.83 (s, 1H) 6.85-6.91 (m, 1H) 6.78-6.83 (m, 1H) 6.69 (dd, J=8.56, 3.18 Hz, 1H) 4.86 (s, 2H) 0.92-0.96 (m, 9H) 0.12-0.18 (m, 6H).

[1128] Step 2

[1129] To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenol (1 g, 3.90 mmol) and 5-chloro-2-nitropyridine (0.618 g, 3.90 mmol) in DMF (10 mL) was added cesium carbonate (1.271 g, 3.90 mmol). The reaction was stirred overnight, diluted with EtOAc (200 mL), washed with water (2×50 mL) and brine (50 mL), dried over Na 2 SO 4 , concentrated, and purified on silica (80 g column) eluting with 0-20% EtOAc in heptane to give 660 mg (1.744 mmol, 44.7% yield) of 5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenoxy)-2-nitropyridine, which contained significant impurities and was used directly in the next step. LCMS: (ES, m / z): 379.0[M+H] + .

[1130] Step 3

[1131] A mixture of 5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenoxy)-2-nitropyridine (660 mg, 1.744 mmol) and Pd—C (93 mg, 0.087 mmol) in ethyl acetate (10 mL) was stirred under hydrogen for 3 h, filtered, concentrated and purified on silica (24 g column) eluting with 0-50% EtOAc in heptane to give 323 mg (0.927 mmol, 53.1% yield) of 5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenoxy)pyridin-2-amine as a yellow oil. LCMS: (ES, m / z): 349.2 [M+H] + . 1 H NMR (400MHz, chloroform-d) δppm 7.85 (d, J=2.93Hz, 1H) 7.28-7.31 (m, 1H) 7.11 (dd, J=8.80, 2.93Hz, 1H) 6.84 (td, J=8.4 4, 3.18Hz, 1H) 6.66 (dd, J=9.05, 4.65Hz, 1H) 6.51 (d, J=8.80Hz, 1H) 4.81 (s, 2H) 4.34 (br s, 2H) 0.92-1.02 (m, 9H) 0.06-0.19 (m, 6H).

[1132] Step 4

[1133] To a solution of (R)-2-bromopropanoic acid (0.042 mL, 0.459 mmol) and 5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenoxy)pyridin-2-amine (160 mg, 0.459 mmol) in DCM (2 mL) was added DCC (123 mg, 0.597 mmol). The reaction was stirred overnight, filtered, concentrated and purified on silica (12 g column) eluting with 0-20% EtOAc in heptane to give 210 mg (0.434 mmol, 95% yield) of (R)-2-bromo-N-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenoxy)pyridin-2-yl)propanamide. LCMS: (ES, m / z): 483.2 [M+H] + , rt=1.65min; Method 3. 1H NMR (400MHz, chloroform-d) δppm 8.58(br s, 1H) 8.15 (d, J = 9.29Hz, 1H) 8.04 (d, J = 2.45Hz, 1H) 7.32 (dd, J = 9.05, 3.18Hz, 1H) 7.26-7.30 (m, 1H) 6.92 (td, J = 8.31, 2.93Hz, 1 H) 6.79 (dd, J=9.05, 4.65Hz, 1H) 4.75 (s, 2H) 4.53 (q, J=6.85Hz, 1H) 1.97 (d, J=6.85Hz, 3H) 0.91-0.98 (m, 9H) 0.07-0.15 (m, 6H).

[1134] Intermediate 109 (from 2-bromo-5-nitropyrazine) was synthesized in an analogous manner. Intermediates 110-111 were synthesized in an analogous manner to Intermediate 108 starting from the appropriate difluorophenyl diol.

[1135]

[1136] Example

[1137] Example 1

[1138] (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide

[1139]

[1140] Step 1

[1141] A mixture of t-BuONa (6.66 g, 69.39 mmol, 2.5 eq) in THF (60 mL) was stirred at room temperature for 10 minutes, followed by the addition of Pd(OAc) (622 mg, 2.78 mmol, 0.1 eq) and (t-Bu) P (5.61 g, 2.78 mmol, 0.1 eq, 10% in hexane). After 5 minutes, 2-(benzyloxy)-5-bromopyridine (7.30 g, 27.76 mmol, 1.0 eq) and tert-butyl 4-oxopiperidine-1-carboxylate (8.28 g, 41.63 mmol, 1.5 eq) were added, and the mixture was purged with nitrogen and stirred at 45 ° C for 18 h. The reaction was quenched with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic extracts were washed with brine (600 mL), dried over sodium sulfate, and concentrated to give the crude product as a yellow oil. The residue was purified on a silica gel column eluting with ethyl acetate in petroleum ether (0-30% over 30 min) to give tert-butyl 3-(6-(benzyloxy)pyridin-3-yl)-4-oxopiperidine-1-carboxylate (4.8 g, 27% yield, 59% purity) as a yellow oil. LCMS: (ES, m / s) 383 [M+H]+, retention time: 1.189 min, LC / MS method 31. 1 H NMR: (300MHz, CDCl3)δppm 8.00-7.99(m, 1H), 7.49-7.31(m, 6H), 6.85-6.82(m, 1H), 5.39(s, 2H), 4.33-4.2 8(m, 2H), 3.76-3.67(m, 1H), 3.48-3.18(m, 2H), 2.70-2.43(m, 2H), 1.52(s, 9H).

[1142] Step 2

[1143] To a solution of tert-butyl 3-(6-(benzyloxy)pyridin-3-yl)-4-oxopiperidine-1-carboxylate (2.40 g, 6.28 mmol, 1.0 eq) in DCM (20 mL) was added DAST (2.02 g, 12.55 mmol, 2.0 eq) at 0 ° C., and the mixture was stirred at room temperature overnight, quenched with ice water (50 mL) and extracted with DCM (50 mL x 3). The combined organic phases were dried over Na2SO4, concentrated and purified on a silica gel column eluted with ethyl acetate: petroleum ether (1:4) to give tert-butyl 3-(6-(benzyloxy)pyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate 1.04 g (purity: 79%, yield: 39%) as a yellow oil. LCMS (ES, m / s): 405 [M + H] +

[1144] Step 3

[1145] A mixture of tert-butyl 3-(6-(benzyloxy)pyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (5 g, 12.4 mmol, 1.0 eq) and Pd / C (2.5 g, 10%) in methanol (100 mL) was evacuated and purged with hydrogen three times. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 h, filtered, concentrated, and purified by reverse phase column (330 g) using a 20-60% AcCN solution in water (10 mM NH4HCO3) to give tert-butyl 4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidine-1-carboxylate (2 g, purity: 95%) as a colorless oil. LCMS: (ES, m / s): 315 [M+H]+ 1 H NMR: (300MHz, DMSO-d6) δppm13.14 (s, 1H), 7.46 (d, J=9.6Hz, 1H), 7.36 (s, 1H), 6.60 (d, J=9.6Hz , 1H), 4.27-4.15(m, 2H), 3.15-3.05(m, 2H), 2.90-2.81(m, 1H), 2.20-1.93(m, 2H), 1.49(s, 9H).

[1146] Step 4

[1147] A mixture of tert-butyl 4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidine-1-carboxylate (1.2 g, 3.82 mmol, 1.0 eq), 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.21 g, 9.56 mmol, 2.5 eq) and Cs2CO3 (3.12 g, 9.56 mmol, 2.5 eq) in DMF (20 mL) was stirred at 25 °C for 6 h, quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was dried over sodium sulfate, concentrated, and purified on a silica gel column eluting with ethyl acetate:petroleum ether (1:1) to afford 0.69 g (90% purity, 46% yield) of tert-butyl 4,4-difluoro-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidine-1-carboxylate as a white solid. LCMS: (ES, m / z): 397 [M+H]. 1 HNMR (400MHz, DMSO-d6) δ7.67-7.66 (m, 1H), 7.50-7.48 (m, 1H), 6.49 (d, J=9.6Hz, 1H), 4.88-4.80 (m, 2H), 4.09-3.97 (m, 2H), 3.15-3.01 (m, 2H), 2.19-2.11 (m, 1H), 2.05-1.87 (m, 2H), 1.42 (s, 9H).

[1148] Step 5

[1149] A mixture of tert-butyl 4,4-difluoro-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidine-1-carboxylate (0.69 g, 1.74 mmol, 1.0 eq) and HCl (10 mL, 4 M in dioxane) was stirred at room temperature for 2 h. The reaction was concentrated to give 0.5 g (crude) of 5-(4,4-difluoropiperidin-3-yl)-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one as a white solid, HCl salt, which was used without purification. LCMS (ES, m / z): 297 [M+H]. 1 H NMR: (400MHz, DMSO-d6) δ7.77-7.76 (m, 1H), 7.52-7.49 (m, 1H), 6.52 (d, J=9.6Hz, 1H), 4.95 -4.77 (m, 2H), 3.65-3.44 (m, 3H), 3.42-3.32 (m, 1H), 3.12-2.98 (m, 1H), 2.49-2.33 (m, 2H).

[1150] Step 6

[1151] A mixture of 5-(4,4-difluoropiperidin-3-yl)-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (as free base) (0.30 g, 1.0 mmol, 1.0 eq), 2-bromo-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide (Intermediate 14) (0.30 g, 1.0 mmol, 1.0 eq), KI (0.17 g, 1.0 mmol, 1.0 eq) and TEA (1.01 g, 10.0 mmol, 10.0 eq) in THF (10 mL) was stirred at 60 ° C for 15 h, poured into water (30 mL), and extracted with DCM (30 mL x 3). The organic layer was dried over sodium sulfate, concentrated and purified on a silica gel column eluted with methanol: dichloromethane (1:50) to give 0.3 g of the product as a white solid. The collected product (0.3 g) was chirally separated using two sets of conditions. The first chiral separation conditions were: chiral ARTCellulose-SB column, 2 x 25 cm, 5 μm; mobile phase A: Hex (8 mM NH3.MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 1:1 A:B; peaks were obtained with retention times RT1: 5.767; RT2-RT3: 8.621-8.846; and RT4: 10.993. The second peak (RT2-RT3: 8.621-8.846) was concentrated to yield 130 mg of product, which was used for the second chiral separation.

[1152] These secondary conditions were: Column: Chiral PAK IF, 2 x 25 cm, 5 μm; Mobile Phase A: Hex (8 mM NH3.MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; 1:1 A:B; The product obtained had a retention time RT1: 7.107 and RT2: 9.310. The second peak (RT2: 9.310) gave 35 mg (purity: 99.5%, yield: 7%) of (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide as a white solid. LCMS (ES, m / s): 516 [M+H]+ 1 H NMR: (400MHz, CD3OD) δ8.36 (d, J=9.6Hz, 1H), 7.67-7.61 (m, 2H), 7.20 (d, J= 9.6Hz, 1H), 6.56 (d, J=9.6Hz, 1H), 4.85-4.77 (m, 2H), 4.25 (d, J=7.2Hz, 2H), 3.61-3.56(m, 1H), 3.39-3.27(m, 1H), 2.99-2.91(m, 3H), 2.68-2.61(m, 1H), 2.31-2.17 (m, 2H), 1.38-1.29 (m, 4H), 0.65-0.60 (m, 2H), 0.40-0.36 (m, 2H).

[1153] Examples 2 and 3 were synthesized in a similar manner using the indicated intermediates in step 6.

[1154]

[1155] Example 4

[1156] (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide

[1157]

[1158] Step 1

[1159] To a solution of sodium tert-butoxide (278.1 g, 2894 mmol) in THF (2.15 L) was added tert-butyl 4-oxopiperidine-1-carboxylate (287.7 g, 1444 mmol) and 5-bromo-2-methoxypyridine (180.1 g, 958 mmol) and washed with THF (250 mL). The mixture was evacuated and backfilled with nitrogen (3 ×), followed by the addition of XPhos (45.7 g, 96 mmol) and palladium (II) acetate (10.75 g, 47.9 mmol) and washed with THF (0.35 L). The reaction was heated to 45 ° C for 22 h, cooled to 0 ° C, and slowly quenched with water (1.575 L) and brine (675 mL). EtOAc (2.3 L) was added and the mixture was stirred for 10 min. The layers were separated and the aqueous layer was extracted with EtOAc (2 × 1.35 L). The combined organics were washed with brine (900 mL), concentrated and purified by column chromatography eluting with 15-75% EtOAc in heptane to provide tert-butyl 3-(6-methoxypyridin-3-yl)-4-oxopiperidine-1-carboxylate (210 g, 685 mmol, purity: 84%, recovery: 74%). LCMS (m / z) 307 (M+H) + , retention time: 0.91 min, LC / MS method 3. 1 H NMR: (400MHz, CDCl3)δppm 7.99 (d, J=2.4Hz, 1H), 7.41 (dd, J=8.8, 2.4Hz, 1H), 6.77 (d, J=8.8Hz, 1H), 4.24-4.39 (m, 2H), 3.95 (s, 3 H), 3.69 (dd, J=10.5, 6.1Hz, 1H), 3.43 (ddd, J=13.3, 10.1, 4.4Hz, 2H), 2.53-2.65 (m, 2H), 1.53 (s, 9H).

[1160] Step 2

[1161] To a solution of XtalFluor-E (199 g, 868 mmol) in DCM (585 mL) was slowly added triethylamine trihydrofluoride (140 g, 868 mmol) and pyridine (34.3 g, 434 mmol) in DCM (414 mL) at -1.1 ° C, followed by addition of a solution of tert-butyl 3-(6-methoxypyridin-3-yl)-4-oxopiperidine-1-formate (133 g, 434 mmol) in DCM (794 mL). The reaction was warmed to 25 ° C and slowly poured into the stirred saturated NaHCO solution cooled to -5 ° C after 3 h. The mixture was warmed to 25 ° C, separated into layers, and the aqueous layer was extracted with DCM (2 × 1.3 L). The combined organics were dried over sodium sulfate, concentrated, and purified by column chromatography eluting with 5-45% EtOAc in heptane to provide tert-butyl 4,4-difluoro-3-(6-methoxypyridin-3-yl)piperidine-1-carboxylate (64.37 g, 196 mmol, purity: 90%, recovery: 45%). LCMS (m / z) 328 (M+H) + , retention time: 1.02 minutes, LC / MS method 5. 1 H NMR: (400MHz, CDCl3) δppm 8.09 (d, J=2.45Hz, 1H), 7.54 (br d, J=8.31Hz, 1H), 6.74 (d, J=8.31Hz, 1H), 4.19-4.38 (m, 3H), 3.94 (s, 3H), 2.85-3.19 (m, 2H), 1.87-2.09 (m, 2H), 1.42-1.55 (m, 9H).

[1162] Step 3

[1163] To a 48% aqueous solution of hydrobromic acid (40.9 mL, 361 mmol) was added dropwise a solution of tert-butyl 4,4-difluoro-3-(6-methoxypyridin-3-yl)piperidine-1-carboxylate (12.6 g, 38.4 mmol) in toluene (40 mL). The reaction was stirred at 95 ° C overnight, concentrated, taken up in 2-MeTHF (100 mL) and treated with a 3M solution of hydrochloric acid in cyclopentyl methyl ether (CPME) (130 mL). Diluted to a total volume of approximately 250 mL with 2-methyltetrahydrofuran, the gel-salt / organic mixture was sonicated for approximately 5 minutes, and then stirred at room temperature for 30 minutes to give a thick light green suspension. The suspended solid was then collected by suction filtration and dried. In some cases, this material was used as a racemic mixture. In other cases, this material was neutralized with isopropylamine before injection and subjected to chiral separation on an Agilent semi-prep 1200 AD-H column (5 μm - 20 mm × 250 mm) eluted with 70:30 AcCN:MeOH at 45 mL / min. The enantiomers eluted at 3.981 and 8.269 minutes. The first eluting isomer (3.981 minutes) was stirred in acetonitrile (250 mL) at 60°C with activated charcoal (3 g) for 90 minutes. The mixture was filtered through celite, concentrated, and the residue triturated with AcCN to provide (S)-5-(4,4-difluoropiperidin-3-yl)pyridin-2(1H)-one (2.568 g, 11.87 mmol, 31% recovery) as a light brown solid. LCMS (m / z) 215 (M+H) + , retention time: 0.39 minutes, LC / MS method 3. 1 H NMR (400MHz, MeOH-d4) δppm 7.60 (ddd, J=9.54, 2.69, 0.98Hz, 1H), 7.37 (d, J=2.45Hz, 1H), 6.53 (d, J=8.80Hz, 1H), 3 .05-3.23 (m, 2H), 2.92-3.05 (m, 2H), 2.86 (td, J=13.21, 2.93Hz, 1H), 1.84-2.21 (m, 2H).

[1164] Step 4

[1165] To a solution of 2-bromo-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide (Intermediate 71) (92 mg, 0.257 mmol) in DMA (2 mL) was added (S)-5-(4,4-difluoropiperidin-3-yl)pyridin-2(1H)-one (50 mg, 0.233 mmol), KI (42.6 mg, 0.257 mmol) and Et3N (0.163 mL, 1.167 mmol). The resulting mixture was stirred at 60 ° C for 3 h, cooled and purified by preparative HPLC (SunFire C18 OBD Prep column, ), eluted with 40-41% AcCN in water (0.05% TFA), and then purified (XBridge Prep OBD C18 column), eluted with 35-51% AcCN in water (10 mmol / L NH4HCO3) to give 39 mg of a white solid. In some cases this material was used as a racemic mixture and in other cases was isolated by chiral purification (Chiralpak IA, 2×25 cm, 5 μm; mobile phase A: Hex [8 mM NH₃.MeOH], mobile phase B: EtOH; flow rate: 35 mL / min; 1:1 A:B over 17 min) to afford (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide (8.0 mg, 0.016 mmol, 26.5% yield) with a retention time of 14.65 minutes as a white solid. LCMS (m / z) 491 (M+H) + . 1 H NMR: (400MHz, CD3OD)δppm 8.15 (d, J=9.2Hz, 1H), 8.06 (d, J=3.2Hz, 1H), 7.67-7.57 (m, 1H), 7.44-7.38 (m, 2H), 7.26-7.12 (m, 2H), 7.04-6.96 (m, 1H), 6.52 (d, J =9.6Hz, 1H), 3.58-3.48 (m, 1H), 3.40-3.22 (m, 1H), 3.03-2.85 (m, 3H), 2.68-2.57 (m, 1H), 2.34-2.10 (m, 2H), 1.34 (d, J = 6.8Hz, 3H).

[1166] Examples 5-102 were synthesized in a similar manner using the indicated intermediates in step 4.

[1167]

[1168]

[1169]

[1170]

[1171]

[1172]

[1173]

[1174]

[1175]

[1176]

[1177]

[1178]

[1179]

[1180]

[1181]

[1182]

[1183]

[1184]

[1185]

[1186]

[1187]

[1188]

[1189]

[1190]

[1191]

[1192]

[1193]

[1194]

[1195]

[1196]

[1197]

[1198]

[1199]

[1200]

[1201]

[1202]

[1203]

[1204] Example 103

[1205] (S)-2-((R)-4,4-difluoro-3-(5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide

[1206]

[1207] Step 1

[1208] To a solution of 5-bromopyrazin-2-ol (5.0 g 28.7 mmol, 1.0 eq) in toluene (200 mL) at 25° C. was added (bromomethyl)benzene (7.4 g, 43.1 mmol, 1.5 eq) and AgCO (15.7 g, 57.5 mmol, 2.0 eq). After 15 h, the reaction was filtered, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with water (300 mL), dried over NaSO, concentrated, and purified on a silica gel column eluting with ethyl acetate:petroleum ether (1:20) to give 6.0 g of 2-(benzyloxy)-5-bromopyrazine (purity: 80%, yield: 79%) as a yellow solid. LCMS: (ES, m / s) 265 [M+H]. 1 H NMR: (300MHz, CDCl3) δppm 8.23 ​​(d, J=1.2Hz, 1H), 8.09 (d, J=1.6Hz, 1H), 7.48-7.35 (m, 5H), 5.39 (s, 2H).

[1209] Step 2

[1210] A mixture of t-BuONa (1.82 g, 18.95 mmol, 2.5 eq) in THF (16 mL) was stirred at 43 ° C for 5 minutes, and then Pd (OAc) 2 (170 mg, 0.76 mmol, 0.1 eq) and (t-Bu) 3 P (153 mg, 0.76 mmol, 0.1 eq, 10% in hexanes) were added. After 5 minutes, 2- (benzyloxy) -5-bromopyrazine (2.0 g, 7.58 mmol, 1.0 eq) and tert-butyl 4-oxopiperidine-1-carboxylate (2.26 g, 11.36 mmol, 1.5 eq) were added, and the mixture was stirred at 43 ° C for 15 h, quenched with water (200 mL), and extracted with ethyl acetate (200 mL x 3). The combined organic extracts were washed with brine (600 mL), dried over sodium sulfate, concentrated, and purified on a silica gel column eluting with ethyl acetate:petroleum ether (1:3) to give 7.8 g of crude tert-butyl 3-(5-(benzyloxy)pyrazin-2-yl)-4-oxopiperidine-1-carboxylate as a yellow oil. LCMS: (ES, m / s) 384 [M+H]. 1 H NMR: (300MHz, CDCl3)δppm 8.25 (d, J=1.2Hz, 1H), 7.99 (d, J=1.5Hz, 1H), 7.50-7.35 (m, 5H), 5.39 (s, 2H), 4.25-4.17 (m, 1 H), 3.95-3.63(m, 3H), 3.55-3.45(m, 1H), 2.65-2.60(m, 1H), 2.47-2.43(m, 1H), 1.49(m, 9H).

[1211] Step 3

[1212] To a solution of tert-butyl 3-(5-(benzyloxy)pyrazin-2-yl)-4-oxopiperidine-1-carboxylate (7.8 g, 20.36 mmol, 1.0 eq) in DCM (20 mL) was added DAST (6.6 g, 40.7 mmol, 2.0 eq) at 25° C., and the mixture was stirred for 12 h, quenched with ice / water (100 mL), and extracted with DCM (100 mL x 3). The combined organic phases were dried over Na2SO4, concentrated, and purified on a silica gel column eluted with ethyl acetate: petroleum ether (1:4) to give 3.6 g of tert-butyl 3-(5-(benzyloxy)pyrazin-2-yl)-4,4-difluoropiperidine-1-carboxylate (purity: 50%, yield: 44%) as a yellow oil. LCMS (ES, m / s): 406 [M+H]+ 1H NMR: (300MHz, CDCl3)δppm 8.25(d, J=1.5Hz, 1H), 8.10(s, 1H), 7.48-7.31(m, 5H), 5.39(s, 2H), 4.21-4.15(m, 1H), 3 .73-3.52(m, 2H), 3.34-3.20(m, 2H), 2.30-2.20(m, 1H), 2.10-1.90(m, 1H), 1.46(m, 9H).

[1213] Step 4

[1214] A mixture of tert-butyl 3-(5-(benzyloxy)pyrazin-2-yl)-4,4-difluoropiperidine-1-carboxylate (1.38 g, 3.40 mmol, 1.0 eq) and Pd / C (1.0 g, 10%) in methanol (10 mL) was stirred at 25° C. under a hydrogen atmosphere for 1 h, filtered, concentrated, and purified on a silica gel column eluted with ethyl acetate in petroleum ether (0-10%) to give tert-butyl 4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidine-1-carboxylate (600 mg, yield: 34%, purity: 60%) as a light yellow oil. LCMS: (ES, m / s): 316 [M+H]+, retention time 0.948 min, LCMS method 32.

[1215] Step 5

[1216] A mixture of tert-butyl 4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidine-1-carboxylate (600 mg, 1.90 mmol, 1.0 eq), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.10 g, 4.76 mmol, 2.5 eq) and CsCO (1.55 g, 4.76 mmol, 2.5 eq) in DMF (8 mL) was stirred at 25° C. for 6 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic layer was washed with brine (100 mL x 2), dried over sodium sulfate, concentrated, and purified on a silica gel column eluted with ethyl acetate in petroleum ether (0-20%) to afford 0.69 g (90% purity, 46% yield) of tert-butyl 4,4-difluoro-3-(5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydropyrazin-2-yl)piperidine-1-carboxylate as a light yellow oil. LCMS: (ES, m / z): 398 [M+H]+, retention time 1.278 min, LCMS method 32. 1H NMR (400MHz, DMSO-d6) δ8.13 (d, J=1.2Hz, 1H), 7.66 (s, 1H), 4.05-3.85 (m, 3H), 3.29-3.12(m, 3H), 2.25-2.15(m, 1H), 2.05-1.90(m, 2H), 1.39(s, 9H).

[1217] Step 6

[1218] A mixture of tert-butyl 4,4-difluoro-3-(5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydropyrazine-2-yl)piperidine-1-carboxylate (280 mg, 0.71 mmol, 1.0 eq) and HCl (5 mL, 4 M in dioxane) was stirred at room temperature for 2 h. The reaction mixture was concentrated, diluted with NaHCO (30 mL, saturated aqueous solution) and extracted with DCM (30 mL x 2). The organic layers were combined, dried over NaSO and concentrated. The residue was purified by preparative HPLC (column: Sun Fire C18 OBD) eluting with 15-20% AcCN in water (0.05% TFA) to give 100 mg of 5-(4,4-difluoropiperidin-3-yl)-1-(2,2,2-trifluoroethyl)pyrazin-2(1H)-one (purity: 90%, yield: 47%) as a light yellow oil. LCMS (ES, m / z): 298 [M+H]+, retention time 0.616, LCMS method 33.

[1219] Step 7

[1220] A mixture of 5-(4,4-difluoropiperidin-3-yl)-1-(2,2,2-trifluoroethyl)pyrazin-2(1H)-one (100 mg, 0.34 mmol, 1.0 eq), 2-bromo-N-(5-fluoropyridin-2-yl)propanamide (Intermediate 1) (83 mg, 0.34 mmol, 1.0 eq), KI (56 mg, 0.34 mmol, 1.0 eq) and TEA (0.38 mL, 2.69 mmol, 8.0 eq) in THF (5 mL) was stirred at 60 °C for 12 h, filtered, concentrated and purified by preparative TLC using 1:3 EtOAc:petroleum ether. The collected product (40 mg) was chirally purified and separated (Chiralpak IG, 20×250 mm, 5 μm; mobile phase A: Hex [8 mM NH 3 .MeOH], mobile phase B: EtOH; flow rate: 20 mL / min; 85:15 A:B over 17 min) to give four isomers with retention times: RT1, 13.989 min; RT2, 16.569 min; RT3, 18.549 min; and RT4, 20.702 min. Isomer 3 was collected (RT 18.549 min) to give 4.0 mg of (S)-2-((R)-4,4-difluoro-3-(5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide (purity: 98.7%, yield: 3%) as a white solid. LCMS (ES, m / s): 464 [M+H]+ 1 H NMR: (400MHz, CD3OD) δ8.20-8.16(m, 3H), 7.62-7.57(m, 2H), 4.82-4.75(m, 2H), 3.59-3.4 1 (m, 2H), 3.04-2.88 (m, 3H), 2.75-2.71 (m, 1H), 2.40-2.16 (m, 2H), 1.32 (d, J=6.8Hz, 3H).

[1221] Example 104

[1222] (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide

[1223]

[1224] Step 1

[1225] To a solution of t-BuONa (15.2 g, 159.0 mmol, 3 eq) in THF (80 mL) was added Pd(OAc) (1.2 g, 5.3 mmol, 0.1 eq), (t-Bu) P (21.6 g, 10.7 mmol, 0.2 eq, 10% in hexanes), 2-bromo-5-methoxypyrazine (10 g, 52.9 mmol, 1 eq) and benzyl 4-oxopiperidine-1-carboxylate (15.9 g, 68 mmol, 1.3 eq), and the resulting mixture was stirred at 42° C. After 16 h, the reaction was quenched with water (400 mL) and extracted with EA (300 mL×3). The combined organic phases were dried over NaSO, concentrated, and loaded onto a silica gel column, eluted with ethyl acetate:petroleum ether (1:3) to afford 11 g (purity: 71%, yield: 44%) of benzyl 3-(5-methoxypyrazin-2-yl)-4-oxopiperidine-1-carboxylate as a yellow oil. LCMS: (ES, m / s) 342 [M+H]. 1 H NMR: (300MHz, CDCl3)δppm 8.17(s, 1H), 7.97(s, 1H), 7.48-7.33(m, 5H), 5.28-5.17(m, 2H), 4.42-4.26(m, 1H), 3.97(s, 3H), 3.88-3.13(m, 4H), 2.73-2.52(m, 2H).

[1226] Step 2

[1227] To a solution of benzyl 3-(5-methoxypyrazin-2-yl)-4-oxopiperidine-1-carboxylate (11 g, 32.2 mmol, 1 eq) in DCM (60 ml) was added DAST (10.4 g, 64.4 mmol, 2 eq) at 0 ° C. The resulting mixture was stirred at 25 ° C for 15 h, quenched with ice water (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over Na2SO4, concentrated and loaded onto a silica gel column and eluted with ethyl acetate: petroleum ether (1:5) to give 4.2 g (purity: 81%, yield: 28.5%) of benzyl 4,4-difluoro-3-(5-methoxypyrazin-2-yl)piperidine-1-carboxylate as a yellow oil. LCMS: (ES, m / s) 364 [M + H] +. 1 H NMR: (300MHz, CDCl3)δppm 8.19(s, 1H), 8.09(s, 1H), 7.45-7.31(s, 5H), 5.33-4.97(m, 2H), 4.25-4.10( m, 1H), 3.99 (s, 3H), 3.90-3.59 (m, 2H), 3.42-3.19m, 2H), 2.44-1.83 (m, 2H).

[1228] Step 3

[1229] To a solution of benzyl 4,4-difluoro-3-(5-methoxypyrazin-2-yl)piperidine-1-carboxylate (4.2 g, 11.5 mmol, 1 eq) in DCM (60 ml) was added m-CPBA (4.0 g, 23 mmol, 2 eq) at 0 ° C. The resulting mixture was stirred at 25 ° C for 4 h, quenched with Na2S2O3 (100 mL, saturated aqueous solution) and extracted with DCM (100 mL x 3). The organic layer was dried over sodium sulfate, concentrated and loaded onto a silica gel column and eluted with ethyl acetate: petroleum ether (1:5) to give 3.0 g (purity: 91%, yield: 62.3%) of 2-(1-((benzyloxy)carbonyl)-4,4-difluoropiperidin-3-yl)-5-methoxypyrazine 1-oxide as a yellow oil. LCMS (ES, m / s): 380 [M + H] + 1 H NMR: (300MHz, CDCl3)δppm 8.21 (s, 1H), 7.88 (s, 1H), 7.43-7.31 (m, 5H), 5.30-5.04 (m, 2H), 4.54-4.23 (m, 3H), 4.00 (s, 3H), 3.29-3.08 (m, 2H), 2.33-1.93 (m, 2H).

[1230] Step 4

[1231] To 2-(1-((benzyloxy)carbonyl)-4,4-difluoropiperidin-3-yl)-5-methoxypyrazine 1-oxide (3.0 g, 7.8 mmol, 1 eq) was added POCl (8 mL), and the resulting mixture was stirred at 25 ° C for 15 h and poured into ice water (50 mL). The pH was adjusted to 9 with 4M NaOH (aq.) at 0 ° C, and the reaction was extracted with dichloromethane (100 mL x 3). The combined organic layers were dried over sodium sulfate, concentrated and loaded onto a silica gel column, eluted with ethyl acetate: petroleum ether (1:5) to give 2.4 g (purity: 100%, yield: 76%) of benzyl 3-(6-chloro-5-methoxypyrazin-2-yl)-4,4-difluoropiperidine-1-carboxylate as an off-white oil. LCMS: (ES, m / s): 398 [M + H] + 1 H NMR: (300MHz, CDCl3)δppm 8.04(s, 1H), 7.46-7.30(m, 5H), 5.23-5.11(m, 2H), 4.37-4.14(m, 2H), 4.06 (s, 3H), 3.76-3.57 (m, 1H), 3.47-3.16 (m, 2H), 2.38-1.86 (m, 2H).

[1232] Step 5

[1233] In a 40ml sealed tube, 3-(6-chloro-5-methoxypyrazine-2-yl)-4,4-difluoropiperidine-1-carboxylic acid benzyl ester (2.4g, 6mmol, 1eq) was stirred in N2H4 (1M in THF, 10ml). The tube was sealed and the resulting mixture was stirred at 115°C for 8h and then poured into water (100mL). The resulting solution was extracted with ethyl acetate (100mL x 3). The combined organic layers were dried over sodium sulfate and concentrated to give 2.3g (purity: 93%, yield: 95%) of 4,4-difluoro-3-(6-hydrazino-5-methoxypyrazine-2-yl)piperidine-1-carboxylic acid benzyl ester as a yellow oil, which was used without purification. LCMS: (ES, m / z): 394[M+H]+.

[1234] Step 6

[1235] A solution of benzyl 4,4-difluoro-3-(6-hydrazino-5-methoxypyrazin-2-yl)piperidine-1-carboxylate (2.3 g, 5.8 mmol, 1 eq) and Raney nickel (3.4 g, 40 mmol, 6.9 eq) in ethanol (8 mL) was stirred under H (3 atm) for 15 h. The reaction was filtered, and the filtrate was concentrated to give 1.2 g (92% purity, 85% yield) of 6-(4,4-difluoropiperidin-3-yl)-3-methoxypyrazin-2-amine as a yellow oil, which was used without purification. LCMS (ES, m / z): 245 [M+H]. 1 H NMR: (400MHz, DMSO-d6) δppm 7.23 (s, 1H), 6.30 (s, 2H), 3.92-3.90 (m, 1H), 3.86 (s, 3H), 3.12-2.83 (m, 4H), 2.13-1.81 (m, 3H).

[1236] Step 7

[1237] To a solution of 6-(4,4-difluoropiperidin-3-yl)-3-methoxypyrazin-2-amine (1.2 g, 4.9 mmol, 1 eq) in dioxane (3 mL) was added HCl (3 mL, 6 M in H2O) in a test tube. The tube was sealed and the resulting mixture was stirred at 80°C for 15 h. The reaction was concentrated to give 1.2 g (90% purity, 92% yield) of 3-amino-5-(4,4-difluoropiperidin-3-yl)pyrazin-2(1H)-one hydrochloride as a red solid, which was used without purification. LCMS (ES, m / z): 231 [M+H]. 1HNMR: (400MHz, DMSO-d6) δppm 12.39 (s, 1H), 8.60 (br, 2H), 6.82 (s, 1H), 3.70-3.62 (m, 1H), 3.52-3.35 (m, 3H), 3.17-2.83 (m, 1H), 2.44-2.28 (m, 2H).

[1238] Step 8

[1239] A mixture of 3-amino-5-(4,4-difluoropiperidin-3-yl)pyrazin-2(1H)-one hydrochloride (120 mg, 0.521 mmol, 1 eq), 2-bromo-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide (Intermediate 14) (188 mg, 0.625 mmol, 1.2 eq), KI (87 mg, 0.521 mmol, 1 eq) and TEA (0.218 mL, 1.564 mmol, 3 eq) in N,N-dimethylacetamide (5 mL) was stirred at 60 ° C for 3 h, quenched with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with brine (15 mL), dried over sodium sulfate, concentrated and purified by preparative TLC using 1:10 MeOH:DCM. The collected product (125 mg) was chirally separated (XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; mobile phase A: water [10 mmol / L NH 4 HCO 3 ], mobile phase B: ACN; flow rate: 60 mL / min; 22-42% B in A over 10 min) to obtain products with retention times of 8.18 and 9.25 minutes. The first peak of product (8.18 min) was chirally separated again (Chiralpak IE, 2×25 cm, 5 μm; mobile phase A: Hex:DCM (10 mM NH 3 -MeOH), 3:1; mobile phase B: EtOH; flow rate: 20 mL / min; 7:3 A:B over 10 min) to obtain two peaks with retention times of 5.396 and 7.166 minutes. The second peak (7.166 min) was collected to give 6 mg (purity: 96.0%, 5% yield) (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide as a white solid. LCMS (ES, m / s): 450 [M+H]+ 1H NMR: (400MHz, DMSO-d6) δ11.54 (s, 1H), 10.68 (s, 1H), 8.24 (d, J=9.2Hz, 1H), 7 .27 (d, J=9.6Hz, 1H), 6.60 (s, 2H), 6.52 (s, 1H), 4.21 (dd, J=1.6, 7.2Hz, 2H), 3 .70-3.61(m, 1H), 3.12-2.78(m, 4H), 2.51-2.40(m, 1H), 2.20-1.91(m, 2H), 1. 29-1.23 (m, 1H), 1.21 (d, J=6.8Hz, 3H), 0.59-0.55 (m, 2H), 0.38-0.34 (m, 2H).

[1240] Examples 105-108 were synthesized in a similar manner using the indicated intermediates in step 8.

[1241]

[1242]

[1243]

[1244] Example 109

[1245] 4-((S)-1-((S)-1-((6-(cyclopropylmethoxy)pyridazin-3-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[1246]

[1247] Step 1

[1248] t-BuONa (61.10 g, 635.7 mmol, 2.5 eq) was stirred in THF (600 mL) for 10 minutes, and then Pd(OAc)2 (5.74 g, 25.64 mmol, 0.1 eq) and (t-Bu)3P (51.79 g, 25.64 mmol, 0.1 eq, 10% in hexanes) were added. After 5 minutes, 4-bromopyridine (40.00 g, 256.41 mmol, 1.0 eq) and tert-butyl 4-oxopiperidine-1-carboxylate (76.54 g, 384.62 mmol, 1.5 eq) were added, and the resulting mixture was stirred at 43 ° C. After 16 h, the reaction was dissolved in methanol (500 mL), treated with silica (100-200 mesh, 200 g), concentrated, and loaded onto a silica gel column (100-200 mesh, 330 + 330 g). Eluent was ethyl acetate in petroleum ether (0-85%) to afford 21.0 g (30% yield, 72% purity) of tert-butyl 4-oxo-3-(pyridin-4-yl)piperidine-1-carboxylate as a yellow oil. LCMS: (ES, m / s) 277 [M+H]+, retention time 0.957 min, LCMS method 34. 1 H NMR: (300MHz, CDCl3)δppm 8.60 (d, J=6.0Hz, 2H), 7.15 (d, J=5.7Hz, 2H), 4.39-4.17 (m, 2H), 3.76-3.68 (m, 1H), 3.62-3.46 (m, 2H), 2.65-2.40 (m, 2H), 1.52 (s, 9H).

[1249] Step 2

[1250] To a solution of tert-butyl 4-oxo-3-(pyridin-4-yl)piperidine-1-carboxylate (5.00 g, 18.05 mmol 1.0 eq) in DCM (400 ml) was added DAST (5.83 g, 36.10 mmol, 2.0 eq) dropwise at 0°C. The resulting mixture was stirred at 25°C for 16 h, quenched with ice water (500 mL) and extracted with DCM (100 mL x 3). The combined organic phases were washed with brine (1 L), dried over Na2SO4 and concentrated. The crude product was dissolved in methanol (32 mL) and purified by preparative HPLC (column: C18 cirregular 40-60 μm 60A 330 g) eluting with 5-70% AcCN in water (0.1% formic acid) to give 900 mg (yield: 17%, purity: 91%) of tert-butyl 4,4-difluoro-3-(pyridin-4-yl)piperidine-1-carboxylate as a yellow oil. LCMS: (ES, m / s) 299 [M+H]+, retention time 1.232, LCMS method 35. 1H NMR: (300MHz, CDCl3) δppm 8.62 (d, J=2.0Hz, 2H), 7.30 (d, J=3.2Hz, 2H), 4.42-4.15 (m, 2H), 3.49-3.07 (m, 3H), 2.24-1.95 (m, 2H), 1.50 (s, 9H).

[1251] Step 3

[1252] To a solution of tert-butyl 4,4-difluoro-3-(pyridin-4-yl)piperidine-1-carboxylate (900 mg, 3.02 mmol, 1.0 eq) in DCM (20 ml) was added m-CPBA (1.04 g, 6.03 mmol, 2.0 eq) at 0°C. The resulting mixture was stirred for 2 h, quenched with Na2S2O3 (100 mL, saturated aqueous solution) and extracted with DCM (100 mL x 3). The organic layer was washed with brine (200 mL), dried over sodium sulfate and concentrated. The crude product was dissolved in MeOH (4 mL) and purified by preparative HPLC (column: C18 spherical 20-35um 100A 120 g) eluting with 5-50% AcCN in water (10 mM NH4HCO3) to give 550 mg (yield: 58.0%, purity: 100%) of 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide as a yellow oil. LCMS (ES, m / s): 315 [M+H]+, retention time 1.156 min, LCMS method 10. 1 H NMR: (300MHz, CDCl3)δppm 8.20 (d, J=6.9Hz, 2H), 7.23 (d, J=9.6Hz, 2H), 4.23-4.21 (m, 2H), 3.23-3.02 (m, 3H), 2.23-2.15 (m, 1H), 1.97-1.92 (m, 1H), 1.49 (s, 9H).

[1253] Step 4

[1254] To a solution of 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (550 mg, 1.75 mmol, 1.0 eq) in dichloromethane (25 mL) was added TFA (5 mL). After 14 h, the mixture was concentrated to give 520 mg (yield: 86%, purity: 92%) of the TFA salt of 4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide as a pale yellow oil, which was used without purification. In some cases this material was used as a racemic mixture, and in other cases was first separated into single enantiomers by chiral chromatography (see Example 133, Step 4). LCMS (ES, m / s): 215 [M+H]+, retention time 0.396 min, LCMS method 36. 1 H NMR: (300MHz, CD3OD-d4) δppm 8.33 (d, J=6.9Hz, 2H), 7.58 (d, J=6.9Hz, 2H), 4.31-4.18 (m, 2H), 3.47-3.17 (m, 3H), 2.25-2.10 (m, 2H).

[1255] Step 5

[1256] A mixture of 4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (520 mg, 1.58 mmol, 1.0 eq), 2-bromo-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide (Intermediate 14) (476 mg, 1.58 mmol, 1.0 eq), KI (263 mg, 1.58 mmol, 1.0 eq) and TEA (160 mg, 15.84 mmol, 10.0 eq) in N,N-dimethylacetamide (5 mL) was stirred at 60 ° C for 2 h, quenched with ice water (100 mL) and extracted with DCM (100 mL x 4). The combined organic phases were dried over sodium sulfate and concentrated. The product was chirally separated (XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; mobile phase A: water [10 mmol / L NH₄HCO₃ + 0.1% NH₃.H₂O], mobile phase B: ACN; flow rate: 60 mL / min; 18-40% B in A over 10 min) to obtain the product with retention times of 8.57 and 9.07 minutes. The product of the second peak (9.07 min) was chirally separated again (Chiralpak IF, 2×25 cm, 5 μm; mobile phase A: MTBE [8 mM NH₃.MeOH], mobile phase B: EtOH; flow rate: 11 mL / min; 1:1 A:B over 20 min) to obtain two peaks with retention times of 13.564 and 16.488 minutes. The first peak (13.564 min) was collected to give 23.5 mg (yield: 3.36%, purity: 98.1%, ee: 100%) of 4-((S)-1-((S)-1-((6-(cyclopropylmethoxy)pyridazin-3-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide as a yellow solid. LCMS (ES, m / s): 434 [M+H]+ 1 H NMR: (400MHz, CDCl3) δ10.55 (br, 1H), 8.62-8.51 (m, 1H), 8.14-8.10 (m, 2H), 7.38-7.32 (m, 2H), 7.23-7.15 (m, 1H), 4.31-4.2 9(m, 2H), 3.69-3.55(m, 2H), 3.03-2.96(m, 4H), 2.39-2.26(m, 2H), 1.41-1.32(m, 4H), 0.68-0.64(m, 2H), 0.41-0.36(m, 2H).

[1257] Examples 110-132 were synthesized in a similar manner using the indicated intermediates in step 5.

[1258]

[1259]

[1260]

[1261]

[1262]

[1263]

[1264]

[1265]

[1266]

[1267]

[1268] Example 132

[1269] 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[1270]

[1271] Step 1

[1272] To a mixture of sodium tert-butoxide (158.19 g, 1646 mmol) and THF (2 L) was added 4-bromopyridine hydrochloride (80.10 g, 412 mmol) and 2-Me-THF (100 mL). The vessel was evacuated and backfilled with nitrogen (3×). An exotherm was observed and the reaction was warmed to approximately 33° C. After approximately 20 minutes, tert-butyl 4-oxopiperidine-1-carboxylate (111.40 g, 559 mmol) and 2-Me-THF (200 mL) were added, and the vessel was evacuated and backfilled with nitrogen (3×). After approximately 10 minutes, XPhos (39.390 g, 83 mmol) and palladium(II) acetate (9.260 g, 41.2 mmol) and 2-Me-THF (100 mL) were added, and the vessel was evacuated and backfilled with nitrogen (5×). An exotherm was observed and the reaction was warmed to 36.8°C over 30 minutes. A heating mantle was used to heat the mixture with a target temperature of 48°C. The temperature rose to about 53°C and then steadily dropped to 48°C. After about 7 hours, the reaction was stirred overnight at ambient temperature, diluted with hexane (1200mL), cooled on an ice bath, and quenched by adding saturated NH4Cl (1200mL) in batches, keeping the internal temperature below 20°C. The resulting solid was collected by filtration and the aqueous and organic layers were separated. The aqueous layer was extracted with Et2O (500 ml) and then with EtOAc (500 ml). The filtered solid was rinsed with Et2O (50 ml) and then with DCM (2×50 ml), and these organic rinses were combined with the organic extracts. The organic matter was concentrated, diluted with EtOAc (250 mL), heated to 50°C, and filtered through diatomaceous earth while hot. The filter pad was rinsed with EtOAc (2×50 ml) and the filtrate was concentrated. The obtained residue was diluted with Et2O (250mL) and filtered through diatomaceous earth. The obtained filtrate was stirred and hexane (500 milliliters) was slowly added. The obtained solid was crushed and stirred vigorously to make a suspension. The solid was collected by filtration and rinsed with 2: 1 hexane: Et2O (2X100mL) to obtain 90.69g (328mmol, 80% yield) of tert-butyl 4-oxo-3-(pyridin-4-yl)piperidine-1-carboxylate as a tan solid. LCMS retention time = 0.41 minute, method 2, (ES, m / s): 277.2[M+H]+. 1 H NMR (400MHz, DMSO-d6) δ8.55-8.49 (m, 2H), 7.26-7.20 (m, 2H), 4.21-3.99 (m, 2H), 3.90 (dd, J= 10.8, 5.9Hz, 1H), 3.70-3.39 (m, 2H), 2.66-2.55 (m, 1H), 2.41 (dt, J=14.9, 4.3Hz, 1H), 1.43 (br s, 9H).

[1273] Step 2

[1274] To a solution of triethylamine trihydrofluoride (131 g, 814 mmol, 3 eq) in DCM (1.8 L) was slowly added XtalFluor-E (124 g, 543 mmol, 2 eq) over 5 min. The reaction was cooled to approximately 0°C and tert-butyl 4-oxo-3-(pyridin-4-yl)piperidine-1-carboxylate (75 g, 271 mmol) was slowly added over 5 minutes, maintaining the temperature at approximately 5°C. After 3.5 hours, the reaction mixture was added to 0°C water (1.8 liters) over 44 minutes, maintaining the temperature in the range of 2.4-3.6°C. The reaction mixture was stirred for approximately 5 minutes, the layers were separated, and the aqueous layer was washed with dichloromethane (300 mL). The combined organic layers were cooled to approximately 0°C and quenched with saturated sodium bicarbonate (650 mL) for 12 minutes (the reaction temperature was maintained in the range of 3.8-9.1°C). After approximately 5 minutes, the organic layer was separated, and water (600 mL), Celite 454 (120.44 g), and potassium permanganate (32.22 g, 204 mmol, 0.75 eq) were added. After 1 hour, the mixture was cooled in an ice bath and quenched with saturated sodium metabisulfite (4 x 100 mL batches, maintaining the temperature within the range of 8.9-15°C). The reaction was warmed to room temperature and filtered, and the filter cake was washed with dichloromethane. The organic layer was separated, concentrated, and purified by silica gel chromatography (330 g Gold column), eluting with 0-32.8% (3:1 ethyl acetate:ethanol) in hexanes to provide partially pure product, which was triturated with 1:1 ethyl acetate:hexanes to give 31.59 g (39% yield) of tert-butyl 4,4-difluoro-3-(pyridin-4-yl)piperidine-1-carboxylate as a cream-colored powder. LCMS retention time = 0.60 min, method 2, (ES, m / s): 299.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.58-8.51 (m, 2H), 7.36 (d, J=5.4 Hz, 2H), 4.16-3.88 (m, 2H), 3.51-3.27 (m, 2H, water overlap), 3.19-2.98 (m, 1H), 2.22-2.10 (m, 1H), 2.10-1.90 (m, 1H), 1.41 (s, 9H).

[1275] Step 3

[1276] To a solution of tert-butyl 4,4-difluoro-3-(pyridin-4-yl)piperidine-1-carboxylate (24.395 g, 82 mmol) in acetone (400 mL) and water (400 mL) was added KCO (22.661 g, 164 mmol) and the reaction was cooled in an ice bath. Potassium monopersulfate (OXONE monopersulfate) (37.778 g, 123 mmol) was added portionwise over approximately 13 minutes (approximately one teaspoon every 15 seconds). The temperature rose from 4.6°C to 5.5°C over 14 minutes and then fell. After 2 hours, additional potassium monopersulfate (5.021 g, 16.33 mmol) was added over approximately 3 minutes, and no exotherm was detected. After an additional 2 hours, the reaction mixture was diluted with DCM (1 L) and saturated sodium metabisulfite (500 mL) was added over approximately 1 hour and 54 minutes, at which point the internal temperature rose from 3.8°C to 8.3°C. After 15 minutes, the mixture was transferred to a separatory funnel and the organic layer was collected, leaving behind an aqueous layer and an emulsion layer. The emulsion layer was separated and filtered, rinsed with DCM, and the filtrate collected. The remaining aqueous layer was extracted with DCM (100 mL). All organic extracts and the filtrate were combined, dried over MgSO4, filtered through Celite, and concentrated to give 26.43 g (84 mmol, quantitative yield) of 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide as a cream-colored foamy solid. LCMS retention time = 0.74 minutes, Method 3, (ES, m / s): 315.1 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 8.23-8.17 (m, 2H), 7.37 (d, J = 6.8 Hz, 2H), 4.14-3.87 (m, 2H), 3.47-3.21 (m, 2H, water overlap), 3.15-2.96 (m, 1H), 2.22-2.12 (m, 1H), 2.07-1.87 (m, 1H), 1.41 (s, 9H).

[1277] Step 4

[1278] To a solution of 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide (20.5 g, 65.2 mmol) in ethyl acetate (350 mL) and methanol (35 mL) was added HCl (4.0 M in dioxane; 100 mL, 400 mmol) over 30 min. After 16 h, the reaction was concentrated and diluted with diethyl ether (200 mL). After 1 h, the resulting solid was collected by filtration and washed with additional diethyl ether (100 mL) to give the hydrochloride salt of 4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (16.3 g, 95% yield). The racemic mixture was purified by chiral chromatography (Agilent 1260 autoprep, column: Chiralpak IG, 30x250 mm, 5 micron; mobile phase: 50:50 acetonitrile:methanol; flow rate: 45 mL / min; 0.5 g sample mixture in 9 mL mobile phase, and 0.5 mL Et3N was added to neutralize the HCl salt) to give two isomers with retention times of 4.3 and 6.4 min. The fractions corresponding to the earlier peak (rt = 4.3 min) were collected and concentrated to give (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (5.8 g) as an oil (free base). LCMS retention time = 0.35 min, Method 3, (ES, m / s): 215.2 [M+H]+. 1 HNMR (400MHz, DMSO-d6) δ8.28-8.06 (m, 2H), 7.34 (d, J=6.8Hz, 2H), 3.25-3.00 (m, 3H), 2.94-2.81 (m, 1H), 2.69 (td, J=12.7, 2.9Hz, 2H), 2.11-1.99 (m, 1H), 1.95-1.74 (m, 1H).

[1279] Step 5

[1280] To (S)-4-(4,4-difluoropiperidin-3-yl)pyridine 1-oxide (4.0 g, 18.67 mmol) and (R)-2-bromo-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propionamide (Intermediate 65) (8.03 g, 22.41 mmol) mixed as solids in a vessel cooled to 0°C was added DMA (16.98 ml). Once a solution was formed, TEA (3.12 ml, 22.41 mmol) was slowly added and the reaction mixture was stirred at 0°C. After 48 hours, the reaction mixture was poured into ice (approximately 150 g) with some stirring. DCM (150 ml) was added with stirring, the layers were separated, and the organic layer was washed with saturated NH4Cl (100 ml). The organic layer was dried over magnesium sulfate, filtered through celite, concentrated, and purifi...

Claims

1. A compound according to formula (II) or a pharmaceutically acceptable salt thereof: in: W is N or CH; Each X 1 are independently N or CR 10 ; Each X 2 are independently N or CR 11 ; Y 1 N or CR 12 ; Y 2 N or CR 12 ; Z is n is 0 or 1; R 1 is hydrogen, halogen, (C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-aryl, 5- or 6-membered heteroaryl (C1-C4) Alkyl-, (C3-C8) cycloalkyl, (C2-C6) alkenyl, -(C2-C6) alkenyl-(C3-C8) cycloalkyl, -OH, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C1-C6) alkyl-aryl, -O-(C1-C6) alkyl-5-6 membered heteroaryl, -O-(C2-C6) alkenyl, -O-(C3-C 8) cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2H, -CO2(C1-C6)alkyl, -CO2(C3-C8)cycloalkyl, -O2C(C1-C6)alkyl, -O2C(C3-C8)cycloalkyl, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)((C1-C6)alkyl), aryl or 5-6 membered heteroaryl wherein any of the (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, -(C1-C6)alkyl-aryl, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-5-6-membered heteroaryl, -C(O)-aryl, aryl or 5-6-membered heteroaryl is optionally replaced by R 14 Replace once, twice or thrice; R 2 is hydrogen, halogen, (C1-C6)alkyl, or -OH, wherein any of said (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen; R 3 is hydrogen, halogen, (C1-C6)alkyl, or -OH, wherein any of said (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen; R 4 is hydrogen, halogen or (C1-C6) alkyl; R 5 is hydrogen, halogen or (C1-C6) alkyl; R 6 is hydrogen, halogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C4) alkoxy, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-O-(C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-NH((C1-C6) alkyl)-OH, -(C1-C6) alkyl-NH (((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl)-OH, -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-NH-(C3-C8) cycloalkyl, -(C1-C6) alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-4- to 6-membered heterocycloalkyl, 6) alkyl-NHC(O)-((C1-C6) alkyl), -(C1-C6) alkyl-SO2-(C1-C6) alkyl, -(C1-C6) alkyl-SO2-NH-(C1-C6) alkyl, -CN, -C(O)NH2, -C(O)NH(C1-C6) alkyl), -C(O)N(C1-C6) alkyl)(C1-C6) alkyl), -NH2, -NH(C1-C6) alkyl, -N((C1-C6) alkyl)((C1-C6) alkyl), -SO2((C1-C6) alkyl ), -SO2-NH((C1-C6)alkyl), or aryl, wherein any of said (C1-C6)alkyl, (C3-C8)cycloalkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice, or three times with halogen; R 7 is hydrogen, (C1-C6)alkyl, or -OH; R 8 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy; R 9 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy; Each R 10 are independently hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), (C2-C6)alkenyl, -O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)((C1-C6)alkyl), -NCH2, or -CHNH; or R 1 and any R 10 together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl; Each R 11 are independently hydrogen, halogen, (C1-C6)alkyl or (C2-C6)alkenyl; or any R 10 and any R 11 together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl; R 12 is hydrogen, halogen or (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted once, twice or three times with halogen; R 13 is hydrogen, (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl, wherein said (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl is optionally substituted once, twice, or three times with halogen; Each R 14 is independently halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -CN, -(C1-C6)-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -OH, (C1-C4)alkoxy, -O-(C3-C8)cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein the (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl or 5-6 membered heteroaryl is further optionally substituted with one, two or three substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl or (C1-C4)alkoxy; wherein the aryl group is phenyl, and the heteroaryl group is a 5-6 membered heteroaryl group comprising at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein W is N.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 1 CR 12 , where R 12 For hydrogen.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 1 CR 12 , where R 12 is (C1-C6)alkyl optionally substituted with 1, 2 or 3 halogens.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, Y 2 is N.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 2 CR 12 , where R 12 For hydrogen.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is where R 13 is hydrogen, (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl, wherein the (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen; wherein the aryl group is phenyl, and the heteroaryl group is a 5-6 membered heteroaryl group comprising at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

8. The compound or pharmaceutically acceptable salt according to claim 1, wherein Z is And R 6 is hydrogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NHC(O)-((C1-C6)alkyl), or -C(O)NH2, wherein any of said (C1-C6)alkyl or -(C1-C6)alkyl-OH is optionally substituted once, twice, or three times with halogen.

9. The compound or pharmaceutically acceptable salt according to claim 1, wherein Z is And R 6 is hydrogen, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl, -C(O)NH2, wherein any of said -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice or three times with halogen.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen, (C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-aryl, 5- or 6-membered heteroaryl (C1-C4) alkyl-, (C3-C8) cycloalkyl, (C2-C6) alkenyl, -(C2-C6) alkenyl-(C3-C8) cycloalkyl, -OH, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C1-C6) alkyl-5-6 membered heteroaryl, -O-(C3-C8) Cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2(C3-C8)cycloalkyl, -NH2, aryl or 5-6 membered heteroaryl, wherein any of said (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, -(C1-C6)alkyl-aryl, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-5-6-membered heteroaryl, -C(O)-aryl, aryl or 5-6 membered heteroaryl is optionally replaced by R 14 Replace once, twice or thrice; And each R 14 is independently halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -CN, -(C1-C6)-OH, -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -OH, (C1-C4)alkoxy, or a 5-6-membered heteroaryl group, wherein the (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl, or 5-6-membered heteroaryl group is further optionally substituted with one, two, or three substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, or (C1-C4)alkoxy group; wherein the aryl group is phenyl, and the heteroaryl group is a 5-6 membered heteroaryl group comprising at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, halogen or (C1-C6)alkyl; and / or where R 3 is hydrogen, halogen or (C1-C6) alkyl.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are hydrogen.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen or halogen; and / or where R 5 is hydrogen or halogen.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 For fluorine.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-NH((C1-C6) alkyl)-OH, -(C1-C6) alkyl-NH((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-NH-(C3-C8) cycloalkyl, -(C1-C6) alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-NHC(O)-((C1-C6) alkyl) -C6)alkyl), -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1-C6)alkyl, -CN, -C(O)NH2, -NH2, -SO2((C1-C6)alkyl), -SO2-NH((C1-C6)alkyl) or phenyl, wherein any of the (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice or three times with halogen.

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen; and / or where R 8 is (C1-C6) alkyl and R 9 For hydrogen.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: W is N or CH; Each X 1 are independently N or CR 10 ; Each X 2 are independently N or CR 11 ; Y 1 N or CR 12 ; Y 2 N or CR 12 ; Z is n is 0 or 1; R 1 is halogen, (C1-C6) alkyl, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-(C3-C8) cycloalkyl, -(C1-C6) alkyl-aryl, 5- or 6-membered heteroaryl (C1-C4) alkyl-, (C3-C8) cycloalkyl, (C2-C6) alkenyl, -(C2-C6) alkenyl-(C3-C8) cycloalkyl, -OH, (C1-C4) alkoxy, -O-(C1-C6) alkyl-(C3-C8) cycloalkyl, -O-(C1-C6) alkyl-5-6 membered heteroaryl, -O-(C3-C8) Cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2(C3-C8)cycloalkyl, -NH2, aryl or 5-6 membered heteroaryl, wherein any of said (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, -(C1-C6)alkyl-aryl, (C1-C4)alkoxy, -O-(C1-C6)alkyl-(C3-C8)cycloalkyl, -O-(C3-C8)cycloalkyl, -O-aryl, -O-5-6-membered heteroaryl, -C(O)-aryl, aryl or 5-6 membered heteroaryl is optionally replaced by R 14 Replace once, twice or thrice; R 2 is hydrogen, halogen or (C1-C6)alkyl, wherein any of said (C1-C6)alkyl is optionally substituted once, twice or three times with halogen; R 3 is hydrogen, halogen, (C1-C6)alkyl, wherein any of said (C1-C6)alkyl is optionally substituted once, twice or three times with halogen; R 4 is hydrogen, halogen or (C1-C6) alkyl; R 5 is hydrogen, halogen or (C1-C6) alkyl; R 6 is hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C4) alkoxy, -(C1-C6) alkyl-OH, -(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NH((C1-C6) alkyl), -(C1-C6) alkyl-N-((C1-C6) alkyl)((C1-C6) alkyl), -(C1-C6) alkyl-NH((C1-C6) alkyl) C6) alkyl)-OH, -(C1-C6) alkyl-NH(((C1-C6) alkyl)-O-(C1-C6) alkyl), -(C1-C6) alkyl-NH-(C3-C8) cycloalkyl, -(C1-C6) alkyl-NH-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-4- to 6-membered heterocycloalkyl, -(C1-C6) alkyl-NHC(O)-((C1 -(C1-C6)alkyl), -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-SO2-NH-(C1-C6)alkyl, -CN, -C(O)NH2, -NH2, -SO2((C1-C6)alkyl), -SO2-NH((C1-C6)alkyl), or aryl, wherein any of said (C1-C6)alkyl, (C3-C8)cycloalkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-NH2, -(C1-C6)alkyl-NH((C1-C6)alkyl), -(C1-C6)alkyl-NH-(C3-C8)cycloalkyl, -(C1-C6)alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C1-C6)alkyl-4- to 6-membered heterocycloalkyl is optionally substituted once, twice, or three times with halogen; R 7 is hydrogen, (C1-C6)alkyl, or -OH; R 8 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy; R 9 is hydrogen, (C1-C6)alkyl or (C1-C4)alkoxy; Each R 10 are independently hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, -NCH2, or -CHNH; or R 1 and any R 10 together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-(C3-C8)cycloalkyl, halo(C1-C6)alkyl, and (C3-C8)cycloalkyl; Each R 11 are independently hydrogen or halogen; R 12 is hydrogen or (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted once, twice or three times with halogen; R 13 is hydrogen, (C1-C6)alkyl, -(C1-C6)alkyl-SO2-(C1-C6)alkyl, -(C1-C6)alkyl-aryl, or -(C1-C6)alkyl-5-6-membered heteroaryl, wherein the (C1-C6)alkyl is optionally substituted once, twice, or three times with halogen; and Each R 14 is independently halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -CN, -(C1-C6)-OH, -(C1-C6)alkyl-N((C1-C6)alkyl)((C1-C6)alkyl), -OH, (C1-C4)alkoxy, or a 5-6-membered heteroaryl group, wherein the (C1-C6)alkyl, (C3-C8)cycloalkyl, aryl, or 5-6-membered heteroaryl group is further optionally substituted with one, two, or three substituents independently selected from halogen, (C1-C6)alkyl, -(C1-C6)alkyl-OH, -(C1-C6)alkyl-O-(C1-C6)alkyl, or (C1-C4)alkoxy group; wherein the aryl group is phenyl, and the heteroaryl group is a 5-6 membered heteroaryl group comprising at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein W is N; Each X 1 are independently N or CR 10 ; Each X 2 are independently N or CR 11 ; Y 1 CR 12 ; Y 2 CR 12 ; Z is n is 1; R 1 is -O-phenyl, which is optionally replaced by R 14 Replace once, twice or thrice; R 2 is hydrogen; R 3 is hydrogen; R 4 is a halogen; R 5 is a halogen; R 6 is hydrogen; R 7 is hydrogen; R 8 is (C1-C6)alkyl; R 9 is hydrogen; Each R 10 are independently hydrogen; Each R 11 are independently hydrogen; R 12 is hydrogen; and Each R 14 are independently halogen.

20. The compound according to claim 1, which is: (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-phenoxypyridin-2-yl)propanamide; (S)-N-(5-benzylpyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-(cyclopentyloxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-((E)-2-cyclopropylvinyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(6-benzylpyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyridin-4-ylmethyl)pyridin-2-yl)propanamide; (S)-N-(5-cyclopentylpyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-cyclopropylpyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(m-tolyl)pyridin-2-yl)propanamide; (S)-N-(2-cyclopropyloxazolo[4,5-b]pyridin-5-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-cyclobutylpyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6-phenoxypyridazin-3-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6-(o-tolyloxy)pyridazin-3-yl)propanamide; N-(5-(2-cyclopropylethyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-(benzyloxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-phenylpyridin-2-yl)propanamide; N-(5-(cyclohexyloxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(6-cyclopropylquinolin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-isopropoxypyridin-2-yl)propanamide; N-(5-(cyclohexylmethyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)-3-fluoropyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyrazin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; N-(5-(cyclobutylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; N-(5-(1-cyclopropylethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; N-(5-(cyclopentylmethyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(isoquinolin-3-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyrimidin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl)propanamide; 6-((S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propionamido)cyclobutylnicotinate; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(oxazol-2-ylmethoxy)pyridin-2-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(4,5-difluoropyridin-2-yl)propanamide; N-(1-(cyclopropylmethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; N-(5-(cyclopropylmethyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; N-(5-cyclohexylpyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6-methoxypyridazin-3-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-methoxypyridin-2-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyridin-3-ylmethyl)pyridin-2-yl)propanamide; 6-((S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propionamido)cyclopentylnicotinate; N-(5-(cyclopentylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; N-(5-(cyclopropyloxymethyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,2-difluoroethoxy)pyridin-2-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(thiophen-2-yl)pyridin-2-yl)propanamide; N-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(thiazol-2-ylmethyl)pyridin-2-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(oxazol-2-ylmethyl)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(quinolin-2-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(isoxazol-3-yl)pyridin-2-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyridin-2-ylmethyl)pyridin-2-yl)propanamide hydrochloride; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyridin-3-yloxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-phenoxypyrazin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyridin-2-yloxy)pyridin-2-yl)propanamide; N-(6-(2-cyanophenoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6-(4-fluorophenoxy)pyridazin-3-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyridin-4-yloxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((3-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((5-fluoropyridin-3-yl)oxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyrazin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide; (S)-N-(5-cyclopropylpyrazin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(6-(cyclobutylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((2-oxo-1,2-dihydropyridin-3-yl)oxy)pyridin-2-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(spiro[3.3]hept-2-yloxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(pyrimidin-4-yloxy)pyridin-2-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)-4-fluoropyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; N-(6-cyclopropyl-1,8-naphthyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; N-(5-cyclobutyloxypyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-N-(5-((Z)-2-cyclopropylvinyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-chloropyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-isopropylpyridin-2-yl)propanamide; 6-(2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propionamido)cyclopropylnicotinate; (S)-N-(5-(cyclobutylmethyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(3-fluoro-5-(4-fluorophenoxy)pyridin-2-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)-3-fluoropyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6-(neopentyloxy)pyridazin-3-yl)propanamide; N-(5-((3-chloro-5-fluoropyridin-2-yl)oxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(3-fluoro-5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide; N-(5-((3-cyano-5-fluoropyridin-2-yl)oxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6-(spiro[3.3]hept-2-yloxy)pyridazin-3-yl)propanamide; N-(5-bromopyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((6-methoxypyridin-2-yl)oxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4,6-trifluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4,5-trifluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2-((dimethylamino)methyl)-4-fluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2-fluoro-4-(2-methylthiazol-4-yl)phenoxy)pyridin-2-yl)propanamide; (S)-N-(6-cyclobutyloxypyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(6-(cyclopentyloxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-(difluoro(4-fluorophenyl)methyl)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((R)-4,4-difluoro-3-(5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide; (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)propanamide; (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)-4,4-difluoropiperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide; (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; 4-((S)-1-((S)-1-((6-(cyclopropylmethoxy)pyridazin-3-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-(4,4-difluoro-1-(1-oxo-1-((5-phenoxypyridin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-((5-(cyclopropylmethoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-((5-chloropyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-(1-((5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-(1-((5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(2,4,6-trifluorophenoxy)pyrazin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(2,4,5-trifluorophenoxy)pyrazin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-((5-(2,6-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(2,3,4-trifluorophenoxy)pyrazin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(2,4,6-trifluorophenoxy)pyridin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(2,4,5-trifluorophenoxy)pyridin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-((5-((3-fluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(pyridin-2-yloxy)pyridin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-((5-(difluoro(4-fluorophenyl)methyl)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluorobenzoyl)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((3S)-4,4-difluoro-1-(1-((5-((4-fluorophenyl)(hydroxy)methyl)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-((5-(2,6-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-oxo-1-((5-(2,3,4-trifluorophenoxy)pyridin-2-yl)amino)propan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)propanamide; (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)propanamide; (S)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-N-(5-chloropyridin-2-yl)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)propanamide; (S)-N-(5-cyclopropylpyridin-2-yl)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)propanamide; (S)-2-((S)-3-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)propanamide; 2-(3-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-phenoxypyridin-2-yl)propanamide; (S)-2-((S)-3-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide; (S)-2-((S)-3-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide; (S)-2-((S)-3-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-2-((R)-3-(5-amino-6-oxo-1,6-dihydropyridazin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-2-((R)-3-(5-amino-6-oxo-1,6-dihydropyridazin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)propanamide; (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-cyclopropylpyridin-2-yl)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)propanamide; (S)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-5-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-(5-(2-hydroxypropan-2-yl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-(4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; N-(5-chloropyridin-2-yl)-2-(4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((S)-(4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide; (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((3S,4R)-(4-fluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((3S,4S)-(4-fluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((3S,4R)-4-Fluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-2-((3S,4S)-4-Fluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-N-(5-fluoropyridin-2-yl)-2-((3S,5R)-3-methyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-4,4-difluoro-3-methyl-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-(3,3-difluoro-4-(6-oxo-1,6-dihydropyridin-3-yl)pyrrolidin-1-yl)propanamide; 2-(3,3-difluoro-4-(6-oxo-1,6-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-N-(5-chloropyridin-2-yl)-2-((R)-(3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)propanamide; (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((S)-3-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((S)-3-(6-oxo-4-(trifluoromethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; ((S)-2-((S)-3-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((R)-3-hydroxy-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-chloropyridin-2-yl)-2-((3S,5S)-(3-methyl-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-chloropyridin-2-yl)-2-((3R,5S)-(3-methyl-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((R)-3-(6-amino-5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide; (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-chloropyridin-2-yl)propanamide; (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(6-oxo-5-phenyl-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(5-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 4-((S)-1-((S)-1-((5-chloropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-2-methylpropanamide; (S)-N-(5-chloropyridin-2-yl)-2-((S)-3-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((R)-3-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-chloropyridin-2-yl)-2-((R)-3-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-1-yl)propanamide; (2S)-2-(3-(5-amino-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (2S)-2-(3-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-(3-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide; (2S)-2-(4,4-difluoro-3-(1-(2-(methylsulfonyl)ethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (2S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-(4,4-difluoro-3-(1-(2-(methylsulfonyl)ethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-(4,4-difluoro-3-(1-(2-(methylsulfonyl)ethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-(3-(1-(2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (2S)-2-(4,4-difluoro-3-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-2-((S)-(3-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; 2-(4,4-difluoro-3-(6-oxo-1-(pyridin-2-ylmethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; 2-(4,4-difluoro-3-(6-oxo-1-(pyridin-4-ylmethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; 2-(4,4-difluoro-3-(1-(oxazol-2-ylmethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (2S)-2-(4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (2S)-2-(4,4-difluoro-3-(5-methyl-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; 2-(3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-phenoxypyridin-2-yl)propanamide; (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide; (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyrazin-2-yl)propanamide; (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-phenoxypyrazin-2-yl)propanamide; (S)-2-((S)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(6-oxo-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (2S)-2-(4,4-difluoro-3-(6-oxo-5-(2,2,2-trifluoro-1-hydroxyethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; (2S)-2-(4,4-difluoro-3-(6-oxo-5-(2,2,2-trifluoro-1-hydroxyethyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; 2-(4,4-difluoro-3-(5-((methylsulfonyl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(5-((methylsulfonyl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(5-((methylsulfonyl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyrazin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(5-((methylsulfonyl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; 4-(4,4-difluoro-1-((S)-1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-methylpyridine 1-oxide; 4-((R)-4,4-difluoro-1-((R)-1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-methylpyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-methylpyridine 1-oxide; 4-((S)-4,4-difluoro-1-((S)-1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl 1-(2,2,2-trifluoroethyl)pyridine-1-oxide; 4-((S)-1-((S)-1-((6-(cyclopropylmethoxy)pyridazin-3-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-(2,2,2-trifluoroethyl)pyridine 1-oxide; (2S)-2-(3-(5-bromo-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide; (2S)-2-(3-(5-(1-aminoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide; (2S)-2-(3-(5-cyano-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)propanamide; (2S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-(4,4-difluoro-3-(pyridin-4-yl)piperidin-1-yl)propanamide; (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; 2-(4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propanamide; 2-(3-(5-((dimethylamino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; (S)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((S)-3-(5-((dimethylamino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide; (2S)-2-(3-(5-(1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (S)-2-((S)-3-(5-((S)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-3-(5-((R)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-3-(5-((S)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-3-(5-((R)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; 2-(4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; 2-(4,4-difluoro-3-(5-(((2-hydroxyethyl)amino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; 2-(4,4-difluoro-3-(5-(((2-methoxyethyl)amino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; (S)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-((S)-3-(5-((4,4-difluoropiperidin-1-yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide; (S)-2-((S)-3-(5-(((3,3-difluorocyclobutyl)amino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-5-(((2,2,2-trifluoroethyl)amino)methyl)-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; S)-2-((S)-4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propanamide; (S)-2-((S)-3-(5-(acetylaminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-(5-(methylsulfonyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-3-(5-(methylsulfonyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-(5-(N-methylsulfamoyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-3-(5-(N-methylsulfamoyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide; (S)-2-((S)-3,3-difluoro-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; (R)-2-((R)-3,3-difluoro-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; 2-(3-(5-cyano-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-fluoropyridin-2-yl)propanamide; 2-(3-(5-cyano-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyrazin-2-yl)propanamide; (S)-2-((S)-3-(5-cyano-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; 5-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(4,4-difluoro-1-(1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide; 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide; 4-(4,4-difluoro-1-(1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine 1-oxide; 4-(4,4-difluoro-1-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine 1-oxide; 2-Carbamoyl-4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 2-Carbamoyl-4-((S)-4,4-difluoro-1-((S)-1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; 2-Carbamoyl-4-(1-(1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-(1-((S)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine-2-carboxamide; 2-(Acetylaminomethyl)-4-(1-(1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 2-(Acetylaminomethyl)-4-(4,4-difluoro-1-(1-((5-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; 2-(3-(2-(aminomethyl)pyridin-4-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; (2S)-2-(4,4-difluoro-3-(5-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; 3-(1-(1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine 1-oxide; 2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-((6-oxo-1,6-dihydropyridin-2-yl)oxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(3,4-difluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluoro-2-methoxyphenoxy)pyridin-2-yl)propanamide; (2S)-2-(3-(2-((3,3-difluoroazetidin-1-yl)methyl)pyridin-4-yl)-4,4-difluoropiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluoro-2-(hydroxymethyl)phenoxy)pyridin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(4-fluoro-2-(hydroxymethyl)phenoxy)pyrazin-2-yl)propanamide; 4-((S)-4,4-difluoro-1-((S)-1-((5-(4-fluoro-2-(hydroxymethyl)phenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; 4-((3S)-4,4-difluoro-1-(1-((5-(4-fluoro-2-(hydroxymethyl)phenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide; (R)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide; (R)-N-(6-(cyclopropylmethoxy)pyridazin-3-yl)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide; (R)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)-N-(5-fluoropyridin-2-yl)propanamide; 2-(4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide; (R)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide; (R)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide; (R)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)-N-(5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide; (R)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-((1S,3R)-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide; (R)-N-(5((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)-2-((1S,3R)-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide; N-(5-(4-fluorophenoxy)pyrazin-2-yl)-2-((3R)-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide; (R)-N-(5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)-2-((1S,3R)-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide; (R)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-((1S,3R)-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)propanamide; 4-((1R,3S)-3-((R)-1-((5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)cyclohexyl)pyridine 1-oxide; 4-((1R,3S)-3-((R)-1-((5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)cyclohexyl)pyridine 1-oxide; 4-((1R,3S)-3-((R)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)cyclohexyl)pyridine 1-oxide; 4-((1R,3S)-3-((S)-1-((5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)cyclohexyl)pyridine 1-oxide; 4-((1R,5S)-5-((R)-1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-difluorocyclohexyl)pyridine 1-oxide; 4-((1R,5S)-2,2-difluoro-5-((R)-1-((5-(4-fluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)cyclohexyl)pyridine 1-oxide; 4-((1R,5S)-5-((R)-1-((5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-difluorocyclohexyl)pyridine 1-oxide; 4-((1R,5S)-2,2-difluoro-5-((R)-1-((5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)cyclohexyl)pyridine 1-oxide; and 4-((1R,5S)-5-((R)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-2,2-difluorocyclohexyl)pyridine 1-oxide; (R)-2-((1S,3R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)cyclohexyl)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)acrylamide; (S)-2-((S)-4,4-difluoro-3-(pyridin-4-yl)piperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propanamide; 4-((S)-1-((S)-1-((5-(2,4-difluoro-6-(hydroxymethyl)phenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; 4-((S)-1-((S)-1-((5-(2,4-difluoro-6-(hydroxymethyl)phenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluoro-6-(hydroxymethyl)phenoxy)pyrazin-2-yl)propanamide; (S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(5-(2,4-difluoro-6-(hydroxymethyl)phenoxy)pyridin-2-yl)propanamide; or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1, which is 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide, represented by the following formula: or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 21, wherein the compound is the hydrochloride salt of 4-((S)-1-((S)-1-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

24. Use of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, for the preparation of a medicament for treating a MrgX2-mediated disease or disorder in a human in need thereof.

25. The use according to claim 24, wherein the disease or disorder is selected from chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic pruritus, drug-induced anaphylactoid reactions, metabolic syndrome, oesophageal reflux, asthma, cough, migraine, chronic induced urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudoallergic reactions and contact urticaria.

26. Use of a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating an MrgX2-mediated disease or disorder.

27. The use according to claim 26, wherein the disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic pruritus, drug-induced anaphylactoid reaction, metabolic syndrome, oesophageal reflux, asthma, cough, migraine, chronic induced urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudoallergic reaction or contact urticaria.

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