H4 antagonist compounds

Abstract

The contents disclosed herein relate to novel compounds of formula (1) and their salts: where Y, Z, and R 1 R 2 R 3 R 4 R 5 And n as defined in this article, and their uses in treating, preventing, improving, controlling or reducing the risk of conditions associated with the H4 receptor.

Description

Technical Field

[0001] This application relates to novel compounds and their use as histamine H4 receptor antagonists. The compounds described herein can be used to treat or prevent diseases involving H4 receptors. This application also relates to pharmaceutical compositions comprising these compounds, the preparation of these compounds and compositions, and their use in the prevention or treatment of such diseases involving H4 receptors. Background Technology

[0002] Histamine is a short-acting biogenic amine produced in mast cells, stored in cytoplasmic granules, and released in response to various immune and non-immune stimuli. Histamine released from mast cells has traditionally been associated with signs and symptoms characteristic of mild to severe hypersensitivity reactions, including erythema, urticaria, pruritus, tachycardia, hypotension, ventricular fibrillation, bronchospasm, and cardiac and respiratory arrest. Many other sources have been identified to date, including basophils, neurons, and cancer cells. In addition to regulating a wide range of physiological processes, histamine is also associated with pathological conditions, including allergies and anaphylactic reactions, asthma and chronic inflammation, autoimmune diseases, cardiovascular diseases, neuropsychiatric and endocrine disorders, and cancer.

[0003] Histamine exerts its pleiotropic effects primarily by binding to four types of G protein-coupled receptors (GPCRs), known as H1-H4. These receptors are differentially expressed across various cell types and exhibit considerable variability across different substances. H2 receptors are responsible for gastric acid secretion; H3 receptors control the release of histamine and other neuromodulators in the central nervous system; and H1 receptors are associated with insomnia and inflammatory responses.

[0004] In 2000, the high-affinity H4 receptor was identified as exhibiting constitutive activity, primarily but not limited to expression on cells of the immune system, including mast cells, monocytes, dendritic cells, eosinophils, basophils, neutrophils, and T cells. This discovery has opened up promising prospects for novel drug targets with therapeutic potential in acute and chronic inflammation, autoimmune diseases, host defense, and neuropathic pain.

[0005] H4R shares only 40% homology with its nearest neighbor, H3R, and neither H2 nor H1 antagonists have shown inhibition of histamine-induced eosinophil chemotaxis. Histamine has been shown to inhibit the trichodin-induced cAMP response in a pertussis toxin (PTx)-sensitive manner, suggesting that H4R signals via the heterotrimeric Gαi / o protein. Transient expression of H4R in heterologous cell systems (e.g., HEK293 cells) is a widely used method for measuring H4 ligand signaling and binding to yield estimates of functional potency and receptor affinity, respectively.

[0006] Using these technologies, H4R antagonists were discovered and studied in various animal disease models, including asthma, chronic pruritus, dermatitis, rheumatoid arthritis, gastric ulcers, and colitis. This demonstrated the profound anti-inflammatory effects of H4R antagonism and validated the therapeutic benefits of targeting this receptor. The first phase 2a clinical trial of an H4R antagonist has been conducted in patients with moderate to severe atopic dermatitis, further confirming H4 as a drug target for these patients.

[0007] Despite the publication of numerous H4R ligands, there remains a need to develop novel H4R antagonists with good candidate drug quality. These antagonists should exhibit excellent low nM potency and fully selective affinity for H1-H3 receptors. They should not exhibit agonist activity due to the risks associated with inducing pro-inflammatory responses; ideally, they should demonstrate similar pharmacological profiles across different substances to support PK / PD in various animal models of disease. They should be metabolically stable, possess excellent PK, be non-toxic, and demonstrate excellent H4 specificity in extensive safety analyses.

[0008] The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activated delayed rectifier potassium channel (IKr), which plays a crucial role in ventricular repolarization and determining the QT interval on an electrocardiogram (ECG). The QT interval is the time required for ventricular depolarization and repolarization. hERG is widely considered to be highly sensitive to inhibition by a wide variety of structurally diverse compounds. When the channel's ability to conduct electrical currents across the cell membrane is inhibited or impaired by applied drugs, a potentially fatal condition known as QT syndrome may occur. Many clinically successful drugs on the market tend to inhibit hERG, with the associated risk of sudden death as a side effect, making hERG inhibition an important anti-target that must be avoided during drug development.

[0009] The compounds of this invention are H4 receptor antagonists. Some compounds have low hERG inhibitory activity, making them particularly beneficial. Summary of the Invention

[0010] This invention provides compounds having H4 receptor antagonist activity. More specifically, this invention provides compounds that combine H4 receptor antagonism with low hERG activity.

[0011] Therefore, in one embodiment, the present invention provides a compound of formula (1) or a salt thereof:

[0012]

[0013] in:

[0014] Z is H, NH2, or C.1-3 alkyl;

[0015] Y is selected from the group composed of the following substances:

[0016]

[0017] n is 0 or 1;

[0018] R 1 It is H or C, which is optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 1 With R 3 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms;

[0019] R 2 H is the arbitrarily substituted C. 1-6 Alkyl groups, optionally substituted C 3-6 Cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic groups, wherein the optional substituents are selected from OC. 1-3 Alkyl group or 1 to 6 fluorine atoms, or R 2 With R 3 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms;

[0020] R 3 It is H or C, which is optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 3 With R 1 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms, or R 3 With R 2 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms, or R 3 With R 4 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms;

[0021] R 4 It is H or C, which is optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 4 With R 3 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms, or R 4 With R 5 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms;

[0022] R 5 It is H or C, which is optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 5 With R 4 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms;

[0023] And R 6It is H or methyl.

[0024] Specific compounds include compounds of formulas (1a) and (1b) or their salts:

[0025]

[0026] Among them, Y and R 1 R 2 R 3 R 4 R 5 And n is defined as above.

[0027] Specific compounds include compounds of formulas (2a) and (2b) or their salts:

[0028]

[0029] Among them, Z and R 1 R 2 R 3 R 4 R 5 And n is defined as above.

[0030] Specific compounds include compounds of formulas (2c) and (2d) or their salts:

[0031]

[0032] Among them, Z and R 1 R 2 R 3 R 4 R 5 And n is defined as above.

[0033] Specific compounds include compounds of formula (2e) or their salts:

[0034]

[0035] Among them, Z and R 1 R 2 R 3 R 4 R 5 And n is defined as above.

[0036] Specific compounds include compounds of formulas (3a) and (3b) or their salts:

[0037]

[0038] Among them, Z and R 1 R 2 R 3 R 4 R 5And n is defined as above.

[0039] Specific compounds include compounds of formula (3c) or their salts:

[0040]

[0041] Among them, Z and R 1 R 2 R 3 R 4 R 5 And n is defined as above.

[0042] Specific compounds include compounds of formula (4) or their salts:

[0043]

[0044] Among them, Y, Z, and R 1 R 2 R 3 R 4 R 5 And n is defined as above.

[0045] Specific compounds include compounds of formula (5) or their salts:

[0046]

[0047] Among them, Y and R 2 R 3 And n is defined as above.

[0048] Specific compounds include compounds of formula (5a) or their salts:

[0049]

[0050] Among them, Y and R 2 R 3 And n is defined as above.

[0051] Specific compounds include compounds of formulas (6a) and (6b) or their salts:

[0052]

[0053] Among them, Y and R 2 and R 3 As defined above.

[0054] Specific compounds include compounds of formulas (7a) and (7b) or their salts:

[0055]

[0056] Among them, Y and R 2 and R3 As defined above.

[0057] These compounds can be used as H4 receptor antagonists. These compounds can be used to prepare pharmaceuticals. The compounds or pharmaceuticals can be used to treat, prevent, improve, control, or reduce the risk of inflammatory conditions, including asthma, chronic pruritus, dermatitis, rheumatoid arthritis, gastric ulcers, and colitis. Invention Details

[0059] This invention relates to novel compounds. It also relates to the use of these novel compounds as H4 receptor antagonists. Furthermore, it relates to the use of these novel compounds in the preparation of medicaments for use as H4 receptor antagonists or for treating H4 system dysfunction. Finally, it relates to compounds, compositions, and medicaments that are selective H4 receptor antagonists.

[0060] The present invention also relates to compounds, compositions and pharmaceuticals that can be used to treat acute and chronic inflammation, autoimmune diseases, host defense disorders and neuropathic pain.

[0061] The present invention also relates to compounds, compositions and pharmaceuticals that can be used to treat inflammatory conditions, including asthma, chronic pruritus, dermatitis, rheumatoid arthritis, gastric ulcers and colitis.

[0062] The compounds of the present invention include compounds according to formula (1) or salts thereof:

[0063]

[0064] in:

[0065] Z is H, NH2, or C. 1-3 alkyl;

[0066] Y is selected from the group composed of the following substances:

[0067]

[0068] n is 0 or 1;

[0069] R 1 It is H or C, which is optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 1 With R 3 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms;

[0070] R 2 H is the arbitrarily substituted C. 1-6 Alkyl groups, optionally substituted C 3-6 Cycloalkyl or optionally substituted 3- to 6-membered heterocyclic groups, wherein the optional substituents are selected from OC. 1-3 Alkyl group or 1 to 6 fluorine atoms, or R2 With R 3 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms;

[0071] R 3 It is H or C, which is optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 3 With R 1 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms, or R 3 With R 2 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms, or R 3 With R 4 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms;

[0072] R 4 It is H or C, which is optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 4 With R 3 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms, or R 4 With R 5 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms;

[0073] R 5 It is H or C, which is optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 5 With R 4 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms;

[0074] And R 6 It is H or methyl.

[0075] In the compounds described in this article, Z can be H. Z can be NH2. Z can be C. 1-3 Alkyl group. Z can be methyl.

[0076] In the compounds described herein, Y can be an optionally substituted 3-aminopyrrolidine ring. Y can be an optionally substituted 3-aminoazacyclic butane ring. Y can be an optionally substituted piperazine ring. Y can be an optionally substituted octahydro-1H-pyrrolo[3,4-b]pyridine ring system. Y can be 3-aminopyrrolidine. Y can be 3-aminoazacyclic butane. Y can be piperazine. Y can be octahydro-1H-pyrrolo[3,4-b]pyridine. Y can be N-methylazacyclic butane-3-amine. Y can be N-methylpyrrolidine-3-amine. Y can be N-methylpiperazine. Y can be (3R)-N-methylpyrrolidine-3-amine. Y can be (3R)-pyrrolidine-3-amine. Y can be (4aR,7aR)-octahydro-1H-pyrrolo[3,4-b]pyridine.

[0077] Y can be:

[0078] Y can be:

[0079] Y can be:

[0080] Y can be:

[0081] In the compounds described in this article, R 1 It can be H or C, optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl group. R 1 It can be H or methyl. R 1 It can be H. R 1 It can be C 1-3 Alkyl group. R 1 Can be used with R 3 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms. R 1 It can be methyl. R 1 Can be used with R 3 Linkage is used to form 3- to 6-membered rings optionally substituted with 1 to 6 fluorine atoms. R 1 Can be used with R 3 Linked to form a 5-membered ring optionally substituted with 1 to 6 fluorine atoms. R 1 Can be used with R 3 Linked to form a 3- to 6-membered heterocyclic alkyl ring optionally substituted with 1 to 6 fluorine atoms. R 1 Can be used with R 3 Linked to form a 5-membered heterocyclic alkyl ring optionally substituted with 1 to 6 fluorine atoms.

[0082] In the compounds described in this article, R 2 It can be H, or any C that can be substituted. 1-6 Alkyl groups, optionally substituted C 3-6 Cycloalkyl or optionally substituted 3- to 6-membered heterocyclic groups, wherein the optional substituents are selected from OMe or 1 to 3 fluorine atoms, or R 2 With R 3 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms. R 2 The following groups of substances can be selected: H, methyl, ethyl, isopropyl, cyclopropyl, isobutyl, trifluoromethyl, CH2OMe, CH(CH3)OMe, C(CH3)2OMe, and oxacyclobutyl. R 2 It can be H. R 2 It can be methyl. R 2 It can be ethyl. R 2 It can be isopropyl. R 2It can be cyclopropyl. R 2 It can be isobutyl. R 2 It can be trifluoromethyl. R 2 It could be CH2OMe. R 2 It could be CH(CH3)OMe. R 2 It could be C(CH3)2OMe. R 2 It can be an oxocyclic butyl group. R 2 Can be used with R 3 Linkage is used to form 3- to 6-membered rings optionally substituted with 1 to 6 fluorine atoms. R 2 Can be used with R 3 Linked to form a 5-membered ring optionally substituted with 1 to 6 fluorine atoms. R 2 Can be used with R 3 Linked to form a 4-membered ring optionally substituted with 1 to 6 fluorine atoms. R 2 Can be used with R 3 Linkage is used to form a 3- to 6-membered alkyl ring, optionally substituted with 1 to 6 fluorine atoms. R 2 Can be used with R 3 Linked to form a 5-membered alkyl ring optionally substituted with 1 to 6 fluorine atoms. R 2 Can be used with R 3 Linked to form a 4-membered alkyl ring optionally substituted with 1 to 6 fluorine atoms.

[0083] In the compounds described in this article, R 3 It can be H or C, optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl group. R 3 It can be H. R 3 It can be C 1-3 Alkyl group. R 3 Can be used with R 1 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 2 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 4 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms. R 3 It can be methyl. R 3 Can be used with R 1 Linkage is used to form 3- to 6-membered rings optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 2 Linkage is used to form 3- to 6-membered rings optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 4 Linkage is used to form 3- to 6-membered rings optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 1Linked to form a 5-membered ring optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 2 Linked to form a 5-membered ring optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 2 Linked to form a 4-membered ring optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 1 Linked to form a 3- to 6-membered heterocyclic alkyl ring optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 2 Linkage is used to form a 3- to 6-membered alkyl ring, optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 4 Linkage is used to form a 3- to 6-membered alkyl ring, optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 1 Linked to form a heterocyclic alkyl ring optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 2 Linked to form a cycloalkyl ring optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 4 Linked to form a cycloalkyl ring optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 1 Linked to form a 5-membered heterocyclic alkyl ring optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 2 Linked to form a 5-membered alkyl ring optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 2 Linked to form a 4-membered alkyl ring optionally substituted with 1 to 6 fluorine atoms. R 3 Can be used with R 4 Linked to form a 5-membered alkyl ring optionally substituted with 1 to 6 fluorine atoms.

[0084] In the compounds described in this article, R 4 It can be H or C, optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 4 Can be used with R 3 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms, or R 4 Can be used with R 5 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms. R 4 It can be selected from H, methyl, ethyl, or isopropyl. R 4 It can be H. R 4 It can be C 1-3 Alkyl group. R 4 It can be methyl. R 4It can be ethyl. R 4 It can be isopropyl. R 4 Can be used with R 3 Linkage is used to form 3- to 6-membered rings optionally substituted with 1 to 6 fluorine atoms. R 4 Can be used with R 5 Linkage is used to form 3- to 6-membered rings optionally substituted with 1 to 6 fluorine atoms. R 4 Can be used with R 3 Linked to form a 5-membered ring optionally substituted with 1 to 6 fluorine atoms. R 4 Can be used with R 5 Linked to form a 5-membered ring optionally substituted with 1 to 6 fluorine atoms. R 4 Can be used with R 3 Linked to form a cycloalkyl ring optionally substituted with 1 to 6 fluorine atoms. R 4 Can be used with R 5 Linked to form a cycloalkyl ring optionally substituted with 1 to 6 fluorine atoms. R 4 Can be used with R 3 Linkage is used to form a 3- to 6-membered alkyl ring, optionally substituted with 1 to 6 fluorine atoms. R 4 Can be used with R 5 Linkage is used to form a 3- to 6-membered alkyl ring, optionally substituted with 1 to 6 fluorine atoms. R 4 Can be used with R 3 Linked to form a 5-membered alkyl ring optionally substituted with 1 to 6 fluorine atoms. R 4 Can be used with R 5 Linked to form a 5-membered alkyl ring optionally substituted with 1 to 6 fluorine atoms.

[0085] In the compounds described in this article, R 5 It can be H or C, optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 5 Can be used with R 4 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms. R 5 It can be H. R 5 C can be optionally replaced by 1 to 6 fluorine atoms. 1-3 Alkyl group. R 5 It can be C 1-3 Alkyl group. R 5 Can be used with R 4 Linked to form a ring optionally substituted with 1 to 6 fluorine atoms. R 5 It can be methyl. R 5 Can be used with R 4 Linkage is used to form 3- to 6-membered rings optionally substituted with 1 to 6 fluorine atoms. R 5 Can be used with R 4 Linked to form a 5-membered ring optionally substituted with 1 to 6 fluorine atoms. R5 Can be used with R 4 Linked to form a cycloalkyl ring optionally substituted with 1 to 6 fluorine atoms. R 5 Can be used with R 4 Linked to form a 5-membered alkyl ring optionally substituted with 1 to 6 fluorine atoms.

[0086] In the compounds described in this paper, n can be 0. n can also be 1.

[0087] The compounds of the present invention include compounds according to formula (4) or salts thereof:

[0088]

[0089] Among them, Y, Z, and R 1 R 2 R 3 R 4 R 5 And n is defined as above.

[0090] Including the group R 1 R 2 R 3 R 4 and R 5 The following groups of substances can be selected:

[0091]

[0092] The compound may be selected from the group consisting of the following compounds or their salts:

[0093]

[0094]

[0095]

[0096]

[0097]

[0098] The compound may be selected from the group consisting of the following compounds or their salts:

[0099] (R)-4-(3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0100] 7-Methyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0101] (R)-7-ethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0102] (R)-7-isopropyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0103] (S)-7-isopropyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0104] (R)-7-cyclopropyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0105] 7-Isobutyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0106] 4-((R)-3-(methylamino)pyrrolidone-1-yl)-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0107] (R)-7-(methoxymethyl)-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0108] (S)-7-((R)-1-methoxyethyl)-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0109] (S)-7-((S)-1-methoxyethyl)-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0110] (S)-7-(2-methoxypropane-2-yl)-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0111] 4-((R)-3-(methylamino)pyrrolidine-1-yl)-7-(oxetane-3-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0112] (R)-7,7-dimethyl-4-(3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0113] 6-Methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0114] (6S,7R)-6,7-dimethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0115] (6R,7R)-6,7-dimethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0116] (6S,7S)-6,7-dimethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0117] (6R,7S)-6,7-dimethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0118] 7-Isopropyl-8-methyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0119] 4-((R)-3-(methylamino)pyrrolidine-1-yl)-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazine-2-amine;

[0120] (R)-6a-methyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazine-2-amine;

[0121] (S)-6a-methyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazine-2-amine;

[0122] (R)-4-((R)-3-aminopyrrolidone-1-yl)-7-ethyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0123] (R)-4-((R)-3-aminopyrrolidone-1-yl)-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0124] 4-((R)-3-aminopyrrolidone-1-yl)-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0125] (S)-4-((R)-3-aminopyrrolidone-1-yl)-7-((R)-1-methoxyethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0126] (S)-4-((R)-3-aminopyrrolidone-1-yl)-7-((S)-1-methoxyethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0127] (S)-4-((R)-3-aminopyrrolidone-1-yl)-7-(2-methoxypropane-2-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0128] (R)-7-ethyl-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0129] (R)-7-isopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0130] (R)-7-cyclopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0131] (S)-7-((R)-1-methoxyethyl)-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0132] (S)-7-((S)-1-methoxyethyl)-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0133] (S)-7-(2-methoxypropane-2-yl)-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0134] (R)-4-(3-aminoazacyclobutane-1-yl)-7-ethyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0135] (R)-4-(3-aminoazacyclobutane-1-yl)-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0136] (R)-7-Isopropyl-4-(4-methylpiperazin-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0137] (R)-7-Isopropyl-4-(piperazin-1-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine-2-amine;

[0138] (R)-1-((R)-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine;

[0139] (R)-1-((R)-7-cyclopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine;

[0140] (3R)-1-(7-(methoxymethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine;

[0141] (R)-1-((S)-7-((R)-1-methoxyethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine;

[0142] (3R)-N-methyl-1-(6-methyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-amine;

[0143] (R)-1-((R)-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-amine;

[0144] (R)-1-((S)-7-((R)-1-methoxyethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-amine;

[0145] (R)-1-(7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylazacyclobutane-3-amine;

[0146] (3R)-1-(7-isopropyl-2-methyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine;

[0147] (R)-4-(3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0148] (R)-8-methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0149] (S)-8-methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0150] (R)-8-ethyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0151] (S)-8-isopropyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0152] (R)-8-isopropyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0153] 7-Methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0154] 7-Ethyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0155] 7-Isopropyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0156] (S)-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,7a,8,9,10-hexahydropyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazazepone-2-amine;

[0157] (S)-4-((R)-3-aminopyrrolidone-1-yl)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0158] (R)-4-((R)-3-aminopyrrolidone-1-yl)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0159] (S)-8-isopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazapyro-2-amine;

[0160] (R)-8-isopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazapyro-2-amine;

[0161] (R)-1-((S)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazono-4-yl)-N-methylpyrrolidine-3-amine;

[0162] (R)-1-((R)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazono-4-yl)-N-methylpyrrolidine-3-amine;

[0163] 4-[(3R)-3-(methylamino)pyrrolidine-1-yl]-6a,7,8,9,9a,10-hexahydro-6H-cyclopentano[e]pyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0164] 4-[(3R)-3-aminopyrrolidine-1-yl]-6a,7,8,9,9a,10-hexahydro-6H-cyclopentano[e]pyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0165] 4-[3-(methylamino)azacyclobutane-1-yl]-6a,7,8,9,9a,10-hexahydro-6H-cyclopentano[e]pyrimidino[5,4-b][1,4]oxazapyro-2-amine;

[0166] 4'-[(3R)-3-(methylamino)pyrrolidine-1-yl]-6'H,8'H-spiro[cyclobutane-1,7'-pyrimidino[5,4-b][1,4]oxazine]-2'-amine;

[0167] 7,7-Dimethyl-4-[(3R)-3-(methylamino)pyrrolidine-1-yl]-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0168] 8-Ethyl-4-[3-(methylamino)azacyclobutane-1-yl]-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazapyro-2-amine;

[0169] 4-[(3R)-3-aminopyrrolidone-1-yl]-8-ethyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0170] 8-Ethyl-4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0171] (3R)-1-(8-ethyl-8-methyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazono-4-yl)-N-methylpyrrolidine-3-amine;

[0172] 8-Ethyl-8-methyl-4-[(3R)-3-(methylamino)pyrrolidine-1-yl]-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0173] 4'-[(3R)-3-(methylamino)pyrrolidine-1-yl]-6'H,8'H-spiro[cyclopentan-1,7'-pyrimidino[5,4-b][1,4]oxazine]-2'-amine;

[0174] (3R)-N-methyl-1-(6'H,8'H-spiro[cyclopentan-1,7'-pyrimido[5,4-b][1,4]oxazine]-4'-yl)pyrrolidine-3-amine;

[0175] (3R)-1-(3,3-difluoro-6'H,8'H-spiro[cyclobutane-1,7'-pyrimido[5,4-b][1,4]oxazine]-4'-yl)-N-methylpyrrolidine-3-amine;

[0176] 7-Ethyl-7-methyl-4-[(3R)-3-(methylamino)pyrrolidine-1-yl]-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0177] 3,3-Difluoro-4'-[(3R)-3-(methylamino)pyrrolidine-1-yl]-6'H,8'H-spiro[cyclobutane-1,7'-pyrimidino[5,4-b][1,4]oxazine]-2'-amine.

[0178] The compound can be a salt of any of the above compounds. The compound can be a dihydrochloride. The compound can be a hydrochloride. The compound can be a di(trifluoroacetate). The compound can be a trifluoroacetate.

[0179] The compound may be selected from:

[0180] (R)-7-ethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine-2-amine dihydrochloride;

[0181] (R)-7-cyclopropyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine di(trifluoroacetate);

[0182] (S)-7-((R)-1-methoxyethyl)-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride;

[0183] (S)-7-((S)-1-methoxyethyl)-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride;

[0184] (R)-7,7-dimethyl-4-(3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride;

[0185] (6S,7R)-6,7-dimethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride;

[0186] (6R,7R)-6,7-dimethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride;

[0187] (6S,7S)-6,7-dimethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride;

[0188] (6R,7S)-6,7-dimethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine-2-amine dihydrochloride;

[0189] (R)-4-((R)-3-aminopyrrolidone-1-yl)-7-ethyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride;

[0190] (R)-4-((R)-3-aminopyrrolidone-1-yl)-7-isopropyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine-2-amine dihydrochloride;

[0191] (S)-4-((R)-3-aminopyrrolidone-1-yl)-7-((R)-1-methoxyethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride;

[0192] (S)-4-((R)-3-aminopyrrolidone-1-yl)-7-((S)-1-methoxyethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride;

[0193] (R)-7-ethyl-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine di(trifluoroacetate);

[0194] (R)-7-cyclopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine di(trifluoroacetate);

[0195] (S)-7-((R)-1-methoxyethyl)-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride;

[0196] (R)-4-(3-aminoazacyclobutane-1-yl)-7-ethyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine di(trifluoroacetate);

[0197] (R)-1-((S)-7-((R)-1-methoxyethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-4-yl)-N-methylpyrrolidine-3-amine hydrochloride;

[0198] (R)-1-((S)-7-((R)-1-methoxyethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-amine hydrochloride;

[0199] (R)-8-methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine di(trifluoroacetate);

[0200] (S)-8-methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine di(trifluoroacetate);

[0201] (R)-8-ethyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine di(trifluoroacetate);

[0202] (S)-8-isopropyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine di(trifluoroacetate);

[0203] (R)-8-isopropyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine di(trifluoroacetate);

[0204] 7-Methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine di(trifluoroacetate);

[0205] 7-Ethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine di(trifluoroacetate);

[0206] 7-Isopropyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine di(trifluoroacetate);

[0207] (S)-4-((R)-3-aminopyrrolidone-1-yl)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine di(trifluoroacetate);

[0208] (R)-4-((R)-3-aminopyrrolidone-1-yl)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine di(trifluoroacetate);

[0209] (S)-8-isopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazapyro-2-amine di(trifluoroacetate);

[0210] (R)-8-isopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazapyro-2-amine di(trifluoroacetate);

[0211] (R)-1-((S)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazapheno-4-yl)-N-methylpyrrolidine-3-amine trifluoroacetate; and

[0212] (R)-1-((R)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazono-4-yl)-N-methylpyrrolidine-3-amine trifluoroacetate.

[0213] Specific examples of compounds include those with low hERG activity.

[0214] Specific examples of compounds with low hERG activity may include compounds selected from the group consisting of or salts thereof:

[0215] (R)-4-(3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0216] (R)-7-ethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0217] (R)-7-isopropyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0218] 4-((R)-3-(methylamino)pyrrolidone-1-yl)-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0219] (R)-7-(methoxymethyl)-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0220] (S)-7-((R)-1-methoxyethyl)-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0221] (S)-7-(2-methoxypropane-2-yl)-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0222] (R)-7,7-dimethyl-4-(3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0223] 6-Methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0224] 4-((R)-3-(methylamino)pyrrolidine-1-yl)-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazine-2-amine;

[0225] (R)-4-((R)-3-aminopyrrolidone-1-yl)-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0226] 4-((R)-3-aminopyrrolidone-1-yl)-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0227] (R)-7-isopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0228] (S)-7-((R)-1-methoxyethyl)-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine;

[0229] (R)-7-Isopropyl-4-(piperazin-1-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine-2-amine;

[0230] (R)-1-((R)-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-amine;

[0231] (R)-8-methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0232] (S)-8-isopropyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0233] (S)-4-((R)-3-aminopyrrolidone-1-yl)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine;

[0234] (S)-8-isopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine.

[0235] definition

[0236] In this application, unless otherwise stated, the following definitions apply.

[0237] The term “treatment” in connection with the use of any compound described herein (including compounds of formula (1), (1a), (1b), (2a), (2b), (2c), (2d), (2e), (3a), (3b), (3c), and (4)) is used to describe any form of intervention in which a compound is administered to a subject who has, is at risk of having, or is potentially at risk of having, the disease or condition described herein. Therefore, the term “treatment” includes both preventative (avoidant) treatment and treatment that displays measurable or detectable symptoms of a disease or condition.

[0238] The term "effective therapeutic amount" (e.g., in relation to a method of treating a disease or condition) refers to the amount of a compound that effectively produces the desired therapeutic effect. For example, if the condition is pain, then the effective therapeutic amount is an amount sufficient to provide the desired degree of pain relief. The desired degree of pain relief could be, for example, complete elimination of pain or reduction of the severity of pain.

[0239] Unless otherwise stated, the term "C" is used in conjunction with other terms. 1-3 The "alkyl" and "C" in "alkyl group" 3-6 The terms “cycloalkyl”, “heterocyclic alkyl”, and “heterocyclic” in “3- to 6-membered heterocyclic” are used in their conventional sense (e.g., as defined in the IUPAC Gold Book).

[0240] With respect to any compound described having a chiral center, the scope of this invention extends to all optical isomers of these compounds, whether racemic or resolved enantiomers. The invention described herein relates to all crystalline forms, solvates, and hydrates of any disclosed compound, regardless of their preparation. With respect to any compound disclosed herein having an acid or base center (such as a carboxylate or amino group), all salt forms of the compound are included herein. In the case of pharmaceutical use, such salt should be considered pharmaceutically acceptable.

[0241] Salts that may be mentioned, or pharmaceutically acceptable salts, include acid addition salts and base addition salts. Such salts can be formed by conventional methods, such as by reacting a compound in its free acid or free base form with one or more equivalents of a suitable acid or base, optionally in a solvent or in a salt-insoluble medium, followed by removal of the solvent or medium using standard techniques (e.g., under vacuum, by freeze-drying or filtration). Salts can also be prepared by exchanging the counter ion of a compound in its other counter ion exchange form, for example, using a suitable ion exchange resin.

[0242] Examples of pharmaceutically acceptable salts include acid addition salts derived from inorganic and organic acids, as well as salts derived from metals such as sodium, magnesium, potassium, and calcium.

[0243] Examples of acid addition salts include those formed from the following acids: acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acids (e.g., benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetaminobenzoic acid, butyric acid, (+)camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexylaminosulfonic acid, dodecyl sulfate, 1,2-ethanedisulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactopyric acid, gentian acid, glucoheponic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid. (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutarate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethanesulfonic acid, lactic acid (e.g., (+)-L-lactic acid and (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid), malonic acid, (±)-DL-mandelic acid, metaphosphoric acid, methanesulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanate, undecenoic acid, and valeric acid.

[0244] This also includes any solvates of these compounds and their salts. Preferred solvates are those formed by incorporating a non-toxic, pharmaceutically acceptable solvent molecule (hereinafter referred to as a solvating solvent) into the solid structure (e.g., crystal structure) of the compounds of the invention. Examples of such solvents include water, alcohols (such as ethanol, isopropanol, and butanol), and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compounds of the invention with a solvent or solvent mixture containing a solvating solvent. Whether a solvate has been formed in any given case can be determined by analyzing the crystals of the compound using well-known standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography.

[0245] Solvates can be stoichiometric or non-stoichiometric. Specific solvates can be hydrates, and examples of hydrates include hemihydrates, monohydrates, and dihydrates. For a more detailed discussion of solvates and the methods used to prepare and characterize them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc. of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0246] In the context of this invention, the term "pharmaceutical composition" refers to a composition comprising an active agent and further comprising one or more pharmaceutically acceptable carriers. Depending on the manner of administration and the nature of the dosage form, the composition may further comprise, for example, diluents, adjuvants, excipients, carriers, preservatives, fillers, disintegrants, humectants, emulsifiers, suspending agents, sweeteners, flavorings, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants. The composition may be in the following forms: for example, tablets, sugar-coated pills, powders, elixirs, syrups, liquid formulations including suspensions, sprays, inhalers, tablets, lozenges, emulsions, solutions, capsules, granules, capsules, and suppositories, as well as injectable liquid formulations, including liposome formulations.

[0247] The compounds of this invention may contain one or more isotopic substitutions, and when a particular element is mentioned, all isotopes of that element within its scope are included. For example, when hydrogen is mentioned, its scope includes... 1 H, 2 H(D) and 3 H(T). Similarly, when referring to carbon and oxygen, their respective ranges include... 12 C 13 C and 14 C and 16 O and 18 O. In a similar manner, unless the context otherwise requires, references to a particular functional group also include isotopic variants within its scope. For example, references to alkyl groups such as ethyl or alkoxy groups such as methoxy also include variants where one or more hydrogen atoms in the group are in deuterium or tritium isotopic form, such as ethyl where all five hydrogen atoms are in deuterium isotopic form (all-deuterium ethyl) or methoxy where all three hydrogen atoms are in deuterium isotopic form (trideuterium methoxy). Isotopes can be radioactive or non-radioactive.

[0248] The therapeutic dosage can vary depending on the patient's requirements, the severity of the condition being treated, and the compound used. Determining the appropriate dosage for a specific situation is within the scope of the art. Typically, treatment begins with a smaller dose than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimal effect is achieved. For convenience, the total daily dose can be divided into several doses administered throughout the day if necessary.

[0249] Of course, the effective dose of a compound will vary depending on the severity of the condition being treated and the specific compound and its route of administration. The selection of an appropriate dose is within the capabilities of a person skilled in the art and does not impose an undue burden. Typically, the daily dose range can be from about 10 μg to about 30 mg per kilogram of body weight for humans and non-human animals, preferably from about 50 μg to about 30 mg per kilogram of body weight for humans and non-human animals, for example from about 50 μg to about 10 mg per kilogram of body weight for humans and non-human animals, for example from about 100 μg to about 30 mg per kilogram of body weight for humans and non-human animals, for example from about 100 μg to about 10 mg per kilogram of body weight for humans and non-human animals, and most preferably from about 100 μg to about 1 mg per kilogram of body weight for humans and non-human animals.

[0250] Preparation method of compound of formula (1)

[0251] Compounds of formula (1) can be prepared according to synthetic methods well known to those skilled in the art, as described herein. Therefore, in one embodiment, the present invention provides a method for preparing compounds as defined in formula (1) above, the method comprising:

[0252] (A) When it is necessary to prepare a compound of formula (1) in which Z is NH2, the reaction sequence is shown in Scheme 1 below:

[0253]

[0254] Therefore, 2,4,6-trichloropyrimidine-5-ol (10), which is readily available by dealkylation of commercially available 2,4,6-trichloropyrimidine, reacts with the protected amino alcohol of formula (11), wherein R 1 R 2 R 3 R 4 R 5 As defined above, PG 1 Representing a suitable amino protecting group, such as Boc, Cbz, Fmoc, Teoc, or Bn, substituted trichloropyrimidines of formula (12) are obtained under Mitsunobu conditions, wherein R 1 R 2 R 3 R 4 R 5 And n is as defined above, and PG 1 This represents a suitable amino protecting group, such as Boc, Cbz, Fmoc, Teoc, or Bn. Typically, the Mitsunobu reaction is carried out using a trisubstituted phosphine reagent such as Ph3P or Bu3P in the presence of azodicarbonate esters such as DEAD, DIAD, or TMAD, in solvents such as THF, toluene, MeCN, or DCM, at about 0°C to about room temperature, or occasionally with moderate heating at about 50°C to 100°C.

[0255] Once formed, the substituted amino functional group of trichloropyrimidine in formula (12) can be used with the protecting group PG. 1 The properties of the product are subject to deprotection under conditions that are relevant to those skilled in the art, and the resulting product is then cyclized to form a compound of formula (13) by intramolecular SNAr substitution reaction or by intramolecular transition metal-catalyzed coupling reaction, wherein R 1 R 2 R 3 R 4 R 5 And n as defined above. SNAr substitution reactions typically proceed under the following conditions: in a tertiary amine base such as TEA or DIPEA, or an inorganic base such as K2CO3, Cs2CO3, Na2CO3 or NaHCO3, or a strong base such as KO. t In the presence of Bu, NaH, or LiHMDS, in suitable solvents such as 1,4-dioxane, THF, DMF, acetone, DCM, MeCN, H2O, EtOH, IPA, DMSO, or NMP, or a suitable combination of solvents, at a temperature of about room temperature to about 200°C, using conventional heating or optionally microwave radiation, in an open container or optionally in a sealed container, optionally at a pressure greater than atmospheric pressure. Transition metal-catalyzed coupling reactions are generally carried out under the following conditions: in an alkoxide base such as NaO t Bu or KO t In the presence of Bu, inorganic bases such as K3PO4, K2CO3, Cs2CO3, or NaOCN, or tertiary amine bases such as TEA or DIPEA, or a suitable combination of bases, and in a suitable solvent such as 1,4-dioxane, THF, or DME, the following conditions may be met. t The reaction is carried out in BuOH or toluene, or a suitable combination of solvents, in the presence of substoichiometric transition metal catalysts such as Pd(OAc)2 (CAS: 33375-31-3), Pd2(dba)3 (CAS: 51364-51-3), Pd(dppf)Cl2 (CAS: 72287-26-4), Pd(PPh3)2Cl2 (CAS: 13965-03-2), or Pd(PPh3)4 (CAS: 14221-01-3), optionally in the presence of substoichiometric phosphine ligands such as Ph3P, Bu3P, etc. t Bu3P, XPhos(CAS: 564483-18-7), Xantphos(CAS: 161265-03-8), tIn the presence of BuBrettPhos (CAS: 1160861-53-9) or BINAP (CAS: 76189-55-4, 76189-56-5), at a temperature between about room temperature and about 200°C, using conventional heating or optionally by microwave radiation, in an open container or optionally in a sealed container, optionally at a pressure greater than atmospheric pressure.

[0256] Once formed, the compound of formula (13) can react with the amine of formula (14), where Y is as defined above, using an SNAr substitution reaction or one of those reactions similar to the transition metal-catalyzed coupling reactions described above to replace the 4-chloro substituent in the compound of formula (13) and form the compound of formula (15), where R 1 R 2 R 3 R 4 R 5 n and Y are as defined above. Once formed, the 2-chloro substituent in the compound of formula (15) can be replaced by a suitably protected NH3 equivalent (16), where PG 2 This refers to a reaction using one or more protecting groups, such as Boc, Cbz, (Boc)2, Ac, Bz, Bn, Bn2, PMB, or DMB, and employing a coupling reaction similar to the one described above, catalyzed by another transition metal. Finally, those skilled in the art will fully understand that reactions can be used with protecting groups PG... 2 Properties related to the removal of one or more protecting groups PG 2 To obtain the desired compound of formula (17), wherein R 1 R 2 R 3 R 4 R 5 , n, and Y are defined as above.

[0257] Those skilled in the art will understand that the sequence of steps listed in Scheme 1 can be performed in a different order than that shown without affecting the overall success of the synthesis of the desired compound of formula (17). For example, in Scheme 2 below, the 4-chloro substituent in the substituted trichloropyrimidine of formula (12) can be replaced in step 2 by using the SNAr substitution reaction or transition metal-catalyzed coupling reaction as described above with the amine of formula (14) to form the substituted aminodichloropyrimidine of formula (18), wherein R 1 R 2 R 3 R 4 R 5 n and Y are defined as above, PG 1 This represents a suitable amino protecting group, such as Boc, Cbz, Fmoc, Teoc, or Bn. Once formed, it can be used with the protecting group PG. 1The properties of the product are used to deprotect the amino functional group of the substituted aminodichloropyrimidine of formula (18), and those skilled in the art will fully understand that the resulting product is then cyclized by an intramolecular SNAr substitution reaction or by an intramolecular transition metal-catalyzed coupling reaction as described above, to form a compound of formula (15). Then, according to scheme 1, the desired compound of formula (17) is synthesized from the compound of formula (15).

[0258]

[0259] Alternatively, as described in Scheme 3 below, in step 1 of the sequence, the 4-chloro substituent of formula (14) can be directly replaced by an amine of formula (14) on 2,4,6-trichloropyrimidin-5-ol (10) using a coupling reaction similar to the above-described SNAr substitution reaction or transition metal-catalyzed reaction to form a 4-amino-2,6-dichloropyrimidin-5-ol analog of formula (19), where Y is as defined above. Once formed, the 4-amino-2,6-dichloropyrimidin-5-ol analog of formula (19) can be reacted with a protected amino alcohol of formula (11) in step 2 using Mitsunobu conditions similar to those described above to form a substituted aminodichloropyrimidin of formula (18). Then, as described in Scheme 2, the desired compound of formula (17) is synthesized from the substituted aminodichloropyrimidin of formula (18).

[0260]

[0261] Scheme 4 below shows another variation, in which the protected 2,4,6-trichloropyrimidine-5-ol of formula (20) (wherein PG) 3 (representing a suitable phenolic OH protecting group such as Me or PMB) and an amino alcohol of formula (21) (where R 1 R 2 R 3 R 4 R 5 The reaction with n (as defined above) involves replacing the 4-chloro substituent in the protected 2,4,6-trichloropyrimidin-5-ol of formula (20) using a coupling reaction similar to the SNAr substitution reaction or transition metal-catalyzed reaction described above, to form the protected 4-amino-2,6-dichloropyrimidin-5-ol of formula (22). This is achieved through a suitable PG... 3 The protecting group PG in the protected 4-amino-2,6-dichloropyrimidin-5-ol of formula (22) is removed under conditions known to those skilled in the art. 3 Then, an intramolecular Mitsunobu reaction similar to that described above is allowed to form a compound of formula (13). Then, the desired compound of formula (17) is synthesized from the compound of formula (13) as described in Scheme 1.

[0262]

[0263] Those skilled in the art will understand that the reaction steps described in schemes 1 to 4 can be combined in different ways as needed to successfully prepare the desired compound of formula (17). It will also be apparent that additional steps involving functional group modification, protection, or deprotection may be introduced throughout the synthetic sequence. For example: a carboxylic acid or ester group may be reduced to an alcohol, and the resulting alcohol may be protected with a silyl protecting group; an amide, nitrile, or nitro group may be reduced to an amine, and the resulting amine may be protected with a carbamate protecting group; a primary or secondary amine may be further substituted using an alkylation reaction; and a Boc protecting group may be reduced to a methyl group.

[0264] (B) When it is necessary to prepare a compound of formula (1) with Z being H: follow the reaction sequence described above in schemes 1 to 4, but start with 4,6-dichloropyrimidin-5-ol of formula (23) or the protected 4,6-dichloropyrimidin-5-ol of formula (24), wherein PG 3 Representing a suitable phenolic OH protecting group, such as Me or PMB, to obtain the desired compound of formula (25), wherein R 1 R 2 R 3 R 4 R 5 n and Y are defined as above:

[0265]

[0266] Alternatively, the 2-chloro substituent in compound (15) can be removed using reducing conditions to obtain the desired compound (25), said reducing conditions being, for example, treatment with H2 gas, in a solvent such as MeOH or EtOH, in the presence of a transition metal catalyst such as palladium-carbon or palladium hydroxide-carbon, optionally in the presence of a tertiary amine base such as Et3N or DIPEA, optionally at a pressure greater than atmospheric pressure. Alternatively, reductive dechlorination can be carried out using ammonium formate in a solvent (such as MeOH or EtOH), in the presence of a transition metal catalyst (such as palladium-carbon or palladium hydroxide-carbon), at a temperature (such as between about room temperature and about the boiling point of the solvent used).

[0267]

[0268] (C) When it is necessary to prepare a compound of formula (1) in which Z is methyl: follow the reaction sequence described above in schemes 1 to 4, but begin with 4,6-dichloro-2-methylpyrimidin-5-ol of formula (26) or the protected 4,6-dichloro-2-methylpyrimidin-5-ol of formula (27), in which PG 3 Representing a suitable phenolic OH protecting group, such as Me or PMB, to obtain the desired compound of formula (28), wherein R 1 R2 R 3 R 4 R 5 n and Y are defined as above:

[0269]

[0270] Alternatively, the 2-chloro substituent in compound (15) can be replaced with methyl under the following conditions: such as in the presence of a palladium catalyst (e.g., Pd(PPh3)4 (CAS: 14221-01-3), PdCl2(dppe) (CAS: 19978-61-1), Pd(dppf)Cl2 (CAS: 72287-26-4) or Pd2(dba)3 (CAS: 51364-51-3)), using a transition metal-catalyzed coupling reaction, for example with MeB(OH)2, MeB Treatment with Pin (CAS: 94242-85-0) or trimethylcyclotriboroxane (CAS: 823-96-1), optionally in the presence of a phosphine ligand such as P(Cy)3, in the presence of an inorganic base such as K2CO3 or Cs2CO3, in a suitable solvent such as 1,4-dioxane, H2O, THF or DME, or a mixture of suitable solvents, at a temperature of about room temperature to about 200°C, using conventional heating or optionally by microwave radiation, in an open container or optionally in a sealed container, optionally at a pressure greater than atmospheric pressure. Alternatively, other methods well known to those skilled in the art can be used, such as combining MeMgBr or MeMgCl with a nickel catalyst (e.g., Ni(dppf)Cl2 (CAS: 67292-34-6)), in a solvent (e.g., THF, Et2O, DME, or 1,4-dioxane), at elevated temperatures; or combining Me2Zn with a palladium catalyst (e.g., PdCl2(dppe) (CAS: 19978-61-1) or Pd(dppf)Cl2 (CAS: 19978-61-1). 72287-26-4)) in a solvent (such as toluene or 1,4-dioxane) at elevated temperatures; or in combination with a palladium catalyst (such as Pd(PPh3)4 (CAS:14221-01-3)) in a solvent (such as THF, hexane or heptane) at elevated temperatures; or in combination with a palladium catalyst (such as Pd(PPh3)4 (CAS:14221-01-3)) in a solvent (such as THF or DMF) at elevated temperatures.

[0271]

[0272] (E) Converting a compound of formula (1) into a compound of formula (1):

[0273] Furthermore, a compound of formula (1) can be converted into another compound of formula (1) by methods well known to those skilled in the art. Examples of synthetic methods for converting one functional group into another are listed in standard textbooks, such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition, Michael B. Smith, John Wiley, 2013, (ISBN: 978-0-470-46259-1), Organic Syntheses, Online Edition, www.orgsyn.org, (ISSN 2333-3553), and Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2).

[0274] In many of the reactions described above, it may be necessary to protect one or more groups to prevent the reaction from occurring at undesirable sites on the molecule. Examples of protecting groups and methods for protecting and deprotecting functional groups can be found in Greene's Protective Groups in Organic Synthesis, Fifth Edition, Editor: Peter GMWuts, John Wiley, 2014 (ISBN: 9781118057483).

[0275] Compounds prepared by the above methods can be separated and purified by any of a variety of methods known to those skilled in the art, examples of which include recrystallization and chromatographic techniques, such as column chromatography (e.g., rapid chromatography), HPLC, and SFC under normal or reversed-phase conditions.

[0276] pharmaceutical preparations

[0277] Although the active compound can be administered alone, it is preferred to be in the form of a pharmaceutical composition (e.g., a formulation).

[0278] Therefore, in another embodiment of the invention, a pharmaceutical composition is provided comprising at least one compound of formula (1) as defined above and at least one pharmaceutically acceptable excipient.

[0279] The composition may be a tablet composition.

[0280] The composition may be a capsule composition.

[0281] Pharmaceutically acceptable excipients may be selected from, for example, carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents (e.g., solid diluents, such as fillers or fillers; and liquid diluents, such as solvents and cosolvents), granulating agents, binders, flow aids, coating agents, controlled-release agents (e.g., polymers or waxes that delay or prolong release), adhesives, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, tension modifiers, thickeners, flavoring agents, sweeteners, colorants, plasticizers, taste maskers, stabilizers, or any other excipients conventionally used in pharmaceutical compositions.

[0282] As used herein, "pharmaceutically acceptable" means a compound, material, composition, and / or dosage form that, within reasonable medical judgment, is suitable for contact with the tissues of a subject (e.g., a human subject) without excessive toxicity, irritation, allergic reactions, or other problems or complications, and has a reasonable benefit / risk ratio. Each excipient must also be "acceptable," meaning compatible with other components of the formulation.

[0283] Pharmaceutical compositions containing compounds of formula (1) can be formulated using known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[0284] The pharmaceutical composition can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ocular, ear, rectal, vaginal, or transdermal administration.

[0285] Suitable dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), capsules, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, rice paper capsules, or patches such as oral patches.

[0286] Tablet compositions may contain a unit dose of an active compound and an inert diluent or carrier such as sugars or sugar alcohols, for example, lactose, sucrose, sorbitol, or mannitol; and / or non-sugar-derived diluents such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, and starch such as corn starch. Tablets may also contain such standard ingredients as binders and granulators (e.g., polyvinylpyrrolidone), disintegrants (e.g., swelling cross-linking polymers such as cross-linked carboxymethyl cellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and effervescent agents (e.g., citrate / bicarbonate mixtures). Such excipients are well-known and do not require detailed discussion here.

[0287] Tablets can be designed to release the drug upon contact with gastric juices (immediate-release tablets) or to release the drug in a controlled manner over a prolonged period or in a specific region of the gastrointestinal tract (controlled-release tablets).

[0288] Pharmaceutical compositions typically comprise from about 1% (w / w) to preferably about 95% (w / w) of the active ingredient and from 99% (w / w) to 5% (w / w) of pharmaceutically acceptable excipients (e.g., as described above) or combinations of such excipients. Preferably, the composition comprises from about 20% (w / w) to about 90% (w / w) of the active ingredient and from 80% (w / w) to 10% (w / w) of pharmaceutical excipients or combinations of excipients. Pharmaceutical compositions according to the invention may be in, for example, unit-dose forms, such as ampoules, vials, suppositories, pre-filled syringes, sugar-coated pills, powders, tablets, or capsules.

[0289] Tablets and capsules may contain, for example, 0 to 20% disintegrants, 0 to 5% lubricants, 0 to 5% glidants, and / or 0 to 99% (w / w) fillers / or fillers (depending on the drug dosage). They may also contain 0 to 10% (w / w) polymer binders, 0 to 5% (w / w) antioxidants, and 0 to 5% (w / w) pigments. Furthermore, sustained-release tablets will typically contain 0 to 99% (w / w) controlled-release (e.g., delayed-release) polymers (depending on the dosage). Film coatings of tablets or capsules typically contain 0 to 10% (w / w) polymers, 0 to 3% (w / w) pigments, and / or 0 to 2% (w / w) plasticizers.

[0290] Parenteral preparations typically contain 0 to 20% (w / w) buffer, 0 to 50% (w / w) solubilizer, and / or 0 to 99% (w / w) water for injection (WFI) (depending on the dosage and whether it is lyophilized). Preparations intended for intramuscular injection may also contain 0 to 99% (w / w) oil.

[0291] The drug formulation can be delivered to the patient in the form of a "patient package," which is a single package (usually a blister pack) that includes the entire course of treatment.

[0292] Compounds of formula (1) are typically presented in unit dosage forms and, therefore, will typically contain sufficient amounts of the compound to provide the desired level of biological activity. For example, a formulation may contain 1 nanogram to 2 grams of active ingredient, such as 1 nanogram to 2 milligrams of active ingredient. Within these ranges, specific subranges of the compound are 0.1 milligrams to 2 grams of active ingredient (typically 10 milligrams to 1 gram, such as 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (such as 1 microgram to 10 milligrams, such as 0.1 milligrams to 2 milligrams of active ingredient).

[0293] For oral compositions, the unit dosage form may contain 1 mg to 2 g, more typically 10 mg to 1 g, such as 50 mg to 1 g, or such as 100 mg to 1 g of active compound.

[0294] The active compound is administered to the patient in need (e.g., human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective dose). The precise amount of compound administered can be determined by the attending physician according to standard procedures. Example

[0295] The present invention will now be described with reference to the following embodiments, but the invention is not limited thereto.

[0296] Examples 1-1 to 17-15

[0297] The compounds of Examples 1-1 to 17-15 shown in Table 1 below have been prepared. NMR and LCMS properties and the methods used to prepare them are listed in Table 3. Starting materials are listed in Table 2.

[0298] Table 1 - Compounds from Examples

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305] General Procedure

[0306] If no preparation route is included, the relevant intermediates are commercially available. Commercially available reagents can be used directly without further purification. Name the final compound and intermediates using ChemDraw Professional, Version 17.0.0.206(121). Room temperature (RT) refers to approximately 20°C to 27°C. Record at 400 MHz or 500 MHz on a Bruker, Varian, or Jeol instrument. 1 ¹H NMR spectroscopy. Chemical shift values ​​are expressed in parts per million (ppm), i.e., (δ) values, relative to the following solvents: chloroform - d = 7.26 ppm, DMSO - d6 = 2.50 ppm, methanol - d4 = 3.31 ppm. The following abbreviations are used for the multiplicity of NMR signals: s = singlet, br = broad peak, d = doublet, t = triplet, q = quartet, m = multiplet. Coupling constants are listed in J values ​​in Hz. NMR and mass spectrometry results are corrected to account for background peaks. Chromatography refers to the use of 60-120 mesh or 40-633 μm... Column chromatography using silica gel, performed under nitrogen pressure (rapid chromatography). PL-HCO3 MP SPE refers to StratoSpheres HCO3 available from Polymer Laboratories. - Combined macroporous polystyrene solid-phase extraction column. Microwave-mediated reaction carried out in Biotage Initiator or CEM Discover microwave reactor.

[0307] LCMS Analysis

[0308] LCMS analysis of compounds under electrospray conditions was performed using the instruments and methods given in the table below:

[0309] system Instrument Name LC detector quality detector 1 Agilent 1100 Photodiode array ZQ-2000 2 Waters Acquity UPLC Photodiode array SQ detector 3 Waters Acquity H Class Photodiode array SQ Detector 4 Shimadzu Nexera Photodiode array LCMS-2020 5 Waters Acquity H Class Photodiode array QDa Mass Detector

[0310]

[0311]

[0312] The format of the experimental data and the LCMS data in Tables 2 and 3 is as follows: (Instrument System, Method): mass ions, retention time, ultraviolet detection wavelength.

[0313] Compound purification

[0314] Final purification of the compound was carried out by reversed-phase column chromatography, preparative reversed-phase HPLC, chiral HPLC or chiral SFC, using the instruments and methods detailed below, where data are given in the following format: Purification technique: [phase (column description, column length × inner diameter, particle size), solvent flow rate, gradient - given as % (over time) of mobile phase B in mobile phase A, mobile phase (A) and mobile phase (B)].

[0315] Reversed-phase column chromatography

[0316] Teledyne Isco instruments use pre-packaged disposable Silica-Based C18 (17%) / Silicacycle / 40-63μm. Stationary column, eluent flow rate ranging from 15 mL / min to 200 mL / min, UV detection (254 nm and 280 nm).

[0317] Preparative HPLC purification:

[0318] Shimadzu LC-20AP binary system with SPD-20A ultraviolet detector

[0319] The Waters 2767, equipped with a PDA detector, uses a Waters ZQ for mass triggering, and the Waters ZQ is equipped with an electrospray ionization source operating in positive ion mode.

[0320] Chiral HPLC purification:

[0321] Shimadzu LC-20AP binary system with SPD-20A ultraviolet detector

[0322] Chiral SFC purification:

[0323] Waters SFC 200

[0324] Purification method A

[0325] Preparative HPLC: [reversed phase (BEH C-18, 50×30mm, 5μm), 40mL / min, gradient 5% (over 0.5 min), 5%-25% (over 6.4 min), 100% (over 1.6 min), 100%-5% (over 0.5 min), mobile phase (A): 10mM ammonium carbonate aqueous solution, pH 10, (B): 100% acetonitrile].

[0326] Purification method B

[0327] Preparative HPLC: [reversed phase (BEH C-18, 50×30mm, 5μm), 40mL / min, gradient 10% (over 0.5 min), 10%-30% (over 6.4 min), 100% (over 1.6 min), 100%-10% (over 0.5 min), mobile phase (A): 10mM ammonium carbonate aqueous solution, pH 10, (B): 100% acetonitrile].

[0328] Purification method C

[0329] Preparative HPLC: [reversed phase (BEH C-18, 50×30mm, 5μm), 40mL / min, gradient 10% (over 0.5 min), 10%-30% (over 6.4 min), 100% (over 1.6 min), 100%-10% (over 0.5 min), mobile phase (A): 10mM ammonium bicarbonate aqueous solution, pH 10, (B): 100% acetonitrile].

[0330] Purification method D

[0331] Preparative HPLC: [reversed phase (BEH C-18, 50×30mm, 5μm), 40mL / min, gradient 22% (over 0.5 min), 22%-42% (over 6.4 min), 100% (over 1.6 min), 100%-22% (over 0.5 min), mobile phase (A): 10mM ammonium carbonate aqueous solution, pH 10, (B): 100% acetonitrile].

[0332] Purification method E

[0333] Preparative HPLC: [reversed phase (Gemini NX 30x150mm, 5μm), 40mL / min, gradient 10% (over 0.5 min), 10%-100% (over 6.4 min), 100% (over 1.6 min), 100%-10% (over 0.5 min), mobile phase (A): 10mM ammonium bicarbonate aqueous solution, pH 10, (B) 100% acetonitrile].

[0334] Purification method F

[0335] Preparative HPLC: [reversed phase (X-BRIDGE C-18, 250×19mm, 5μm), 11mL / min, gradient 10%-32% (over 30 min), 32% (over 4 min), 100% (over 2 min), 100%-10% (over 6 min), mobile phase (A): 5mM ammonium bicarbonate + 0.1% ammonia, (B): 100% acetonitrile].

[0336] Purification method G

[0337] Preparative HPLC: [reversed phase (BEH C-18, 150×30mm, 5μm), 40mL / min, gradient 80% (over 0.5 min), 80%-100% (over 6.4 min), 100% (over 1.6 min), 100%-80% (over 0.5 min), mobile phase (A): 10mM ammonium bicarbonate aqueous solution, pH 10, (B): 100% acetonitrile].

[0338] Abbreviations used in this document

[0339] Ac = Acetate

[0340] aq. = aqueous solution

[0341] Bn = benzyl

[0342] Bz = Benzoyl group

[0343] Boc = tert-Butoxycarbonyl

[0344] n BuOH = n-Butanol

[0345] t BuOH = tert-Butanol

[0346] Bu3P = Tri-n-butylphosphine

[0347] t Bu3P = tritert-butylphosphine

[0348] Cbz = benzyloxycarbonyl

[0349] COMU = (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholine-carbomony hexafluorophosphate

[0350] DCM = dichloromethane

[0351] DEAD = Diethyl azodicarbonate

[0352] DIAD = diisopropyl azodicarbonate

[0353] DIC = N,N′-Diisopropylcarbodiimide

[0354] DIPEA = N,N-Diisopropylethylamine

[0355] DMA = N,N-dimethylacetamide

[0356] DMAP = 4-(dimethylamino)pyridine

[0357] DMB = 3,4-Dimethoxybenzyl

[0358] DME = dimethoxyethane

[0359] DMF = N,N-dimethylformamide

[0360] DMSO = dimethyl sulfoxide

[0361] EDC = 1-Ethyl-(3-dimethylaminopropyl)carbodiimide

[0362] ES = Electrospray ionization

[0363] Et3N = Triethylamine

[0364] Et₂O = diethyl ether

[0365] EthOAc = Ethyl acetate

[0366] EtOH = ethanol

[0367] Fmoc = fluorenemethyloxycarbonyl

[0368] h = hours

[0369] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridine 3-oxide hexafluorophosphate

[0370] H2O=water

[0371] HCl = hydrogen chloride, hydrochloric acid

[0372] HOBt = Hydroxybenzotriazole

[0373] HPLC = High Performance Liquid Chromatography

[0374] IPA = Propyl-2-ol

[0375] LC = Liquid Chromatography

[0376] MeCN = Acetonitrile

[0377] MeOH = methanol

[0378] min(s) = minutes

[0379] MS = Mass Spectrometry

[0380] nm = nanometer

[0381] NMP = N-methyl-2-pyrrolidone

[0382] NMR = Nuclear Magnetic Resonance

[0383] P(Cy)3 = Tricyclohexylphosphine

[0384] PMB = 4-Methoxybenzyl

[0385] PPh3, Ph3P = Triphenylphosphine

[0386] PTSA = p-Toluenesulfonic acid

[0387] PyBOP = Hexafluorophosphate (benzotriazol-1-yl-oxy)tripyrrolealkylphosphonium

[0388] RP-flash = Reversed-phase rapid chromatography

[0389] RP-HPLC = Reversed-phase high-performance liquid chromatography

[0390] RT = room temperature

[0391] sat. = saturated

[0392] SFC = Supercritical Fluid Chromatography

[0393] SNAr = Nucleophilic aromatic substitution

[0394] TBAF = Tetrabutylammonium fluoride

[0395] TEA = Triethylamine

[0396] Teoc = β-(trimethylsilyl)ethoxycarbonyl

[0397] TFA = Trifluoroacetic acid

[0398] TFAA = Trifluoroacetic anhydride

[0399] THF = Tetrahydrofuran

[0400] TMAD = N,N,N',N'-Tetramethylazodicarbonamide

[0401] T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane-2,4,6-trioxide

[0402] Synthesis of intermediates:

[0403] Route 1

[0404] Typical procedure for preparing intermediate 2,2,4,6-trichloropyrimidin-5-ol

[0405]

[0406] Under a nitrogen atmosphere, a solution of 2,4,6-trichloro-5-methoxypyrimidine (intermediate 1) (2.60 g, 12.2 mmol) in DCM (121 mL) was cooled to 0 °C and treated dropwise with boron tribromide (pure, 4.05 mL, 42.6 mmol). After stirring at room temperature for 18 hours, the reaction mixture was cooled below 0 °C, carefully quenched with methanol (20 mL), diluted with water (120 mL), and the phases were separated. The aqueous layer was extracted with DCM (3 × 100 mL), and the combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under vacuum to give a light brown solid (2.27 g). The crude material was purified by rapid chromatography on a silica gel (80 g column) using a DCM solution of 0% to 20% EtOAc to give 2,4,6-trichloropyrimidine-5-ol (intermediate 2) (1.67 g, 62%) as a white solid.

[0407] The data for intermediate 2 are shown in Table 2.

[0408] Route 2

[0409] Typical procedures for preparing protected amino alcohols include, for example, the preparation of intermediate 10, (R)-(1-cyclopropyl-2-hydroxyethyl)carbamate tert-butyl ester.

[0410]

[0411] (R)-2-((tert-Butoxycarbonyl)amino)-2-cyclopropylacetic acid (intermediate 9) (2 g, 0.009 mol) was dissolved in THF (20.0 mL) and cooled to 0 °C. A solution of the borane-THF complex in THF (1.0 M, 32 mL, 0.032 mol) was added dropwise at 0 °C, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by adding methanol, and the solvent was removed under vacuum. The residue was partitioned between H₂O (50 mL) and EtOAc (30 mL), and the phases were separated. The aqueous layer was further extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with a saturated aqueous solution of NaHCO₃. The organic layer was dried (Na2SO4), and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by column chromatography (normal phase 60-120 mesh silica gel, 0 to 30% EtOAc in hexane solution) to obtain (R)-(1-cyclopropyl-2-hydroxyethyl)carbamate tert-butyl ester (intermediate 10) (1.8 g, 96%), which was a colorless gel.

[0412] The data for intermediate 10 are shown in Table 2.

[0413] Route 3

[0414] Typical procedures for preparing protected amino alcohols include, for example, the preparation of intermediate 14,(2S,3R)-1-hydroxy-3-methoxybutane-2-yl)carbamate tert-butyl ester.

[0415]

[0416] A solution of sodium carbonate (5.60 g, 52.8 mmol) in H₂O (13 mL) was added to a stirred solution of D-altothreonine (3.0 g, 25.2 mmol) in THF (41 mL) and H₂O (41 mL). The resulting mixture was stirred for 5 minutes before the addition of di-tert-butyl dicarbonate (6.59 g, 30.2 mmol). The mixture was stirred overnight at room temperature, then water (15 mL) was added, and the mixture was extracted with diethyl ether (2 x 10 mL). The aqueous layer was acidified to pH 4 with 1 M HCl aqueous solution and extracted with EtOAc (3 x 25 mL). The combined EtOAc layers were dried (Na₂SO₄) and concentrated under vacuum to give (tert-butyloxycarbonyl)-D-altothreonine (5.10 g, 92%) as a white solid.

[0417] ¹H NMR (500MHz, chloroform-d) δ 1.23–1.36 (m, 3H), 1.45 (s, 9H), 4.06–4.24 (m, 1H), 4.30–4.41 (m, 1H), 5.58 (d, J = 7.4 Hz, 1H), 6.16 (br.s, 2H).

[0418] At room temperature, Ag₂O (26.95 g, 116.0 mmol) and methyl iodine (14.5 mL, 233.0 mmol) were added to a stirred solution of (tert-butyloxycarbonyl)-D-altothreonine (5.10 g, 23.3 mmol) in dry acetonitrile (320 mL), and the resulting mixture was stirred in the dark for 4 days. The mixture was filtered through a Celite filter and washed several times with DCM. The filtrate was concentrated under vacuum to give a crude product, which was purified by rapid chromatography (0–100% EtOAc in hexane solution, 80 g SiO₂ column) to give N-(tert-butyloxycarbonyl)-O-methyl-D-altothreonine methyl ester (3.80 g, 66%) as a colorless liquid.

[0419] 1 ¹H NMR (400MHz, chloroform-d) δ 1.20 (d, J = 6.5Hz, 3H), 1.45 (s, 9H), 3.36 (s, 3H), 3.59–3.67 (m, 1H), 3.76 (s, 3H), 4.39–4.46 (m, 1H), 5.24–5.30 (m, 1H).

[0420] At 0 °C under nitrogen, a solution of LiBH4 in THF (2.0 M, 11.5 mL, 23.1 mmol) was added to a stirred solution of N-(tert-butoxycarbonyl)-O-methyl-D-allothreonine methyl ester (3.80 g, 15.4 mmol) in THF (30 mL), and the mixture was slowly heated to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NH4Cl solution (15 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid chromatography (0-100% EtOAc in hexane solution, 80 g SiO2 column) to give (2S,3R)-1-hydroxy-3-methoxybutane-2-yl)carbamate tert-butyl ester (intermediate 14) (3.10 g, 92%) as a colorless liquid.

[0421] The data for intermediate 14 are shown in Table 2.

[0422] Route 4

[0423] Typical procedures for preparing protected amino alcohols include, for example, the preparation of intermediate 18,(S)-(1-hydroxy-3-methoxy-3-methylbutane-2-yl)carbamate tert-butyl ester.

[0424]

[0425] A solution of methyl iodine (3.6 mL, 57.8 mmol) in dry Et₂O (39 mL) was slowly added to a solution of Mg scrapings (1.17 g, 48.2 mmol) in dry Et₂O (10 mL). After the Mg was completely consumed, a solution of 3-(tert-butyl)-4-methyl(S)-2,2-dimethyloxazolidine-3,4-dicarboxylic acid ester (intermediate 17) (5 g, 19.3 mmol) in dry Et₂O (20 mL) was added dropwise at a rate that allowed the solution to begin to reflux. After the addition was complete, the reaction mixture was stirred for another 10 minutes before carefully adding 70 mL of saturated aqueous NH₄Cl solution. The layers were separated, and the aqueous layer was extracted with Et₂O (2 x 70 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to give (S)-4-(2-hydroxypropane-2-yl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (4.62 g, 92%) as a colorless oil, which was used directly in the next step without any purification.

[0426] 1¹H NMR (400 MHz, chloroform-d) δ 1.16 (s, 3H), 1.17 (s, 3H), 1.49 (s, 9H), 1.50 (s, 3H), 1.58 (s, 3H), 3.72–3.82 (m, 1H), 3.92–4.02 (m, 2H), 5.25 (s, 1H).

[0427] To a solution of (S)-4-(2-hydroxypropane-2-yl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (5.12 g, 19.7 mmol) cooled to 0 °C in DMF (19.0 mL), NaH (60% dispersion in mineral oil, 1.02 g, 25.6 mmol) and methyl iodine (2.46 mL, 39.5 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. MeOH (2.0 mL) was added to quench the reaction, and the mixture was then diluted with DCM (50.0 mL) and washed twice with water. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dry pack) using a gradient of hexane solutions of EtOAc (0-100%) to obtain (S)-4-(2-methoxypropane-2-yl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (4.9 g, 91%) as a colorless oil, which was then allowed to crystallize.

[0428] 1 ¹H NMR (400 MHz, chloroform-d) δ 1.13 (s, 3H), 1.19 (s, 3H), 1.48 (s, 9H), 1.49 (s, 3H), 1.61 (s, 3H), 3.21 (s, 3H), 3.83–3.89 (m, 1H), 3.90–4.11 (m, 1H), 4.12–4.18 (m, 1H).

[0429] PTSA (250 mg, 1.32 mmol) was added to a stirred solution of (S)-4-(2-methoxypropan-2-yl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (3.60 g, 13.2 mmol) in MeOH (55.0 mL), and the resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with a saturated aqueous solution of NaHCO3 (10 mL). The solvent was removed under reduced pressure, and H2O (15 mL) was added. The aqueous layer was extracted with EtOAc (3 × 25 mL), and the combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to give (S)-(1-hydroxy-3-methoxy-3-methylbutan-2-yl)carbamate tert-butyl ester (intermediate 18) (3.0 g, 98%) as a white solid.

[0430] The data for intermediate 18 are shown in Table 2.

[0431] Route 5

[0432] A typical procedure for preparing protected amino alcohols, such as the preparation of intermediate 20,2-(trimethylsilyl)ethyl(2-hydroxy-1-(oxetane-3-yl)ethyl)carbamate.

[0433]

[0434] Under N2, methyl 2-(((benzyloxy)carbonyl)amino)-2-(oxetane-3-yl)acetate (intermediate 19) (4.06 g, 14.6 mmol) and MeOH (240 mL) were added to a 500 mL flask. Then, Mg chips (3.56 g, 146 mmol) were added, and the mixture was stirred at room temperature for 3 hours (WARNING: a large amount of H2 was observed). The resulting mixture was cooled to 0 °C, and a saturated aqueous solution of NH4Cl (85 mL) was slowly and carefully added. The mixture was concentrated under reduced pressure until most of the MeOH was removed, and the residue was extracted with DCM (3 x 60 mL). The organic phases were combined, washed with brine (50 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (dry injection, 80 g SiO2, 0:100 to 90:10, EtOAc: hexane) to obtain methyl 2-(((benzyloxy)carbonyl)amino)-2-(oxetane-3-yl)acetate (2.41 g, 59%) as a colorless solid.

[0435] 1 H NMR (400MHz, DMSO-d6) δ3.20–3.37(m,1H),3.62(s,3H),4.35(t,J=6.3Hz,1H),4.38–4 .48(m,2H),4.50–4.62(m,2H),5.05(s,2H),7.27–7.41(m,5H),7.86(d,J=8.0Hz,1H).

[0436] Under N2, methyl 2-(((benzyloxy)carbonyl)amino)-2-(oxetane-3-yl)acetate (2.35 g, 8.41 mmol) and anhydrous THF (35 mL) were placed in a 100 mL flask. The resulting solution was cooled to 0 °C, and then a solution of LiBH4 in THF (2 M, 8.4 mL, 16.8 mmol) was added dropwise. The resulting mixture was stirred at 0 °C for 30 min, and then stirred further at room temperature for 2 h. The resulting mixture was cooled to 0 °C, carefully quenched by adding water (20 mL), and stirred for another 30 min at room temperature. EtOAc (40 mL) was added to separate the phases, and the aqueous phase was extracted with EtOAc (2 x 20 mL). The organic phases were combined, dried over MgSO4, and concentrated under reduced pressure to give benzyl (2-hydroxy-1-(oxetane-3-yl)ethyl)carbamate (1.90 g, 90%) as a colorless solid.

[0437] 1 H NMR(500MHz,DMSO-d6)δ3.04–3.13(m,1H),3.20–3.27(m,1H),3.30–3.36(m,1H),3.78–3.85(m,1H),4.33–4.41(m,2H ),4.48–4.57(m,2H),4.65(t,J=5.6Hz,1H),5.03(s,2H),7.15(d,J=8.8Hz,1H),7.29–7.33(m,1H),7.33–7.39(m,4H).

[0438] 10% Pd / C (178 mg, 0.167 mmol Pd) was placed in a 100 mL flask, which was then purged with N2. A solution of (2-hydroxy-1-(oxetane-3-yl)ethyl)carbamate (1.68 g, 6.69 mmol) in MeOH (34 mL) was then added. The atmosphere was replaced with H2 by four evacuation / H2 cycles, and the suspension was stirred at room temperature for 5 hours under H2 (1 atm). The atmosphere in the flask was replaced with N2, the suspension was filtered with Celite, and the solid residue was washed several times with MeOH. The filtrate was concentrated under reduced pressure to give 2-amino-2-(oxetane-3-yl)ethane-1-ol (784 mg, 100%) as a colorless oil.

[0439] 1¹H NMR (400 MHz, chloroform-d) δ 2.90–3.00 (m, 1H), 3.18–3.29 (m, 2H), 3.50–3.56 (m, 1H), 4.47 (t, J = 6.2 Hz, 1H), 4.58 (t, J = 6.2 Hz, 1H), 4.73–4.83 (m, 2H). No exchangeable protons were observed.

[0440] Under N2, 2-amino-2-(oxetane-3-yl)ethane-1-ol (784 mg, 6.69 mmol) and 1,4-dioxane (57 mL) were placed in a 200 mL flask. Then, Et3N (1.4 mL, 10.0 mmol) was added, followed by a solution of 2,5-dioxopyrrolidone-1-yl (2-(trimethylsilyl)ethyl) carbonate (CAS: 72869-85-9) (1.77 g, 6.82 mmol) in 1,4-dioxane (10 mL). A thick suspension was immediately formed and stirred at room temperature for 16 hours. The resulting clear solution was concentrated under reduced pressure, and the residue was dissolved in a mixture of EtOAc (75 mL) and a saturated aqueous solution of NH4Cl (50 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with brine (25 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (dry injection, 40 g SiO2, 50:50 to 100:0, EtOAc:hexane) to give 2-(trimethylsilyl)ethyl (2-hydroxy-1-(oxetane-3-yl)ethyl)carbamate (intermediate 20) (1.68 g, 96%) as a colorless oil.

[0441] The data for intermediate 20 are shown in Table 2.

[0442] Route 6

[0443] Typical procedures for preparing protected amino alcohols include, for example, the preparation of intermediate 26,(2,6-dichloro-5-hydroxypyrimidin-4-yl)((2R,3S)-3-hydroxybutane-2-yl)carbamate tert-butyl ester.

[0444]

[0445] To a solution of 2,4-dichloro-6-(((2R,3S)-3-hydroxybutan-2-yl)amino)pyrimidin-5-ol (intermediate 25) (1.02 g, 4.05 mmol) in a mixture of THF (40 mL) and water (20 mL), di-tert-butyl dicarbonate (927 mg, 4.25 mmol) and NaHCO3 (714 mg, 8.5 mmol) were added, and the reaction mixture was stirred at room temperature for 18 hours. The mixture was then concentrated under reduced pressure, and the residue was directly purified by silica gel chromatography (dry pack) using a gradient of EtOAc (0-100%) in hexane solution followed by a gradient of MeOH (0-15%) in DCM solution, yielding (2,6-dichloro-5-hydroxypyrimidin-4-yl)((2R,3S)-3-hydroxybutane-2-yl)carbamate tert-butyl ester (intermediate 26) (155 mg, 11%) as a colorless oil and (2,4-dichloro-6-(((2R,3S)-3-hydroxybutane-2-yl)amino)pyrimidin-5-yl)carbonate tert-butyl ester (350 mg, 25%) as a pale yellow oil. The unwanted O-Boc product could be separately converted to the desired N-Boc product by stirring with a solution of NaHCO3 in THF / H2O.

[0446] The data for intermediate 26 are shown in Table 2.

[0447] Route 7

[0448] Typical procedures for preparing protected amino alcohols include, for example, the preparation of intermediate 36, (1,1,1-trifluoro-3-hydroxypropane-2-yl)carbamate tert-butyl ester.

[0449]

[0450] Under N2, methyl 2-((tert-butoxycarbonyl)amino)-3,3,3-trifluoro-2-hydroxypropionate (intermediate 35) (2.71 g, 9.92 mmol) and anhydrous Et2O (50 mL) were placed in a 100 mL flask. The resulting mixture was cooled to 0 °C, and then TFAA (1.40 mL, 9.92 mmol) and pyridine (1.60 mL, 19.8 mmol) were added. The mixture was stirred at 0 °C for 1 hour and then at room temperature for another 16 hours. The resulting suspension was filtered, and the solid was washed with Et2O (2 x 25 mL). The filtrate was washed with water (25 mL), dried over MgSO4, and concentrated under reduced pressure to give crude methyl 2-((tert-butoxycarbonyl)imino)-3,3,3-trifluoropropionate (2.51 g, 99%) as a clear oil, which was used in the next step without further purification.

[0451] 1¹H NMR (500MHz, chloroform-d) δ 1.58 (s, 9H), 3.95 (s, 3H).

[0452] Under N2 conditions, methyl 2-((tert-Butoxycarbonyl)imino)-3,3,3-trifluoropropionate (2.51 g, 9.84 mmol) and anhydrous Et2O (30 mL) were placed in an oven-dried 100 mL flask. The resulting solution was cooled to -78 °C, and then a solution of LiAlH4 in THF (2 M, 9.84 mL, 19.7 mmol) was slowly added. The mixture was then stirred for 16 hours while being slowly heated to room temperature. The resulting solution was cooled to 0 °C, and the reaction was carefully quenched by the successive addition of water (0.75 mL), NaOH aqueous solution (3.8 M, 0.75 mL), and water (2.3 mL). The resulting suspension was heated to room temperature, and MgSO4 was added. The suspension was filtered, and the solid was washed with THF (4 x 20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dry injection, 40 g SiO2, 5:95 to 70:30, EtOAc: hexane) to give tert-butyl (1,1,1-trifluoro-3-hydroxypropane-2-yl)carbamate (intermediate 36) (1.38 g, 61%) as a colorless solid.

[0453] The data for intermediate 36 are shown in Table 2.

[0454] Route 8

[0455] Typical procedures for preparing protected amino acids, such as the preparation of intermediate 61,2-(((tert-butoxycarbonyl)amino)methyl)butyric acid.

[0456]

[0457] 2-(aminomethyl)butyric acid (intermediate 60) (1.5 g, 9.8 mmol) was dissolved in DCM (5.0 mL), and TEA (379 mg, 14.7 mmol) was added dropwise at 0 °C. Then, di-tert-butyl dicarbonate (512 mg, 11.7 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum, and the residue was partitioned between H₂O (100 mL) and DCM (60 mL). The aqueous layer was washed with 1 M citric acid solution and then further extracted with DCM (2 x 60 mL). All organic layers were combined, dried (Na₂SO₄), and the solvent was removed under vacuum to give a crude product, which was purified by silica column chromatography using a 16% EtOAc solution in hexane to give 2-(((tert-butoxycarbonyl)amino)methyl)butyric acid (intermediate 61) (2.4 g, 86%) as a colorless colloidal substance.

[0458] The data for intermediate 61 are shown in Table 2.

[0459] General synthesis procedure:

[0460] Route A

[0461] A typical procedure for preparing fused pyrimidines, such as the preparation of (R)-4-(3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine in Examples 1-1.

[0462]

[0463] To a solution of 2,4,6-trichloropyrimidin-5-ol (intermediate 2) (384 mg, 1.926 mmol) and (2-hydroxyethyl) tert-butyl carbamate (intermediate 3) (621 mg, 3.851 mmol) cooled to 0 °C in THF (11.0 mL), DIAD (0.57 mL, 2.888 mmol) and PPh3 (758 mg, 2.888 mol) were added, and the reaction mixture was stirred for 2 hours. THF was then removed under reduced pressure, and silica was added. The residue was purified by silica gel chromatography (dry pack) using a gradient of EtOAc (0–60%) in hexane to give (2-((2,4,6-trichloropyrimidin-5-yl)oxy)ethyl) tert-butyl carbamate (633 mg, 96%) as a white solid.

[0464] 1 ¹H NMR (500MHz, chloroform-d) δ 1.45 (s, 9H), 3.56 (q, J = 5.5Hz, 2H), 4.17 (t, J = 5.0Hz, 2H), 5.05 (s, 1H).

[0465] TFA (5.10 mL) was added to a solution of (2-((2,4,6-trichloropyrimidin-5-yl)oxy)ethyl)carbamate tert-butyl ester (633 mg, 1.848 mmol) in DCM (5.10 mL), and the reaction mixture was stirred at room temperature for 10 minutes. The mixture was then concentrated and dried under vacuum to give 2-((2,4,6-trichloropyrimidin-5-yl)oxy)ethane-1-amine trifluoroacetate (675 mg, >100%) as a colorless oil, which was used directly in the next step without any purification.

[0466] LCMS (System 1, Method D): m / z 242 / 244 (M+H) + (ES + At 0.54 minutes, the wavelength was 190-320nm.

[0467] DIPEA (0.97 mL, 5.545 mmol) was added to a solution of 2-((2,4,6-trichloropyrimidin-5-yl)oxy)ethane-1-amine trifluoroacetate (659 mg, 1.848 mmol) in 1,4-dioxane (5.00 mL), and the reaction mixture was heated at 80 °C for 18 hours. The mixture was then diluted with water and extracted with EtOAc (3 x 10.0 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dry pack) using a gradient of hexane solutions of EtOAc (0–100%) to give 2,4-dichloro-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine (279 mg, 73%) as a white solid.

[0468] LCMS (System 1, Method D): m / z 206 / 208 (M+H) + (ES + At 1.87 minutes, the wavelength was 190-320nm.

[0469] To a solution of 2,4-dichloro-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine (279 mg, 1.354 mmol) in 1,4-dioxane (2.90 mL), (R)-methyl(pyrrolidone-3-yl)carbamate tert-butyl ester (intermediate 4) (271 mg, 1.354 mmol) and DIPEA (0.47 mL, 2.708 mmol) were added, and the mixture was heated at 80 °C for 18 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (3 × 10.0 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of hexane solutions of EtOAc (0-100%) to give (R)-(1-(2-chloro-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (218 mg, 44%) as a white solid.

[0470] LCMS (System 1, Method D): m / z 370 / 372 (M+H) + (ES + At 2.40 minutes, the wavelength was 190-320nm.

[0471] To a solution of (R)-(1-(2-chloro-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate (127 mg, 0.343 mmol) in a mixture of THF (0.83 mL) and DMF (0.22 mL), di-tert-butyl dicarbonate (112 mg, 0.515 mmol), Et3N (0.102 mL, 0.755 mmol), and DMAP (21 mg, 0.172 mmol) were added, and the reaction mixture was stirred at room temperature for 18 hours. The mixture was then concentrated under reduced pressure, the residue was diluted with DCM, and silica was added. The residue was purified by silica gel chromatography (dry pack) of a hexane solution with gradients of EtOAc (0–40%) to give (R)-4-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-chloro-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (113 mg, 70%) as a colorless oil.

[0472] LCMS (System 1, Method D): m / z 470 / 472 (M+H) + (ES + At 2.75 minutes, the wavelength was 190-320nm.

[0473] To a degassed solution of (R)-4-(3-((tert-butyloxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-chloro-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (114 mg, 0.243 mmol) and tert-butyl carbamate (28 mg, 0.243 mmol) in 1,4-dioxane (2.40 mL), Cs₂CO₃ (198 mg, 0.606 mmol), tris(dibenzylideneacetone)dipalladium(O) (CAS: 51364-51-3) (22.2 mg, 0.024 mmol) and XPhos (CAS: 564483-18-7) (23.1 mg, 0.049 mmol) were added, and the reaction mixture was heated at 110 °C for 18 hours. After cooling to room temperature, filter the mixture through a Celite pad and wash the residue with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a hexane solution with gradients of EtOAc (0-100%) followed by a DCM solution with gradients of MeOH (0-30%) to give (R)-4-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-((tert-butoxycarbonyl)amino)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (62 mg, 46%) as a pale yellow oil and (R)-2-amino-4-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (54 mg, 49%) as a yellow oil.

[0474] LCMS (System 1, Method D): m / z 551(M+H) + (ES + At 2.11 minutes, the wavelength was 190-320nm.

[0475] LCMS (System 1, Method D): m / z 451 (M+H) + (ES + At 1.96 minutes, the wavelength was 190-320nm.

[0476] TFA (0.8 mL) was added to a solution of (R)-4-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-((tert-butoxycarbonyl)amino)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (62 mg, 0.113 mmol) and (R)-2-amino-4-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (54 mg, 0.120 mmol) in DCM (1.10 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to dryness, and the residue was purified using purification method A to give (R)-4-(3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine as a white solid, Example 1-1 (42 mg, 73%).

[0477] The data for Example 1-1 are shown in Table 3.

[0478] Route B

[0479] Typical procedures for preparing fused pyrimidines, such as those for preparing (R)-7-ethyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride, as described in Examples 1-3.

[0480]

[0481] Under N2, (R)-(1-hydroxybutane-2-yl)carbamate tert-butyl ester (intermediate 6) (2.55 g, 13.5 mmol), 2,4,6-trichloropyrimidin-5-ol (intermediate 2) (1.50 g, 7.50 mmol), and anhydrous THF (30 mL) were transferred into a 100 mL flask. The resulting solution was cooled to 0 °C, and then Ph3P (3.15 g, 12.0 mmol) was added. Once Ph3P was completely dissolved, DIAD (2.36 mL, 12.0 mmol) was added dropwise over approximately 5 minutes. The reaction mixture was stirred at 0 °C for 10 minutes, then heated to room temperature and stirred for 16 hours. The mixture was concentrated to dryness, and the residue was purified by column chromatography (dry injection, 80 g SiO2, 0:100 to 50:50, EtOAc: hexane) to give (R)-(1-((2,4,6-trichloropyrimidin-5-yl)oxy)butane-2-yl)carbamate tert-butyl ester (1.78 g, 64%) as a colorless solid.

[0482] 1H NMR(500MHz,DMSO-d6)δ0.89(t,J=7.4Hz,3H),1.38(s,9H),1.40–1.51(m,1H), 1.59–1.69(m,1H),3.61–3.70(m,1H),3.97–4.11(m,2H),6.86(d,J=8.4Hz,1H).

[0483] (R)-(1-((2,4,6-trichloropyrimidin-5-yl)oxy)butane-2-yl)carbamate tert-butyl ester (1.78 g, 4.80 mmol) and DCM (20 mL) were placed in a 100 mL flask. Then, TFA (10.0 mL, 135 mmol) was added, and the resulting solution was stirred at room temperature for 10 minutes. The mixture was co-evaporated with toluene under reduced pressure to give crude (R)-1-((2,4,6-trichloropyrimidin-5-yl)oxy)butane-2-amine trifluoroacetate as a colorless oil. This product was used in the next step without further purification.

[0484] LCMS (System 1, Method E): m / z 234 / 236 (M-Cl) + (ES + At 2.05 minutes, the wavelength was 190-320nm.

[0485] Under N2, crude (R)-1-((2,4,6-trichloropyrimidin-5-yl)oxy)butane-2-amine trifluoroacetate (approximately 4.80 mmol) and 1,4-dioxane (13.5 mL) were packed into a 20 mL sealable tube. DIPEA (2.5 mL, 14.4 mmol) was then added, the tube was sealed, and the resulting solution was stirred at 80 °C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (dry injection, 40 g SiO2, 0:100 to 80:20, EtOAc:hexane) to give (R)-2,4-dichloro-7-ethyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine (1.01 g, 90%, two-step) as a colorless oil.

[0486] LCMS (System 1, Method D): m / z 234 / 236 (M+H) + (ES + At 2.18 minutes, the wavelength was 190-320nm.

[0487] (R)-2,4-dichloro-7-ethyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine (1.01 g, 4.31 mmol) and THF (21.5 mL) were placed in a 50 mL flask. Then, DIPEA (1.5 mL, 8.6 mmol) was added, followed by di-tert-butyl dicarbonate (1.70 g, 7.77 mmol) and DMAP (53 mg, 0.43 mmol). The resulting solution was stirred at room temperature for 16 hours. The mixture was evaporated under reduced pressure, and the residue was purified by column chromatography (dry injection, 40 g SiO2, 0:100 to 30:70, EtOAc: hexane) to give (R)-2,4-dichloro-7-ethyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (1.36 g, 94%) as a colorless solid.

[0488] LCMS (System 1, Method D): m / z 278 / 280 (M-56+H) + (ES + At 2.68 minutes, the wavelength was 190-320nm.

[0489] Under nitrogen, (R)-2,4-dichloro-7-ethyl-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (680 mg, 2.03 mmol), (R)-methyl(pyrrolidone-3-yl)carbamate tert-butyl ester (intermediate 4) (448 mg, 2.24 mmol), and anhydrous 1,4-dioxane (5.8 mL) were placed into a 20 mL sealable tube. DIPEA (0.71 mL, 4.1 mmol) was added, the tube was sealed, and the mixture was stirred at 80 °C for 16 hours. The resulting mixture was cooled to room temperature and then diluted with DCM (30 mL) to dissolve the precipitated solid. The resulting solution was concentrated under reduced pressure on silica gel, and the residue was purified by column chromatography (dry injection, 40 g SiO2, 0:100 to 50:50, EtOAc: hexane) to give (R)-4-((R)-3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-chloro-7-ethyl-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (878 mg, 87%) as a colorless solid.

[0490] LCMS (System 1, Method D): m / z 442 / 444 (M-56+H) + (ES + At 2.90 minutes, the wavelength was 190-320nm.

[0491] Under N2, tert-butyl carbamate (310 mg, 2.64 mmol), Cs2CO3 (1.15 g, 3.53 mmol), tris(dibenzylideneacetone)dipalladium(0) (CAS: 51364-51-3) (80.7 mg, 0.0882 mmol), and XPos (CAS: 564483-18-7) (168 mg, 0.35 mmol) were placed into a 20 mL sealable tube. Then, a solution of (R)-4-((R)-3-((tert-butyloxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-chloro-7-ethyl-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (878 mg, 1.76 mmol) in 1,4-dioxane (14 mL) was added, and the resulting suspension was bubbled with N2 for 15 minutes. The tube was then sealed, and the mixture was stirred at 100°C for 3 hours. The mixture was concentrated under reduced pressure using silica gel, and the residue was purified by column chromatography (dry injection, 40 g SiO2, 0:100 to 60:10, EtOAc: hexane) to give an impure product as a yellow solid. The product was further purified by reversed-phase column chromatography (MeOH injection, 60 g C-18, 10:90 to 95:5, MeCN: 10 mM ammonium bicarbonate aqueous solution, pH 10), and lyophilized to give (R)-4-((R)-3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-((tert-butoxycarbonyl)amino)-7-ethyl-6,7-dihydro-8H-pyrimidine[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (630 mg, 62%) as a colorless solid.

[0492] LCMS (System 1, Method D): m / z 579 (M+H) + (ES + At 2.20 minutes, the wavelength was 190-320nm.

[0493] Under N2 conditions, (R)-4-((R)-3-((tert-Butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-((tert-Butoxycarbonyl)amino)-7-ethyl-6,7-dihydro-8H-pyrimidin[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (630 mg, 1.09 mmol) and 1,4-dioxane (5.5 mL) were placed in a 50 mL flask. Once the solid dissolved, a solution of 1,4-dioxane in HCl (4 M, 5.5 mL, 22 mmol) was added, and the resulting mixture was stirred vigorously at 45 °C for 3 hours. The resulting suspension was concentrated under reduced pressure, the residue was dissolved in water (10 mL), and lyophilized. The yellow solid obtained by reversed-phase column chromatography (H2O injection, 60g C-18, isocratic 5:95, MeCN:H2O) yielded (R)-7-ethyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride, which was lyophilized into a colorless solid, as described in Examples 1-3 (324 mg, 77%).

[0494] The data for Examples 1-3 are shown in Table 3.

[0495] Route C

[0496] Typical procedures for preparing fused pyrimidines, such as those in Examples 1-8, include the preparation of 4-((R)-3-(methylamino)pyrrolidone-1-yl)-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine.

[0497]

[0498] 4-((R)-3-aminopyrrolidone-1-yl)-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-2-amine (Examples 2-3) (20 mg, 0.0657 mmol) was placed in a 5 mL flask. Then, a solution of di-tert-butyl dicarbonate (15.1 mg, 0.0690 mmol) in THF (0.66 mL) was added, followed by a solution of NaHCO3 (11.6 mg) in water (0.33 mL). The resulting mixture was stirred at room temperature for 60 hours. The mixture was diluted in EtOAc (10 mL) and brine (5 mL), the phases were separated, and the aqueous phase was extracted with EtOAc (2 x 5 mL). The organic phases were combined, dried over Na₂SO₄, and concentrated to dryness to give ((3R)-1-(2-amino-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)carbamate tert-butyl ester (17.0 mg, 64%) as a colorless solid. This product required no further purification for the next step.

[0499] LCMS (System 1, Method D): m / z 405 (M+H) + (ES + At 1.79 minutes, the wavelength was 190-320nm.

[0500] Under N2, 27.0 mg (0.0668 mmol) of ((3R)-1-(2-amino-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)carbamate tert-butyl (THF) and 3.3 mL of anhydrous THF were placed in a 10 mL flask. The solution was cooled to 0 °C, and then a solution of LiAlH4 in THF (2 M, 0.17 mL, 0.34 mmol) was added dropwise. The resulting mixture was refluxed and heated for 5 hours, then cooled to 0 °C and carefully quenched by adding Na2SO4·10H2O (hazard: exothermic and H2 precipitation). The resulting suspension was filtered, and the collected solids were washed several times with MeOH. The filtrate was filtered through a 0.45 μm filter and concentrated under reduced pressure. The residue was purified using purification method B to give 4-((R)-3-(methylamino)pyrrolidone-1-yl)-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine as a colorless solid, Examples 1-8 (14.0 mg, 66%).

[0501] The data for Examples 1-8 are shown in Table 3.

[0502] Route D

[0503] Typical procedures for preparing fused pyrimidines, such as those in Examples 1-13, include 4-((R)-3-(methylamino)pyrrolidone-1-yl)-7-(oxetane-3-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine.

[0504]

[0505] Under nitrogen (N2), 2-(trimethylsilyl)ethyl (2-hydroxy-1-(oxetane-3-yl)ethyl)carbamate (intermediate 20) (1.05 g, 4.01 mmol), 2,4,6-trichloropyrimidin-5-ol (intermediate 2) (0.500 g, 2.51 mmol), and anhydrous THF (12.5 mL) were transferred into a 50 mL flask. The resulting solution was cooled to 0 °C, and then Ph3P (986 mg, 3.76 mmol) was added. Once Ph3P was completely dissolved, DIAD (0.740 mL, 3.76 mmol) was added dropwise over approximately 5 minutes. The reaction mixture was then stirred at 0 °C for 10 minutes, then heated to room temperature and stirred for 16 hours. The mixture was concentrated to dryness, and the residue was purified by column chromatography (dry injection, 40 g SiO2, 0:100 to 80:20, EtOAc: hexane) to obtain the crude product, which was further purified by reversed-phase column chromatography (DMSO injection, 12 g C-18, 5:95 to 95:5, MeCN: 0.1% aqueous formic acid) to obtain 2-(trimethylsilyl)ethyl(1-(oxetane-3-yl)-2-((2,4,6-trichloropyrimidin-5-yl)oxy)ethyl)carbamate (847 mg, 63%).

[0506] LCMS (System 1, Method D): m / z 414 / 416(M-CO+H) + (ES + At 2.20 minutes, the wavelength was 190-320nm.

[0507] Under nitrogen (N2), 2-(trimethylsilyl)ethyl(1-(oxetane-3-yl)-2-((2,4,6-trichloropyrimidin-5-yl)oxy)ethyl)carbamate (690 mg, 1.28 mmol), (R)-methyl(pyrrolidine-3-yl)carbamate tert-butyl ester (intermediate 4) (256 mg, 1.28 mmol), and anhydrous 1,4-dioxane (6.4 mL) were placed into a 20 mL sealable tube. DIPEA (0.45 mL, 2.58 mmol) was then added, the tube was sealed, and the mixture was stirred at 80 °C for 18 hours. The resulting solution was concentrated to dryness, and the residue was purified by column chromatography (dry injection, 40 g SiO2, 0:100 to 90:10, EtOAc: hexane) to obtain a colorless solid ((3R)-1-(2,6-dichloro-5-(2-(oxecyclobutan-3-yl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethoxy)pyrimidin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (730 mg, 94%).

[0508] LCMS (System 1, Method D): m / z 578 / 580 (M-CO+H) + (ES + At 2.32 minutes, the wavelength was 190-320nm.

[0509] Under N2, tert-butyl ((3R)-1-(2,6-dichloro-5-(2-(oxecyclobutan-3-yl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethoxy)pyrimidin-4-yl)pyrrolidine-3-yl)(methyl)carbamate (210 mg, 0.346 mmol) and anhydrous THF (3.5 mL) were placed in a 10 mL flask. A solution of TBAF in THF (1 M, 0.865 mL, 0.865 mmol) was then added, and the resulting yellow solution was stirred at room temperature for 16 hours. The reaction was quenched by adding saturated aqueous NH4Cl solution (1 mL) and water (1 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL), and the combined organic phases were dried over MgSO4 and concentrated to dryness. The residue was purified by column chromatography (dry injection, 12 g SiO2, 0:100 to 10:90, MeOH:DCM) to obtain a crude product, which was combined with the product of a similar reaction carried out on approximately twice the scale and purified by reversed-phase column chromatography (MeOH injection, 12 g C-18, 5:95 to 70:30, MeCN: 10 mM ammonium bicarbonate aqueous solution, pH 10) to obtain ((3R)-1-(5-(2-amino-2-(oxecyclobutane-3-yl)ethoxy)-2,6-dichloropyrimidin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (142 mg, 26%) as a colorless solid.

[0510] LCMS (System 1, Method E): m / z 326 / 328 (M-Cl-BOC+H) + (ES + At 1.97 minutes, the wavelength was 190-320nm.

[0511] Under N2, ((3R)-1-(5-(2-amino-2-(oxecyclobutane-3-yl)ethoxy)-2,6-dichloropyrimidin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (142 mg, 0.307 mmol), Cs2CO3 (200 mg, 0.614 mmol), tris(dibenzylideneacetone)dipalladium(0) (CAS: 51364-51-3) (14.1 mg, 0.0154 mmol), and XPos (CAS: 5564483-18-7) (29.3 mg, 0.0614 mol) were placed into a 5 mL sealable tube. Then 1,4-dioxane (3.0 mL) was added, and the resulting suspension was bubbled with N2 for 15 minutes. The tube was then sealed, and the mixture was stirred at 100 °C for 3 hours. The mixture was concentrated under reduced pressure using silica gel, and the residue was purified by column chromatography (dry injection, 40 g SiO2, 0:100 to 90:10, EtOAc: hexane) to give a colorless solid ((3R)-1-(2-chloro-7-(oxecyclobutan-3-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (70 mg, 54%).

[0512] LCMS (System 1, Method D): m / z 426 / 428 (M+H) + (ES + At 2.00 minutes, the wavelength was 190-320nm.

[0513] Under N2 conditions, tert-butyl carbamate (28.9 mg, 0.247 mmol), Cs2CO3 (107 mg, 0.329 mmol), tris(dibenzylideneacetone)palladium(0) (CAS: 51364-51-3) (15.1 mg, 0.0164 mmol) and XPos (CAS: 564483-18-7) (31.3 mg, 0.0657 mmol) were placed into a 5 mL sealable tube. Then, a solution of ((3R)-1-(2-chloro-7-(oxetane-3-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate (70.0 mg, 0.164 mmol) in 1,4-dioxane (1.6 mL) was added, and the resulting suspension was bubbled with N2 for 15 minutes. The tube was then sealed, and the mixture was stirred at 110 °C for 11 hours. The mixture was concentrated on silica gel under reduced pressure and subjected to reversed-phase column chromatography (DMSO injection, 30 g C-18, 5:95 to 90:10, MeCN: 10 mM ammonium bicarbonate aqueous solution, pH 10). 10) The residue was purified to give ((3R)-1-(2-((tert-butoxycarbonyl)amino)-7-(oxetane-3-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (15 mg, 18%) as a colorless solid and ((3R)-1-(2-amino-7-(oxetane-3-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (15 mg, 22%) as a colorless solid.

[0514] LCMS (System 1, Method D): m / z 507 (M+H) + (ES + At 2.06 minutes, the wavelength was 190-320nm.

[0515] LCMS (System 1, Method D): m / z 407 (M+H) + (ES + At 1.83 minutes, the wavelength was 190-320nm.

[0516] Under N2, a mixture of ((3R)-1-(2-((tert-butoxycarbonyl)amino)-7-(oxetane-3-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester and ((3R)-1-(2-amino-7-(oxetane-3-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (total 0.0620 mmol) and DCM (1.0 mL) was placed into a 5 mL flask. Then TFA (0.2 mL) was added, and the resulting solution was stirred at room temperature for 5 hours. The solution was co-evaporated with toluene under reduced pressure, and the residue was purified using purification method C to obtain 4-((R)-3-(methylamino)pyrrolidine-1-yl)-7-(oxetane-3-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine, which was lyophilized as a colorless solid, Examples 1-13 (13.6 mg, 72%).

[0517] Data from Examples 1-13 are shown in Table 3.

[0518] Route E

[0519] Typical procedures for preparing fused pyrimidines, such as those for preparing Examples 1-14, (R)-7,7-dimethyl-4-(3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride.

[0520]

[0521] To a solution of 2,4,6-trichloro-5-methoxypyrimidine (intermediate 1) (1.00 g, 4.68 mmol) in 1,4-dioxane (7.00 mL), 2-amino-2-methyl-1-propanol (intermediate 21) (0.47 mL, 4.92 mmol) and DIPEA (2.00 mL, 11.7 mmol) were added, and the reaction mixture was heated at 100 °C for 3 hours. After cooling to room temperature, the mixture was diluted with water, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dry pack) using a gradient of hexane solutions of EtOAc (0-80%) to give 2-((2,6-dichloro-5-methoxypyrimidin-4-yl)amino)-2-methyl-1-propanol (891 mg, 72%) as a colorless oil, which was then crystallized to give a white solid.

[0522] LCMS (System 1, Method E): m / z 266 / 268 (M+H)+ (ES + At 2.05 minutes, the wavelength was 190-320nm.

[0523] LiCl (318 mg, 7.51 mmol) was added to a solution of 2-((2,6-dichloro-5-methoxypyrimidin-4-yl)amino)-2-methyl-1-propanol (800 mg, 3.01 mmol) in DMA (6.0 mL), and the mixture was stirred in a microwave oven at 160 °C for 20 min. After cooling to room temperature, the mixture was directly purified by reversed-phase column chromatography (C-18, isocratic 5:95, MeCN: 0.1% aqueous formic acid) to give 2,4-dichloro-6-((1-hydroxy-2-methylpropane-2-yl)amino)pyrimidin-5-ol formate (130 mg, 17%) as a brown oil.

[0524] LCMS (System 1, Method D): m / z 252 / 254 (M+H) + (ES + At 1.99 minutes, the wavelength was 190-320nm.

[0525] Ph3P (416 mg, 1.59 mmol) and DIAD (0.313 mL, 1.59 mol) were added to a solution of 2,4-dichloro-6-((1-hydroxy-2-methylpropane-2-yl)amino)pyrimidin-5-ol carbamate (200 mg, 0.793 mmol) in THF (4.7 mL) cooled to 0 °C, and the reaction mixture was stirred overnight at room temperature. The mixture was then concentrated to dryness to give crude 2,4-dichloro-7,7-dimethyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine, which was used directly for the next step without any purification.

[0526] LCMS (System 1, Method D): m / z 234 / 236 (M+H) + (ES + At 1.87 minutes, the wavelength was 190-320nm.

[0527] To a solution of crude 2,4-dichloro-7,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (0.793 mmol) in THF (7.9 mL), di-tert-butyl dicarbonate (537 mg, 2.46 mmol), Et3N (0.33 mL, 2.46 mol), and DMAP (48 mg, 0.396 mmol) were added, and the reaction mixture was stirred at room temperature for 18 hours. The mixture was then concentrated under reduced pressure and silica was added. The residue was purified by silica gel chromatography (dry pack) using a gradient of hexane solutions of EtOAc (0–50%) to give tert-butyl 2,4-dichloro-7,7-dimethyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazine-8-carboxylic acid (30 mg, 11%, step 2) as a colorless oil.

[0528] LCMS (System 1, Method D): m / z 278 / 280 (M-56+H) + (ES + At 2.26 minutes, the wavelength was 190-320nm.

[0529] To a solution of 2,4-dichloro-7,7-dimethyl-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (30 mg, 0.089 mmol) in 1,4-dioxane (0.3 mL), (R)-methyl(pyrrolidone-3-yl)carbamate tert-butyl ester (intermediate 4) (20 mg, 0.099 mmol) and DIPEA (0.031 mL, 0.18 mmol) were added, and the mixture was heated to 80 °C for 18 hours. After cooling to room temperature, the mixture was diluted with water, and the aqueous layer was extracted with EtOAc (3 x 10.0 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dry pack) using a hexane solution with gradients of EtOAc (0–60%) to give (R)-4-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-chloro-7,7-dimethyl-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (37 mg, 83%) as a colorless oil.

[0530] LCMS (System 1, Method D): m / z 442 / 444 (M-56+H) + (ES + At 2.41 minutes, the wavelength was 190-320nm.

[0531] To a degassed solution of (R)-4-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-chloro-7,7-dimethyl-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (37 mg, 0.074 mmol) and tert-butyl carbamate (13 mg, 0.111 mmol) in 0.74 mL of 1,4-dioxane, Cs₂CO₃ (61 mg, 0.186 mmol), tris(dibenzylideneacetone)dipalladium(O) (CAS: 51364-51-3) (6.8 mg, 0.00743 mmol) and XPhos (CAS: 564483-18-7) (7.1 mg, 0.0149 mmol) were added, and the reaction mixture was heated to 110 °C for 2 hours. After cooling to room temperature, the mixture was filtered through a Celite pad, and the residue was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a hexane solution with gradients of EtOAc (0-100%), followed by reversed-phase column chromatography (C-18, isocratic 5:95, MeCN: 10 mM ammonium bicarbonate in water, pH 10), to give (R)-4-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-((tert-butoxycarbonyl)amino)-7,7-dimethyl-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (22 mg, 51%) as a colorless oil.

[0532] LCMS (System 1, Method D): m / z 579 (M+H) + (ES + At 2.29 minutes, the wavelength was 190-320nm.

[0533] A solution of HCl in 1,4-dioxane (4M, 0.48 mL, 1.9 mmol) was added to a solution of (R)-4-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-((tert-butoxycarbonyl)amino)-7,7-dimethyl-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (22 mg, 0.038 mmol) in 1,4-dioxane (0.48 mL), and the reaction mixture was heated to 45 °C for 3 hours. After cooling to room temperature, the mixture was concentrated to dryness. The residue was diluted with water and purified by reversed-phase column chromatography (H2O injection, 4 g C-18, isocratic 5:95, MeCN:H2O) to give (R)-7,7-dimethyl-4-(3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine dihydrochloride as a white solid, Examples 1-14 (12 mg, 90%).

[0534] The data for Examples 1-14 are shown in Table 3.

[0535] Route F

[0536] Typical procedures for preparing fused pyrimidines, such as those for preparing 7-isopropyl-8-methyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine in Examples 1-20.

[0537]

[0538] To a solution of ((3R)-1-(2-chloro-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate (intermediate 30) (100 mg, 0.243 mmol) in DMF (1.30 mL) cooled to 0 °C, NaH (dispersion in 60% mineral oil, 15 mg, 0.364 mmol) and methyl iodoform (0.018 mL, 0.291 mmol) were added. The reaction mixture was stirred at 0 °C for 30 min, then heated to room temperature and stirred for another 1 h. The mixture was then quenched with water, and the aqueous layer was extracted with EtOAc (3 x 5.00 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dry pack) of a hexane solution with gradients of EtOAc (0–40%) to give ((3R)-1-(2-chloro-7-isopropyl-8-methyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (68 mg, 66%), which was a pale yellow oil.

[0539] LCMS (System 1, Method D): m / z 426 / 428 (M+H) + (ES + At 2.83 minutes, the wavelength was 190-320nm.

[0540] To a degassed solution of ((3R)-1-(2-chloro-7-isopropyl-8-methyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate (68 mg, 0.16 mmol) and carbamate (19 mg, 0.16 mmol) in 1,4-dioxane (1.60 mL), Cs₂CO₃ (130 mg, 0.399 mmol), tris(dibenzylideneacetone)dipalladium(O) (CAS: 51364-51-3) (14.6 mg, 0.016 mmol) and XPhos (CAS: 564483-18-7) (15.2 mg, 0.032 mmol) were added, and the reaction mixture was heated at 110 °C for 18 hours. After cooling to room temperature, the mixture was filtered through a Celite pad and the residue was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dry pack) using a gradient of hexane solutions of EtOAc (0–50%) to give tert-butyl ((3R)-1-(2-((tert-butyloxycarbonyl)amino)-7-isopropyl-8-methyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate (43 mg, 53%) as a pale yellow oil.

[0541] LCMS (System 1, Method D): m / z 507 (M+H) + (ES + At 2.17 minutes, the wavelength was 190-320nm.

[0542] TFA (0.50 mL) was added to a solution of ((3R)-1-(2-((tert-butyloxycarbonyl)amino)-7-isopropyl-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate (43 mg, 0.085 mmol) in DCM (0.50 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to dryness, and the residue was purified by purification method D to give 7-isopropyl-8-methyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine as a white solid, Examples 1-20 (12 mg, 46%).

[0543] The data for Examples 1-20 are shown in Table 3.

[0544] Route G

[0545] Typical procedures for preparing fused pyrimidines, such as those for preparing Examples 1-21, 4-((R)-3-(methylamino)pyrrolidine-1-yl)-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazine-2-amine

[0546]

[0547] To a solution of 2,4,6-trichloro-5-methoxypyrimidine (intermediate 1) (320 mg, 1.5 mmol) in ethanol (10 mL), pyrrolidine-2-ylmethanol (intermediate 31) (227 mg, 2.25 mmol) and TEA (0.42 mL, 3.0 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DCM (10 mL). The DCM solution was washed with water (10 mL) and concentrated by drying with Na2SO4 under reduced pressure. The residue was purified by rapid chromatography using a hexane solution of 0–60% ethyl acetate to give (1-(2,6-dichloro-5-methoxypyrimidin-4-yl)pyrrolidine-2-yl)methanol (400 mg, 96%) as a white solid.

[0548] LCMS (System 1, Method D): m / z 278 / 280 (M+H) + (ES + At 2.13 minutes, the wavelength was 190-320nm.

[0549] To a solution of (400 mg, 1.44 mmol) methanol in DMF (5 mL), LiCl (152 mg, 3.6 mmol) was added, and the mixture was stirred in a microwave oven at 160 °C for 20 min. The reaction mixture was concentrated, and the residue was purified by rapid chromatography using a hexane solution of 0–100% ethyl acetate to give 2,4-dichloro-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazine (150 mg, 42%) as a white solid and 2,4-dichloro-6-(2-(hydroxymethyl)pyrrolo-1-yl)pyrimidino-5-ol (100 mg, 26%) as a white solid.

[0550] 2,4-Dichloro-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazine:

[0551] 1¹H NMR (500MHz, chloroform-d) δ 1.48–1.58 (m, 1H), 1.99–2.10 (m, 1H), 2.14–2.19 (m, 1H), 2.20–2.26 (m, 1H), 3.44–3.50 (m, 1H), 3.56–3.64 (m, 1H), 3.72–3.80 (m, 2H), 4.62–4.67 (m, 1H).

[0552] LCMS (System 1, Method D): m / z 246 / 248 (M+H) + (ES + At 2.20 minutes, the wavelength was 190-320nm.

[0553] 2,4-Dichloro-6-(2-(hydroxymethyl)pyrrolidone-1-yl)pyrimidin-5-ol:

[0554] LCMS (System 1, Method D): m / z 264 / 266 (M+H) + (ES + At 1.97 minutes, the wavelength was 190-320nm.

[0555] DIPEA (0.28 mL, 1.63 mmol) was added to a solution of 2,4-dichloro-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazine (200 mg, 0.813 mmol) and (R)-methyl(pyrrolidine-3-yl)carbamate tert-butyl ester (intermediate 4) (0.163 g, 0.813 mol) in 1,4-dioxane (4 mL), and the resulting mixture was stirred at 80 °C for 24 hours. The reaction mixture was concentrated and the residue was purified by rapid chromatography using a hexane solution of 0–60% ethyl acetate to give ((3R)-1-(2-chloro-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (252 mg, 75%) as a white solid.

[0556] LCMS (System 1, Method D): m / z 410 / 412 (M+H) + (ES + At 2.64 minutes, the wavelength was 190-320nm.

[0557] To a degassed solution of ((3R)-1-(2-chloro-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate (150 mg, 0.366 mmol) and tert-butyl carbamate (42.9 mg, 0.366 mmol) in 1,4-dioxane (4 mL), Cs₂CO₃ (0.477 g, 1.46 mol), tris(dibenzylideneacetone)dipalladium(O) (CAS: 51364-51-3) (21.0 mg, 0.0365 mmol) and XPhos (CAS: 564483-18-7) (34.9 mg, 0.0732 mmol) were added. The solution was degassed with N₂ and stirred at 80 °C for 18 hours. The mixture of ((3R)-1-(2-((tert-butoxycarbonyl)amino)-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester and ((3R)-1-(2-amino-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester was observed by LCMS. The reaction mixture was filtered under vacuum on a Celite bed, the residue was washed with ethyl acetate, and the filtrate was concentrated to give a mixture of the two products as a yellow oil, which was used directly for the next step without any purification.

[0558] LCMS (System 1, Method D): m / z 491 (M+H) + (ES + At 2.11 minutes, the wavelength was 190-320nm.

[0559] LCMS (System 1, Method D): m / z 391(M+H) + (ES + At 1.91 minutes, the wavelength was 190-320nm.

[0560] The yellow oily substance from the above steps was dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and then concentrated to dryness. The residue was purified by reversed-phase column chromatography (C-18, isocratic 5:95, MeCN: 10 mM ammonium bicarbonate aqueous solution, pH 10) to give 4-((R)-3-(methylamino)pyrrolidine-1-yl)-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazine-2-amine as a white solid, Examples 1-21 (21 mg, 20%, two steps).

[0561] The data for Examples 1-21 are shown in Table 3.

[0562] Route H

[0563] A typical procedure for preparing fused pyrimidines, such as the preparation of Example 7-1, (R)-1-((R)-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine

[0564]

[0565] 20% Pd(OH)₂ / C (15.1 mg, 10 mol% Pd) was placed in a 25 mL flask. The atmosphere was purged with N₂, and then a solution of (R)-4-((R)-3-((tert-butyloxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-chloro-7-isopropyl-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (intermediate 41) (110 mg, 0.215 mmol) in EtOH (2.1 mL) was added, followed by ammonium formate (135 mg, 2.15 mmol). The reaction mixture was refluxed and heated for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad, and the residue was washed several times with MeOH. The filtrate was concentrated under reduced pressure to give (R)-4-((R)-3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-7-isopropyl-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (103 mg, 100%) as a white solid, which could be used directly in the next step without further purification.

[0566] LCMS (System 1, Method D): m / z 478 (M+H) + (ES + At 2.22 minutes, the wavelength was 190-320nm.

[0567] TFA (1.00 mL) was added to a solution of (R)-4-((R)-3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-7-isopropyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (103 mg, 0.216 mmol) in DCM (1.00 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to dryness, and the residue was purified by purification method E to give (R)-1-((R)-7-isopropyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine-4-yl)-N-methylpyrrolidine-3-amine as a white foam, Example 7-1 (43 mg, 72%).

[0568] The data for Example 7-1 are shown in Table 3.

[0569] Route I

[0570] Typical procedures for preparing fused pyrimidines, such as those in Examples 7-2, include (R)-1-((R)-7-cyclopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine.

[0571]

[0572] 10% Pd / C catalyst (50 mg) was added to (R)-4-((R)-3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2-chloro-7-cyclopropyl-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (intermediate 42) (270 mg, 0.530 mmol) in a solution of MeOH (20 mL), and the resulting mixture was stirred at room temperature under H2 (1 atm) for 8 hours. The reaction mixture was then filtered through a Celite bed, and the residue was washed with MeOH. The filtrate was concentrated under reduced pressure to give (R)-4-((R)-3-((tert-butyloxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-7-cyclopropyl-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (250 mg, 99%) as a brown solid, which was used directly for the next step without purification.

[0573] LCMS (System 4, Method C): m / z 476 (M+H) + (ES + At 4.84 minutes, 228nm.

[0574] (R)-4-((R)-3-((tert-Butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-7-cyclopropyl-6,7-dihydro-8H-pyrimidino[5,4-b][1,4]oxazine-8-carboxylic acid tert-butyl ester (250 mg, 0.526 mmol) was dissolved in DCM (5.00 mL), and TFA (5 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum, and the residue was treated with hexane (2 x 20 mL) and diethyl ether (2 x 10 mL) to obtain a crude product (150 mg). The crude product was purified by purification method F to obtain (R)-1-((R)-7-cyclopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-4-yl)-N-methylpyrrolidine-3-amine as a white solid, Example 7-2 (35 mg, 22%).

[0575] The data for Example 7-2 are shown in Table 3.

[0576] Route J

[0577] Typical procedures for preparing fused pyrimidines, such as those for preparing Example 10-1, (3R)-1-(7-isopropyl-2-methyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine

[0578]

[0579] ((3R)-1-(2-chloro-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (intermediate 30) (110 mg, 0.267 mmol), trimethylcycloboroxane (CAS: 823-96-1) (0.15 mL, 1.07 mmol), K2CO3 (74 mg, 0.534 mmol), and DME (5.80 mL) were placed in a vial. Then, [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (CAS: 72287-26-4) (20 mg, 0.027 mmol) was added, and the mixture was degassed with nitrogen for 15 minutes. The vial was sealed, and the mixture was heated at 100 °C for 18 hours. After cooling to room temperature, the mixture was filtered through a Celite pad and the residue was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient of hexane solutions of EtOAc (0-100%) to give ((3R)-1-(7-isopropyl-2-methyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (69 mg, 66%) as a colorless oil.

[0580] LCMS (System 1, Method D): m / z 392 (M+H) + (ES + At 2.02 minutes, the wavelength was 190-320nm.

[0581] TFA (1.00 mL) was added to a solution of ((3R)-1-(7-isopropyl-2-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-yl)(methyl)carbamate (61 mg, 0.156 mmol) in DCM (1.00 mL), and the reaction mixture was stirred at room temperature for 1 hour. After concentration to dryness, the residue was purified by purification method D to give (3R)-1-(7-isopropyl-2-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine as a white solid, Example 10-1 (35 mg, 77%).

[0582] The data for Example 10-1 are shown in Table 3.

[0583] Route K

[0584] Typical procedures for preparing fused pyrimidines, such as those used in Examples 11-10, include (S)-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,7a,8,9,10-hexahydropyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazapheno-2-amine.

[0585]

[0586] To a THF (15.5 mL) solution of 2,4,6-trichloropyrimidin-5-ol (intermediate 2) (550 mg, 2.76 mmol) and (S)-2-(2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 66) (1.19 g, 5.52 mmol) cooled to 0 °C, Ph3P (1.09 g, 4.14 mmol) and DIAD (0.815 mL, 4.14 mol) were added, and the reaction mixture was stirred at room temperature for 3 hours. THF was then removed by concentration under reduced pressure and silica was added. The residue was purified by silica gel chromatography (dry pack) using a gradient of EtOAc (0–50%) in hexane to give (S)-2-(2-((2,4,6-trichloropyrimidin-5-yl)oxy)ethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (844 mg, 77%) as a colorless oil.

[0587] 1 ¹H NMR (400MHz, chloroform-d) δ 1.45 (s, 9H), 1.75–1.83 (m, 1H), 1.83–1.97 (m, 3H), 1.99–2.11 (m, 1H), 2.25–2.36 (m, 1H), 3.26–3.48 (m, 2H), 3.95–4.06 (m, 1H), 4.07–4.23 (m, 2H).

[0588] DIPEA (1.08 mL, 6.2 mmol) was added to a solution of (S)-2-(2-((2,4,6-trichloropyrimidin-5-yl)oxy)ethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (820 mg, 2.07 mmol) and (R)-methyl(pyrrolidine-3-yl)carbamate tert-butyl ester (intermediate 4) (414 mg, 2.07 mmol) in 1,4-dioxane (4.73 mL), and the reaction mixture was heated at 80 °C for 3 hours. The mixture was then diluted with water, and the aqueous layer was extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dry pack) using a gradient of hexane solutions of EtOAc (0–80%) to give (S)-2-(2-((4-(((R)-3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2,6-dichloropyrimidin-5-yl)oxy)ethyl)pyrrolidine-2-carboxylic acid tert-butyl ester (1.07 g, 92%) as a colorless oil.

[0589] LCMS (System 1, Method D): m / z 560 / 562 (M+H) + (ES + At 2.39 minutes, the wavelength was 190-320nm.

[0590] TFA (8.00 mL) was added to a solution of (S)-2-(2-((4-((R)-3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)-2,6-dichloropyrimidin-5-yl)oxy)ethyl)pyrrolidine-2-carboxylic acid tert-butyl ester (1.07 g, 1.91 mmol) in DCM (8.00 mL), and the reaction mixture was stirred at room temperature for 10 minutes. The mixture was then concentrated to dryness to provide a crude, yellow, oily (R)-1-(2,6-dichloro-5-(2-(((S)-pyrrolidine-2-yl)ethoxy)pyrimidin-4-yl)-N-methylpyrrolidine-3-amine di(trifluoroacetate), which was used directly in the next step without any purification.

[0591] LCMS (System 1, Method D): m / z 360 / 362 (M+H) + (ES + At 1.35 minutes, the wavelength was 190-320nm.

[0592] DIPEA (1.33 mL, 7.64 mmol) was added to a solution of crude (R)-1-(2,6-dichloro-5-(2-((S)-pyrrolidine-2-yl)ethoxy)pyrimidin-4-yl)-N-methylpyrrolidine-3-amine di(trifluoroacetate) (1.91 mmol) in 1,4-dioxane (5.1 mL), and the reaction mixture was heated at 80 °C for 18 hours. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dry pack) using DCM solutions with gradients of MeOH (0-30%) to give (R)-1-((S)-2-chloro-6,7,7a,8,9,10-hexahydropyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazono-4-yl)-N-methylpyrrolidine-3-amine (620 mg, 100%) as a light brown solid.

[0593] LCMS (System 1, Method D): m / z 324 / 326 (M+H) + (ES + At 1.86 minutes, the wavelength was 190-320nm.

[0594] To a solution of (R)-1-((S)-2-chloro-6,7,7a,8,9,10-hexahydropyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazopyro-4-yl)-N-methylpyrrolidine-3-amine (618 mg, 1.91 mmol) in THF (19.1 mL), di-tert-butyl dicarbonate (833 mg, 3.82 mmol), Et3N (0.567 mL, 4.2 mmol), and DMAP (117 mg, 0.954 mmol) were added, and the reaction mixture was stirred at room temperature for 18 hours. The mixture was then concentrated under reduced pressure, and silica was added. The residue was purified by silica gel chromatography (dry pack) of a hexane solution with gradients of EtOAc (0–70%) to give ((R)-1-((S)-2-chloro-6,7,7a,8,9,10-hexahydropyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazono-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (480 mg, 59%) as a colorless oil.

[0595] LCMS (System 1, Method D): m / z 424 / 426 (M+H) + (ES + At 2.27 minutes, the wavelength was 190-320nm.

[0596] To a degassed solution of ((R)-1-((S)-2-chloro-6,7,7a,8,9,10-hexahydropyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazono-4-yl)pyrrolidine-3-yl)(methyl)carbamate (480 mg, 1.13 mmol) and carbamate (199 mg, 1.7 mmol) in 1,4-dioxane (11.3 mL), Cs₂CO₃ (922 mg, 283 mmol), tris(dibenzylideneacetone)dipalladium(O) (CAS: 51364-51-3) (104 mg, 0.113 mmol) and XPhos (CAS: 564483-18-7) (216 mg, 0.453 mmol) were added, and the reaction mixture was heated at 110 °C for 3 hours. After cooling to room temperature, the mixture was filtered through a Celite pad, and the residue was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dry pack) using a gradient of hexane solutions of EtOAc (0–100%), followed by purification by reversed-phase column chromatography (C-18, isocratic 5:95, MeCN: 10 mM ammonium bicarbonate aqueous solution, pH 10) to give ((R)-1-((S)-2-((tert-butyloxycarbonyl)amino)-6,7,7a,8,9,10-hexahydropyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazono-4-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (291 mg, 51%) as a light brown solid.

[0597] LCMS (System 2, Method F): m / z 505 (M+H) + (ES + At 2.15 minutes, 254nm.

[0598] A solution of HCl in 1,4-dioxane (4M, 5.77 mL, 23.1 mmol) was added to a solution of ((R)-1-((S)-2-((tert-butyloxycarbonyl)amino)-6,7,7a,8,9,10-hexahydropyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazapheno-4-yl)pyrrolidine-3-yl)(methyl)carbamate (291 mg, 0.577 mmol) in 1,4-dioxane (5.77 mL), and the mixture was heated at 45 °C for 3 hours. After cooling to room temperature, the mixture was concentrated to dryness. The residue was diluted with water and purified by reversed-phase column chromatography (C-18, isocratic 5:95, MeCN:H2O), and then purified again by reversed-phase column chromatography (C-18, isocratic 5:95, MeCN: 10 mM ammonium bicarbonate aqueous solution, pH 10) to give (S)-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,7a,8,9,10-hexahydropyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazazepone-2-amine as a white solid, Examples 11-10 (85 mg, 48%).

[0599] The data for Examples 11-10 are shown in Table 3.

[0600] Table 2 - Intermediates

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620] Bioactivity

[0621] H4 antagonist functional cAMP Gi assay

[0622] HEKf cells were infected overnight with a baculovirus expressing the human H4 receptor, then centrifuged at 1,200 rpm for 5 min, frozen in cell freezing medium (Sigma), and stored at -150°C. On the day of assay, cells were thawed and resuspended in HBSS with 500 nM IBMX to achieve a density of 1,500 cells / well. H4 ligands were prepared in DMSO and stamped in low-volume plates at 25 nL using LabCyte ECHO acoustic assay. 10 μL / well of cells were plated in the presence of 1 μM trichomoniasis, centrifuged at 1,200 rpm for 1 min, and incubated for 30 min, then Cisbio cAMP assay reagent was added to a total volume of 20 μL / well. For antagonist assays, cells were pre-incubated with the H4 antagonist ligand for 30 min, followed by ECHO assay. 80 The concentration of histamine was increased and incubated for another 30 minutes. Subsequently, the assay reagent was added and the mixture was shaken at room temperature for 60 minutes. cAMP accumulation was then measured using HTRF on a PheraStar plate reader. EC was generated using a 4-parameter logistic fitting equation. 50 Affinity values ​​for functional antagonists were generated using the Cheng-Prusoff equation to quantify the potency of the agonist. pK values ​​were then calculated using antagonist assay data. b value.

[0623] H4 antagonist functional dynamic mass redistribution determination

[0624] HEKf cells were infected with a baculovirus expressing the human H4 receptor and seeded at a density of 10,000 cells / well in fibronectin-coated EPIC plates and incubated overnight at 37°C. The cell culture medium was then changed to 30 μL HBSS with 20 mM HEPES per well, and 30 nL DMSO was added to each well via LabCyte ECHO acoustic dispensing. After equilibration at room temperature for 2 hours, 30 nL of H4 ligand prepared in DMSO was flushed into the seeded EPIC plates via LabCyte ECHO acoustic dispensing, and cell dynamics were monitored for redistribution using a Corning EPIC plate reader. After 45 minutes of measurement, 30 nL / well of histamine EC was added. 80 And monitoring was conducted to obtain antagonist assay data. The maximum baseline-corrected response, expressed in pm, was used to generate concentration-response curves. EC was generated using a 4-parameter logistic fitting equation. 50 Affinity values ​​for functional antagonists were generated using the Cheng-Prusoff equation to quantify the potency of the agonist. pK values ​​were then calculated using antagonist assay data. b value.

[0625] hERG measurement

[0626] hERG measurement data were determined by Metrion Biosciences, Cambridge, UK using the experimental protocol detailed below:

[0627] Chinese hamster ovary (CHO) cell lines stably expressing the human ether-á-go-go-related gene were grown and passaged under standard culture conditions. Cells for assays were prepared using a dissociation protocol optimized for cell health, yield, and sealing and assay quality. Test samples were provided as a stock solution of 10 mM in 100% DMSO. All sample processing and serial dilutions were performed using glass containers and glass lined plates. The highest working concentration of 30 μM was prepared from the 10 mM sample stock solution by a 1:333 dilution to external recording solution (0.3% dimethyl sulfoxide v / v). In single-concentration assays, test samples were screened against at least three individual cells at 30 μM. (pIC) 50 During the assay, test samples were screened against at least three individual cells at 1 μM, 3 μM, 10 μM, and 30 μM. Each four-point concentration response curve was constructed using cumulative two-sample studies with each concentration added to the same cell.

[0628] All experiments were performed on the QPatch gigaseal automated patch-clamp platform. The composition of the external and internal recording solutions for QPatch experiments is shown in Table A below. All solutions were filtered (0.2 μm) prior to each experiment.

[0629]

[0630] Table A: Composition of external and internal solutions used in hERG studies (unit: mM)

[0631] All recordings were performed in a standard whole-cell configuration at room temperature (~21°C) using a standard single-well chip (Rchip 1.5–4 MΩ). Series resistances (4 MΩ to 15 MΩ) were compensated for >80%. Current was drawn from a holding potential of -90 mV using the industry-standard "+40 / -40" voltage protocol, as shown in Figure A below; this was applied at a stimulation frequency of 0.1 Hz.

[0632]

[0633] Figure A: Schematic diagram of the QPatch voltage scheme used for hERG measurements.

[0634] For whole-cell configuration, apply the vector (0.3% DMSO v / v in external recording solution) to each cell in two bolus additions, with a two-minute recording period between each addition to allow for stable recording. After the vector cycle is complete, perform one of the following steps:

[0635] i) For single-concentration assays – five bolus additions of each test concentration are performed at two-minute intervals, applying a single concentration of the test sample at 30 μM; or

[0636] ii) For pIC 50 Assay - Two bolus additions were performed at two-minute intervals for each test concentration, with the test sample applied at four concentrations from 1 μM to 30 μM;

[0637] The effect on the hERG tail current amplitude was then measured over a 4-minute recording period. For each scan of the voltage protocol, membrane currents and passive properties of individual cells were recorded using QPatch analysis software (version 5.0). The peak outward tail current amplitude induced during the test pulse to -40 mV was measured relative to the transient leakage current measured during the initial pre-pulse step to -40 mV. For QC purposes, the minimum current amplitude determined was a peak outward current >200 pA measured at the end of the vector cycle. The QPatch analysis software calculated the average peak current of the last three scans at the end of each concentration application cycle and exported the data to Excel, which was then queried using a bioinformatics suite developed in Pipeline Pilot (Biovia, USA). The template calculated the percentage of inhibition for each test concentration application cycle as a reduction in the average peak current or charge relative to the value measured at the end of the control (i.e., vector) cycle. Concentration-response curves were constructed using the percentage of inhibition values ​​from each cell, fitted with 4-parameter logistic fitting, where 0 and 100% inhibition levels were fixed at very low and very high concentrations, respectively, and a free Hill slope factor. Then measure IC 50 (50% inhibitory concentration) and Hill coefficient, but only data for cells with a Hill slope between 0.5 and 2.0 are included. The IC50 is reported below. 50 Data represent the average of at least three independent cells (N≥3). As a convention, test samples that fail to achieve >40% block size at the highest concentration will produce fuzzy IC values ​​due to poor or unconstrained fit. 50 Value. In this case, return any IC50 value that is 0.5 log units higher than the highest concentration tested. 50 Value. For example, if a sample fails to demonstrate an average inhibition of >40% blockade at the highest concentration of 30 μM, the reported IC50 value should be... 50 The value is 100 μM, i.e., pIC 50 ≤4.0.

[0638] The vast majority of examples have been prepared as a single enantiomer or a single diastereomer. However, some compounds have been prepared as mixtures of racemic or diastereomers, and occasionally these racemic and diastereomers are separated into single isomers using reversed-phase HPLC, chiral HPLC, or chiral SFC techniques. For these specific compounds, isomer allocation (isomer 1, isomer 2) is based on the retention time of the compound using the separation technique performed in the final isomer separation step. In other words, this can be the retention time of reversed-phase HPLC, chiral HPLC, or chiral SFC, and this will vary from compound to compound.

[0639] Table 4 - H4 and hERG activities

[0640]

[0641]

[0642]

[0643] 1 Changlu Liu et al,J Pharmacol Exp Ther.,299,(2001),121-130.

[0644] 2 Jennifer D.Venable et al,J.Med.Chem.,48,(2005),8289-8298.

[0645] 3 Brad M.Savall et al,J.Med.Chem.,57,(2014),2429-2439.

[0646] 4 Robin L Thurmond et al,Ann Pharmacol Pharm.,2,(2017),1-11.

[0647] 5 Charles E.Mowbray et al,Bioorg.Med.Chem.Lett.,21,(2011),6596–6602.

[0648] 6 Rogier A.Smits et al,Bioorg.Med.Chem.Lett.,23,(2013),2663–2670.

[0649] 7 Chan-Hee Park et al,J.Med.Chem.,61,(2018),2949-2961.

Claims

1. Compounds of formula (1) or their salts: in; Z is H, NH2, or C. 1-3 alkyl; Y is selected from the group consisting of the following groups: n is 0 or 1; R 1 It is H or C, which is optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 1 With R 3 Linked to form a 3- to 6-membered heterocyclic alkyl ring optionally substituted with 1 to 6 fluorine atoms; R 2 H is the arbitrarily substituted C. 1-6 Alkyl groups, optionally substituted C 3-6 Cycloalkyl or optionally substituted 3- to 6-membered heterocyclic groups, wherein the optional substituents are selected from OC. 1-3 Alkyl group or 1 to 6 fluorine atoms, or R 2 With R 3 Linked to form a 3- to 6-membered alkyl ring optionally substituted with 1 to 6 fluorine atoms; R 3 It is H or C, which is optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 3 With R 1 Linked to form a 3- to 6-membered heterocyclic alkyl ring optionally substituted with 1 to 6 fluorine atoms, or R 3 With R 2 Linked to form a 3- to 6-membered cycloalkyl ring optionally substituted with 1 to 6 fluorine atoms, or R 3 With R 4 Linked to form a 3- to 6-membered alkyl ring optionally substituted with 1 to 6 fluorine atoms; R 4 It is H or C, which is optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 4 With R 3 Linked to form a 3- to 6-membered alkyl ring optionally substituted with 1 to 6 fluorine atoms, or R 4 With R 5 Linked to form a 3- to 6-membered alkyl ring optionally substituted with 1 to 6 fluorine atoms; R 5 It is H or C, which is optionally substituted with 1 to 6 fluorine atoms. 1-3 Alkyl, or R 5 With R 4 Linked to form a 3- to 6-membered alkyl ring optionally substituted with 1 to 6 fluorine atoms; And R 6 It is H or methyl.

2. The compound according to claim 1, wherein it is a compound of formula (2a) or (2b) or a salt thereof:

3. The compound according to claim 2, wherein it is a compound of formula (3a) or (3b) or a salt thereof:

4. The compound according to claim 1, wherein it is a compound of formula (2c) or (2d) or a salt thereof:

5. The compound according to claim 1, wherein it is a compound of formula (2e) or a salt thereof:

6. The compound according to claim 5, wherein it is a compound of formula (3c) or a salt thereof:

7. The compound according to claim 1, wherein it is a compound of formula (4) or a salt thereof:

8. The compound according to claim 1, wherein Z is H, NH2 or methyl.

9. The compound according to claim 8, wherein Z is NH2.

10. The compound according to claim 1, wherein R 1 It's H.

11. The compound according to claim 1, wherein R 2 Choose from the group consisting of the following groups: H, methyl, ethyl, isopropyl, cyclopropyl, isobutyl, trifluoromethyl, CH2OMe, CH(CH3)OMe, C(CH3)2OMe and oxecyclobutyl.

12. The compound according to claim 11, wherein R 2 It is ethyl or isopropyl.

13. The compound according to claim 1, wherein R 3 It is H or methyl.

14. The compound according to claim 1, wherein R 2 It is ethyl, and R 3 It is a methyl group.

15. The compound according to claim 1, wherein R 4 It is H, methyl, ethyl, or isopropyl.

16. The compound according to claim 15, wherein R 4 It's H.

17. The compound according to claim 1, wherein n is 0.

18. The compound according to claim 1, wherein: (i) Z is H, NH2, or methyl; (ii)R 1 It is H; (iii)R 2 Choose from the group consisting of the following groups: H, methyl, ethyl, isopropyl, cyclopropyl, isobutyl, trifluoromethyl, CH2OMe, CH(CH3)OMe, C(CH3)2OMe and oxetyl; (iv)R 3 It is H or methyl; (v)R 4 It is H, methyl, ethyl, or isopropyl; (vi)n is 0; and Y, R 5 and R 6 As defined in claim 1.

19. The compound according to claim 1, wherein n is 1.

20. The compound according to claim 1, wherein: (i) Z is H, NH2, or methyl; (ii)R 1 It is H; (iii)R 2 Choose from the group consisting of the following groups: H, methyl, ethyl, isopropyl, cyclopropyl, isobutyl, trifluoromethyl, CH2OMe, CH(CH3)OMe, C(CH3)2OMe and oxetyl; (iv)R 3 It is H or methyl; (v)R 4 It is H, methyl, ethyl, or isopropyl; (vi)n is 1; and Y, R 5 and R 6 As defined in claim 1.

21. The compound according to claim 1, wherein the compound is selected from the group consisting of: (R)-4-(3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; 7-Methyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-ethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-isopropyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (S)-7-isopropyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-cyclopropyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; 7-Isobutyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; 4-((R)-3-(methylamino)pyrrolidone-1-yl)-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-(methoxymethyl)-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (S)-7-((R)-1-methoxyethyl)-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (S)-7-((S)-1-methoxyethyl)-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (S)-7-(2-methoxypropane-2-yl)-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; 4-((R)-3-(methylamino)pyrrolidine-1-yl)-7-(oxetane-3-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7,7-dimethyl-4-(3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; 6-Methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (6S,7R)-6,7-dimethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (6R,7R)-6,7-dimethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (6S,7S)-6,7-dimethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (6R,7S)-6,7-dimethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; 7-Isopropyl-8-methyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; 4-((R)-3-(methylamino)pyrrolidine-1-yl)-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazine-2-amine; (R)-6a-methyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazine-2-amine; (S)-6a-methyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazine-2-amine; (R)-4-((R)-3-aminopyrrolidone-1-yl)-7-ethyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-4-((R)-3-aminopyrrolidone-1-yl)-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; 4-((R)-3-aminopyrrolidone-1-yl)-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (S)-4-((R)-3-aminopyrrolidone-1-yl)-7-((R)-1-methoxyethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (S)-4-((R)-3-aminopyrrolidone-1-yl)-7-((S)-1-methoxyethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (S)-4-((R)-3-aminopyrrolidone-1-yl)-7-(2-methoxypropane-2-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-ethyl-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-isopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-cyclopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (S)-7-((R)-1-methoxyethyl)-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (S)-7-((S)-1-methoxyethyl)-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (S)-7-(2-methoxypropane-2-yl)-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-4-(3-aminoazacyclobutane-1-yl)-7-ethyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-4-(3-aminoazacyclobutane-1-yl)-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-Isopropyl-4-(4-methylpiperazin-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-Isopropyl-4-(piperazin-1-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine-2-amine; (R)-1-((R)-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine; (R)-1-((R)-7-cyclopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine; (3R)-1-(7-(methoxymethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine; (R)-1-((S)-7-((R)-1-methoxyethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine; (3R)-N-methyl-1-(6-methyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-amine; (R)-1-((R)-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-amine; (R)-1-((S)-7-((R)-1-methoxyethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-amine; (R)-1-(7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylazacyclobutane-3-amine; (3R)-1-(7-isopropyl-2-methyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)-N-methylpyrrolidine-3-amine; (R)-4-(3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; (R)-8-methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; (S)-8-methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; (R)-8-ethyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; (S)-8-isopropyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; (R)-8-isopropyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; 7-Methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; 7-Ethyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; 7-Isopropyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; (S)-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,7a,8,9,10-hexahydropyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazazepone-2-amine; (S)-4-((R)-3-aminopyrrolidone-1-yl)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; (R)-4-((R)-3-aminopyrrolidone-1-yl)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; (S)-8-isopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazapyro-2-amine; (R)-8-isopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazapyro-2-amine; (R)-1-((S)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazono-4-yl)-N-methylpyrrolidine-3-amine; (R)-1-((R)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazono-4-yl)-N-methylpyrrolidine-3-amine; 4-[(3R)-3-(methylamino)pyrrolidine-1-yl]-6a,7,8,9,9a,10-hexahydro-6H-cyclopentano[e]pyrimidino[5,4-b][1,4]oxazazepone-2-amine; 4-[(3R)-3-aminopyrrolidine-1-yl]-6a,7,8,9,9a,10-hexahydro-6H-cyclopentano[e]pyrimidino[5,4-b][1,4]oxazazepone-2-amine; 4-[3-(methylamino)azacyclobutane-1-yl]-6a,7,8,9,9a,10-hexahydro-6H-cyclopentano[e]pyrimidino[5,4-b][1,4]oxazapyro-2-amine; 4'-[(3R)-3-(methylamino)pyrrolidine-1-yl]-6'H,8'H-spiro[cyclobutane-1,7'-pyrimidino[5,4-b][1,4]oxazine]-2'-amine; 7,7-Dimethyl-4-[(3R)-3-(methylamino)pyrrolidine-1-yl]-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; 8-Ethyl-4-[3-(methylamino)azacyclobutane-1-yl]-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazapyro-2-amine; 4-[(3R)-3-aminopyrrolidone-1-yl]-8-ethyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; 8-Ethyl-4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; (3R)-1-(8-ethyl-8-methyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazono-4-yl)-N-methylpyrrolidine-3-amine; 8-Ethyl-8-methyl-4-[(3R)-3-(methylamino)pyrrolidine-1-yl]-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; 4'-[(3R)-3-(methylamino)pyrrolidine-1-yl]-6'H,8'H-spiro[cyclopentan-1,7'-pyrimidino[5,4-b][1,4]oxazine]-2'-amine; (3R)-N-methyl-1-(6'H,8'H-spiro[cyclopentan-1,7'-pyrimido[5,4-b][1,4]oxazine]-4'-yl)pyrrolidine-3-amine; (3R)-1-(3,3-difluoro-6'H,8'H-spiro[cyclobutane-1,7'-pyrimido[5,4-b][1,4]oxazine]-4'-yl)-N-methylpyrrolidine-3-amine; 7-Ethyl-7-methyl-4-[(3R)-3-(methylamino)pyrrolidine-1-yl]-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; 3,3-Difluoro-4'-[(3R)-3-(methylamino)pyrrolidine-1-yl]-6'H,8'H-spiro[cyclobutane-1,7'-pyrimidino[5,4-b][1,4]oxazine]-2'-amine.

22. The compound of claim 21, wherein the compound is selected from the group consisting of: (R)-4-(3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-ethyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-isopropyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; 4-((R)-3-(methylamino)pyrrolidone-1-yl)-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-(methoxymethyl)-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (S)-7-((R)-1-methoxyethyl)-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (S)-7-(2-methoxypropane-2-yl)-4-((R)-3-(methylamino)pyrrolidine-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7,7-dimethyl-4-(3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; 6-Methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; 4-((R)-3-(methylamino)pyrrolidine-1-yl)-6a,7,8,9-tetrahydro-6H-pyrimidino[5,4-b]pyrrolo[1,2-d][1,4]oxazine-2-amine; (R)-4-((R)-3-aminopyrrolidone-1-yl)-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; 4-((R)-3-aminopyrrolidone-1-yl)-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-isopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (S)-7-((R)-1-methoxyethyl)-4-(3-(methylamino)azacyclobutane-1-yl)-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazine-2-amine; (R)-7-Isopropyl-4-(piperazin-1-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine-2-amine; (R)-1-((R)-7-isopropyl-7,8-dihydro-6H-pyrimidino[5,4-b][1,4]oxazin-4-yl)pyrrolidine-3-amine; (R)-8-methyl-4-((R)-3-(methylamino)pyrrolidone-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; (S)-8-isopropyl-4-((R)-3-(methylamino)pyrrolidine-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; (S)-4-((R)-3-aminopyrrolidone-1-yl)-8-isopropyl-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine; (S)-8-isopropyl-4-(3-(methylamino)azacyclobutane-1-yl)-6,7,8,9-tetrahydropyrimidino[5,4-b][1,4]oxazazepone-2-amine.

23. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 22 and a pharmaceutically acceptable excipient.

24. Use of the compound according to any one of claims 1 to 22 or the composition according to claim 23 in the preparation of a medicament for treating a disease or condition associated with H4 receptor antagonism.

25. Use of the compound according to any one of claims 1 to 22 or the composition according to claim 23 in the preparation of a medicament for treating an inflammatory condition, said inflammatory condition comprising: Asthma, chronic itching, dermatitis, rheumatoid arthritis, gastric ulcers, and colitis.

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