3-(1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one derivatives useful as factor XIA inhibitors

Abstract

The present invention relates to 3-(1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindole-5(1H)-one derivatives, stereoisomers, isotopologues and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds, and uses of the compounds in treating and / or preventing thromboembolic disorders, inflammatory disorders and diseases or conditions involving plasma kallikrein activity.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 054,826, filed July 22, 2020, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention relates to 3-(1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindole-5(1H)-one derivatives, stereoisomers, isotopomers and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds, and use of the compounds in treating and / or preventing thromboembolic disorders, inflammatory disorders and diseases or conditions involving plasma kallikrein activity. Background Art

[0004] Although anticoagulants such as warfarin are available Heparin, low molecular weight heparin (LMWH), and synthetic pentasaccharides, as well as antiplatelet agents such as aspirin and clopidogrel But thromboembolic disease is still the main cause of death of residents in developed countries. Oral anticoagulant warfarin suppresses the post-translational maturation of coagulation factors VII, IX, X and prothrombin, and has been shown to be effective in both venous thrombosis and arterial thrombosis. However, due to its narrow therapeutic index in terms of bleeding safety, the slow onset of therapeutic effect, diet and drug-drug interaction are numerous and need monitoring and dosage adjustment, so its use is restricted. The oral anticoagulant of novel direct targeting thrombin or factor Xa, such as dabigatran (dabigatran), apixaban (apixaban), betrixaban (betrixaban), edoxaban (edoxaban), rivaroxaban (rivaroxaban), has been approved for venous and arterial indications. However, the risk of bleeding is not completely eliminated, and in patients with atrial fibrillation, can be up to 2% to 3% (Quan et al., J.Med.Chem., 2018, 7425-7447 pages, volume 61) per year. Therefore, the discovery and development of safe and effective oral anticoagulants with minimal impact on hemostasis for the prevention and treatment of a wide range of thromboembolic disorders has become increasingly important. Summary of the Invention

[0005] The present invention relates to compounds of formula (I)

[0006]

[0007] in

[0008] R 1 Selected from the group consisting of halogen, hydroxyl, C1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, cyano, nitro, -NR A R B 、-C(O)-C 1-4 Alkyl, C3-6 cycloalkyl, phenyl and 5- to 6-membered heterocyclic group;

[0009] Among them C 3-6 Cycloalkyl, phenyl or 5- to 6-membered heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, -C(O)OH, -C(O)O-(C 1-4 Alkyl), -NR A R B 、-(C 1-4 Alkyl)-NR A R B 、C 3-7 cycloalkyl and 5 to 6 membered heterocyclyl; and wherein RA and R B are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0010] a is an integer from 0 to 3;

[0011] Each R 2 independently selected from the group consisting of chloro, fluoro, methyl, and methoxy;

[0012] R A and R B are each independently selected from the group consisting of hydrogen and halogen; alternatively, R A and R B Together with the carbon atom to which they are attached, they form an oxo group;

[0013] R C Selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0014] R D Selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 1-4 alkoxy;

[0015] R E Selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0016] Q is selected from the group consisting of:

[0017]

[0018] in

[0019] R 4 Selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0020] R 5 Selected from the group consisting of hydrogen, halogen and C 1-4 alkyl;

[0021] selected from the group consisting of phenyl, 5-6 membered heteroaryl and 9 to 10 membered heterocyclyl;

[0022] b is an integer from 0 to 1;

[0023] R 6 Select from the group consisting of: C 3-8 Cycloalkyl, -O-(C 1-2 Alkylene)-C 3-8 Cycloalkyl, -C(O)-(C 3-8 Cycloalkyl), -NH-(C 3-8 Cycloalkyl), -NH-C(O)-(C 3-8 Cycloalkyl), -C(O)-NH-(C 3-8 Cycloalkyl), 4-6 membered heterocycloalkyl, -O-(C 1-2 alkylene)-(4-6 membered heterocycloalkyl), -C(O)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(O)-NH-(4-6 membered heterocycloalkyl), -NH-C(O)-(4-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -O-(C 1-2 alkylene)-(5-6 membered heteroaryl), -C(O)-(5-6 membered heteroaryl), -NH-(5-6 membered heteroaryl), -NH-C(O)-(5-6 membered heteroaryl), -C(O)-NH-(5-6 membered heteroaryl), 2-oxa-6-azaspiro[3.3]hept-6-yl, 6-oxa-2-azaspiro[3.4]oct-2-yl and 7-oxa-2-azaspiro[3.5]non-2-yl;

[0024] Among them C 3-8 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, whether alone or as part of a substituent group, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-4 Alkyl, hydroxy, oxo, cyano and NR P RQ ; where R P and R Q are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0025] c is an integer from 0 to 3;

[0026] Each R 7 independently selected from the group consisting of halogen, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxy substituted C 1-6 Alkyl, hydroxy substituted fluorinated C 1-2 Alkyl, cyano substituted C 1-2 Alkyl, C 1-4 Alkoxy, fluorinated C 1-2 Alkoxy, hydroxy substituted C 1-4 Alkoxy, -(C 1-2 Alkylene)-O-(C 1-4 alkyl), oxo, -C(O)OH, -C(O)O-(C 1-2 Alkyl), -NR K R L 、-NR K -(hydroxy substituted C 1-4 Alkyl), -NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -C(O)-NR K R L 、-C(O)-NR K -O-(C 1-4 Alkyl), -C(O)-NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -(C 1-2 Alkylene)-C(O)-NR K R L 、-NR K -C(O)-(C 1-4 Alkyl), -NR K -C(O)-(fluorinated C 1-2 Alkyl), -NR K -C(O)O-(C 1-4 Alkyl), -NR K -C(O)-C 3-6 Cycloalkyl, -(C 1-2 Alkylene)-NR K -C(O)-(C 1-4 Alkyl), -(C 1-2 Alkylene)-NRK -C(O)O-(C 1-4 Alkyl), -(C 1-2 Alkylene)-OC(O)-(amino substituted C 1-4 Alkyl), -NR K -SO2-(C 1-4 Alkyl), -C(O)-NR K -SO2-(C 1-2 Alkyl), -(C 1-2 Alkylene)-OP(O)(OH)2 and -(C 1-2 Alkylene)-O-(C 1-2 Alkylene)-P(O)(OH)2; wherein R K and R L are each independently selected from hydrogen and C 1-4 alkyl;

[0027] And as When the heterocyclyl, heteroaryl or heterocycloalkyl group present in any part of the group contains a nitrogen atom, the heterocyclyl, heteroaryl or heterocycloalkyl group may be further substituted to form an N-oxide;

[0028] The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and both R 2 When the group is 2-fluoro and 3-chloro, then Q is not

[0029] and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts.

[0030] The present invention also relates to compounds of formula (II)

[0031]

[0032] Also known as (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-8a-methyl-2,3,8,8a-tetrahydroindole-5(1H)-one; and its tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts.

[0033] The present invention also relates to compounds of formula (III)

[0034]

[0035] Also known as (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)hexahydroindole-5(1H)-one; and its tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts.

[0036] The present invention also relates to compounds of formula (IV)

[0037]

[0038] Also known as (3S,7R,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)hexahydroindole-5(1H)-one; and its tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts.

[0039] The present invention also relates to methods for preparing compounds of formula (I), compounds of formula (II), compounds of formula (III), and compounds of formula (IV). The present invention also relates to compounds of formula (I), compounds of formula (II), compounds of formula (III), or compounds of formula (IV) prepared according to any of the methods described herein.

[0040] Illustrated in the present invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV) as described herein. Illustrated in the present invention are pharmaceutical compositions prepared by mixing a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV) as described herein with a pharmaceutically acceptable carrier. Illustrated in the present invention are methods of preparing pharmaceutical compositions comprising mixing a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV) as described herein with a pharmaceutically acceptable carrier.

[0041] Demonstrated herein are methods for treating and / or preventing thromboembolic disorders, inflammatory disorders, or diseases or conditions in which plasma kallikrein activity is implicated, as described herein, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

[0042] The present invention discloses a method for treating and / or preventing thromboembolic disorders such as arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. Examples of thromboembolic disorders include, but are not limited to, unstable angina, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by medical implants, devices, or procedures in which blood is exposed to artificial surfaces that promote thrombosis.

[0043] In one embodiment, the present invention relates to a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV) for use as a medicament. In another embodiment, the present invention relates to a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV) for use in the treatment and / or prevention of thromboembolic disorders, inflammatory disorders, or diseases or conditions in which plasma kallikrein activity is involved.

[0044] In another embodiment, the present invention relates to a compound of formula (I), a compound of formula (II), a compound of formula (III) or a compound of formula (IV) for use in the treatment and / or prevention of thromboembolic disorders such as arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders and venous cerebrovascular thromboembolic disorders. In another embodiment, the present invention relates to a compound of formula (I), a compound of formula (II), a compound of formula (III) or a compound of formula (IV) for use in the treatment and / or prevention of a thromboembolic disorder selected from the group consisting of unstable angina, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism and thrombosis caused by medical implants, devices or surgeries in which blood is exposed to artificial surfaces that promote thrombosis. In another embodiment, the present invention relates to a compound of formula (I), a compound of formula (II), a compound of formula (III) or a compound of formula (IV) for use in the treatment and / or prevention of a thromboembolic disorder selected from the group consisting of hereditary angioedema (HAE) and diabetic macular edema (DME).

[0045] In another embodiment, the present invention relates to a composition comprising a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV) for use in treating and / or preventing disorders, diseases, or conditions as described herein. In another embodiment, the present invention relates to a composition comprising a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV) for use in treating and / or preventing thromboembolic disorders and inflammatory disorders, or diseases or conditions in which plasma kallikrein activity is involved.

[0046] In another embodiment, the present invention relates to a composition comprising a compound of formula (I), a compound of formula (II), a compound of formula (III) or a compound of formula (IV) for use in the treatment and / or prevention of thromboembolic disorders such as arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders and venous cerebrovascular thromboembolic disorders. In another embodiment, the present invention is directed to a composition comprising a compound of formula (I), a compound of formula (II), a compound of formula (III) or a compound of formula (IV) for use in the treatment and / or prevention of a thromboembolic disorder selected from the group consisting of unstable angina, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism and thrombosis caused by medical implants, devices or surgeries in which blood is exposed to artificial surfaces that promote thrombosis. In another embodiment, the present invention is directed to a composition comprising a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV) for use in the treatment and / or prevention of thromboembolic disorders such as hereditary angioedema (HAE) or diabetic macular edema (DME).

[0047] Another illustration of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating and / or preventing a disorder, disease, or condition as described herein. Another illustration of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating and / or preventing a thromboembolic disorder, an inflammatory disorder, or a disease or condition in which plasma kallikrein activity is implicated.

[0048] Another illustration of the invention is the use of any of the compounds described herein in the preparation of a medicament for the treatment and / or prevention of a thromboembolic disorder selected from the group consisting of: (a) arterial cardiovascular thromboembolic disorders, (b) venous cardiovascular thromboembolic disorders, (c) arterial cerebrovascular thromboembolic disorders, and (d) venous cerebrovascular thromboembolic disorders. Another illustration of the invention is the use of any of the compounds described herein in the preparation of a medicament for the treatment and / or prevention of (a) unstable angina, (b) acute coronary syndrome, (c) atrial fibrillation, (d) first myocardial infarction, (e) recurrent myocardial infarction, (f) sudden ischemic death, (g) transient ischemic attack, (h) stroke, (i) atherosclerosis, (j) peripheral occlusive arterial disease, (k) venous thrombosis, (i) deep vein thrombosis, (m) thrombophlebitis, (n) arterial embolism, (o) coronary thrombosis, (p) cerebral artery thrombosis, (q) cerebral embolism, (r) renal embolism, (s) pulmonary embolism, or (t) thrombosis caused by a medical implant, device, or procedure in which blood is exposed to an artificial surface that promotes thrombosis. Another illustration of the invention is the use of any of the compounds described herein in the preparation of a medicament for the treatment and / or prevention of: (a) hereditary angioedema (HAE) or (b) diabetic macular edema (DME).

[0049] Another illustration of the invention is the use of any of the compounds described herein for use in a method of treating thromboembolism, inflammation, or a disease or condition in which plasma kallikrein activity is implicated as described herein in a subject in need thereof.

[0050] Another illustration of the invention is the use of any of the compounds described herein for use in a method of treating and / or preventing (a) arterial cardiovascular thromboembolic disorder, (b) venous cardiovascular thromboembolic disorder, (c) arterial cerebrovascular thromboembolic disorder, or (d) venous cerebrovascular thromboembolic disorder in a subject in need thereof. Another illustration of the invention is the use of any of the compounds described herein for use in a method of treating and / or preventing (a) unstable angina, (b) acute coronary syndrome, (c) atrial fibrillation, (d) first myocardial infarction, (e) recurrent myocardial infarction, (f) sudden ischemic death, (g) transient ischemic attack, (h) stroke, (i) atherosclerosis, (j) peripheral occlusive arterial disease, (k) venous thrombosis, (i) deep vein thrombosis, (m) thrombophlebitis, (n) arterial embolism, (o) coronary thrombosis, (p) cerebral artery thrombosis, (q) cerebral embolism, (r) renal embolism, (s) pulmonary embolism, or (t) thrombosis caused by a medical implant, device, or procedure in which blood is exposed to an artificial surface that promotes thrombosis. Another illustration of the invention is the use of any of the compounds described herein for use in a method of treating and / or preventing (a) hereditary angioedema (HAE) or (b) diabetic macular edema (DME) in a subject in need thereof.

[0051] In another example, the present invention relates to a compound as described herein for use in a method of treating and / or preventing a disorder, disease or condition as described herein in a subject in need thereof. In another example, the present invention relates to a compound as described herein for use in a method of treating and / or preventing a thromboembolic disorder, an inflammatory disorder, or a disease or condition in which plasma kallikrein activity is involved as described herein in a subject in need thereof.

[0052] In another example, the present invention relates to a compound as described herein for use in a method of treating and / or preventing thromboembolic disorders such as arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders in a subject in need thereof. In another example, the present invention relates to a compound as described herein for use in a method of treating and / or preventing the following diseases in a subject in need thereof: unstable angina, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by medical implants, devices, or surgeries in which blood is exposed to artificial surfaces that promote thrombosis. In another example, the invention relates to a compound as described herein for use in a method of treating and / or preventing hereditary angioedema (HAE) or diabetic macular edema (DME) in a subject in need thereof.

[0053] The present invention also relates to compounds, compositions (eg, pharmaceutical compositions), methods of treatment, methods of preparation, or uses as described herein. DETAILED DESCRIPTION

[0054] 1.3-(1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindole-5(1H)-one derivatives

[0055] Factor XIa is a plasma serine protease involved in regulating blood coagulation. While blood coagulation is an essential and crucial component of biological homeostasis, abnormal blood coagulation can also have harmful effects. For example, thrombosis refers to the formation or presence of a blood clot within a blood vessel or chamber of the heart. Such a clot can become lodged in a blood vessel, obstructing circulation and causing a heart attack or stroke. Thromboembolic disorders are a leading cause of death and disability in the industrialized world.

[0056] Blood coagulation is the blood flow control process necessary for mammals to survive. After vascular injury, coagulation begins and the process of subsequent dissolution of clots occurs after wound healing, and the process can be divided into four stages. The first stage, vasoconstriction (vasoconstriction / vasocontraction), can cause a reduction in blood loss in the injured area. In the next stage, platelets are activated by thrombin, and platelets adhere to the vascular wall injury site and form platelet aggregates. In the third stage, the formation of coagulation complexes causes a large amount of formation of thrombin, which converts soluble fibrinogen into fibrin by cutting two small peptides. In the fourth stage, after wound healing, thrombus is dissolved by the action of the key enzyme (i.e. plasmin) of the endogenous fibrinolytic system.

[0057] Two alternative pathways (i.e., the intrinsic pathway and the extrinsic pathway) can lead to the formation of fibrin clots. These pathways are triggered by different mechanisms, but in the later stages they converge to form the common final pathway of the coagulation cascade. In this final coagulation pathway, coagulation factor X is activated. Activated factor X is responsible for forming thrombin from the inactive precursor prothrombin circulating in the blood. Forming thrombi at the bottom of the abnormal vascular wall without trauma is the result of the intrinsic pathway. The fibrin clot formation as a response to tissue damage or injury is the result of the extrinsic pathway. Both pathways contain relatively large amounts of proteins, which are referred to as coagulation factors. The intrinsic pathway requires coagulation factors V, VIII, Ix, X, XI and XII and prokallikrein, high molecular weight kininogen, calcium ions and phospholipids from platelets.

[0058] Factor XIa, a plasma serine protease involved in the regulation of blood coagulation, is triggered in vivo by the binding of tissue factor (TF) to factor VII (FVII), resulting in the production of factor VIIa (FVIIa). The resulting TF:FVIIa complex activates factor IX (FIX) and factor X (FX), leading to the production of factor Xa (FXa). The generated FXa catalyzes the conversion of prothrombin to small amounts of thrombin before the pathway is shut down by tissue factor pathway inhibitor (TFPI). The coagulation process is then further propagated through feedback activation of factors V, VIII, and XI by catalytic amounts of thrombin. (Gailani, D. et al., Arterioscler. Thromb. Vasc. Biol., Vol. 27: pp. 2507-2513 (2007)). The resulting thrombin burst converts fibrinogen into fibrin, which polymerizes to form the structural framework of the blood clot and activates platelets, which are key cellular components of blood coagulation (Hoffman, M., Blood Reviews, Vol. 17: pp. S1-S5 (2003)). Factor XIa plays a key role in propagating this amplification loop. Epidemiological studies have shown that increased levels of circulating FXI in humans are associated with an increased risk of venous and arterial thrombosis, including stroke (see Quan et al., supra). In contrast, patients with congenital FXI deficiency (hemophilia C) are protected from ischemic stroke and venous thromboembolism. Therefore, factor XIa is an attractive target for antithrombotic therapy.

[0059] Except stimulating via tissue factor, coagulation system specifically can be activated on negatively charged surface, and these surfaces not only comprise the surface structure of foreign cells (such as bacteria), but also comprise artificial surface such as artificial blood vessels, stent and extracorporeal circulation.On this surface, initial factor XII (FXII) is activated to factor XIIa, and this factor XIIa is activated to factor XIa with the factor XI attached to cell surface subsequently.This causes the further activation of coagulation cascade as mentioned above.In addition, factor XIIa also activates the plasma kallikrein combined with plasma kallikrein (PK), and this plasma kallikrein causes further factor XII activation in the enhancing loop, causes the amplification that coagulation cascade starts generally.In addition, PK is a kind of important bradykinin releasing protease, and it causes endothelial permeability to increase.Other substrates described are prorenin and prourokinase, and their activation can affect the regulatory process of renin-angiotensin system and fibrinolysis.Therefore, the activation of PK is the important connection between coagulation process and inflammatory process.

[0060] The present invention relates to compounds of formula (I)

[0061]

[0062] Among them, a, R 1 、R 2 、R A 、R B 、R C 、R D 、R E , Q, etc. are as described herein; and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts. The present invention also relates to compounds of formula (II):

[0063]

[0064] and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts. The present invention also relates to compounds of formula (III)

[0065]

[0066] and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts. The present invention also relates to compounds of formula (IV)

[0067]

[0068] and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts. The compounds of formula (I), formula (II), formula (III) and formula (IV) of the present invention can be used to treat and / or prevent thromboembolic disorders, inflammatory disorders and diseases or conditions in which plasma kallikrein activity is involved.

[0069] Implementation Plan

[0070] In some embodiments, the present invention relates to compounds of formula (I) having formula (IA)

[0071]

[0072] in

[0073] R 1 Selected from the group consisting of halogen, hydroxyl, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, cyano, nitro, -NR A R B 、-C(O)-C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl and 5- to 6-membered heterocyclic groups;

[0074] Among them C 3-6 Cycloalkyl, phenyl or 5- to 6-membered heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, -C(O)OH, -C(O)O-(C 1-4 Alkyl), -NR A R B 、-(C 1-4 Alkyl)-NR A R B 、C 3-7 cycloalkyl and 5 to 6 membered heterocyclyl; and wherein R A and R B are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0075] a is an integer from 0 to 3;

[0076] Each R 2 independently selected from the group consisting of chloro, fluoro, methyl, and methoxy;

[0077] R A and R B are each independently selected from the group consisting of hydrogen and halogen; alternatively, R A and R B Together with the carbon atom to which they are attached, they form an oxo group;

[0078] R C Selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0079] R D Selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 1-4 alkoxy;

[0080] R E Selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0081] Q is selected from the group consisting of:

[0082]

[0083] in

[0084] R 4 Selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0085] R 5 Selected from the group consisting of hydrogen, halogen and C 1-4 alkyl;

[0086] selected from the group consisting of phenyl, 5-6 membered heteroaryl and 9 to 10 membered heterocyclyl;

[0087] b is an integer from 0 to 1;

[0088] R 6 Select from the group consisting of: C 3-8 Cycloalkyl, -O-(C 1-2 Alkylene)-C 3-8 Cycloalkyl, -C(O)-(C 3-8 Cycloalkyl), -NH-(C 3-8 Cycloalkyl), -NH-C(O)-(C 3-8 Cycloalkyl), -C(O)-NH-(C 3-8 Cycloalkyl), 4-6 membered heterocycloalkyl, -O-(C 1-2alkylene)-(4-6 membered heterocycloalkyl), -C(O)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(O)-NH-(4-6 membered heterocycloalkyl), -NH-C(O)-(4-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -O-(C 1-2 alkylene)-(5-6 membered heteroaryl), -C(O)-(5-6 membered heteroaryl), -NH-(5-6 membered heteroaryl), -NH-C(O)-(5-6 membered heteroaryl), -C(O)-NH-(5-6 membered heteroaryl), 2-oxa-6-azaspiro[3.3]hept-6-yl, 6-oxa-2-azaspiro[3.4]oct-2-yl and 7-oxa-2-azaspiro[3.5]non-2-yl;

[0089] Among them C 3-8 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, whether alone or as part of a substituent group, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-4 Alkyl, hydroxy, oxo, cyano and NR P R Q ; where R P and R Q are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0090] c is an integer from 0 to 3;

[0091] Each R 7 independently selected from the group consisting of halogen, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxy substituted C 1-6 Alkyl, hydroxy substituted fluorinated C 1-2 Alkyl, cyano substituted C 1-2 Alkyl, C 1-4 Alkoxy, fluorinated C 1-2 Alkoxy, hydroxy substituted C 1-4 Alkoxy, -(C 1-2 Alkylene)-O-(C 1-4 alkyl), oxo, -C(O)OH, -C(O)O-(C 1-2 Alkyl), -NR K R L 、-NR K -(hydroxy substituted C 1-4 Alkyl), -NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -C(O)-NR K RL 、-C(O)-NR K -O-(C 1-4 Alkyl), -C(O)-NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -(C 1-2 Alkylene)-C(O)-NR K R L 、-NR K -C(O)-(C 1-4 Alkyl), -NR K -C(O)-(fluorinated C 1-2 Alkyl), -NR K -C(O)O-(C 1-4 Alkyl), -NR K -C(O)-C 3-6 Cycloalkyl, -(C 1-2 Alkylene)-NR K -C(O)-(C 1-4 Alkyl), -(C 1-2 Alkylene)-NR K -C(O)O-(C 1-4 Alkyl), -(C 1-2 Alkylene)-OC(O)-(amino substituted C 1-4 Alkyl), -NR K -SO2-(C 1-4 Alkyl), -C(O)-NR K -SO2-(C 1-2 Alkyl), -(C 1-2 Alkylene)-OP(O)(OH)2 and -(C 1-2 Alkylene)-O-(C 1-2 Alkylene)-P(O)(OH)2; wherein R K and R L are each independently selected from hydrogen and C 1-4 alkyl;

[0092] And as When the heterocyclyl, heteroaryl or heterocycloalkyl group present in any part of the group contains a nitrogen atom, the heterocyclyl, heteroaryl or heterocycloalkyl group may be further substituted to form an N-oxide;

[0093] The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and both R 2 When the group is 2-fluoro and 3-chloro, then Q is not

[0094] and their stereoisomers, isotopomers and pharmaceutically acceptable salts. In some embodiments, the present invention relates to a compound of formula (I) having formula (IB)

[0095]

[0096] in

[0097] R 1 Selected from the group consisting of halogen, hydroxyl, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, cyano, nitro, -NR A R B 、-C(O)-C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl and 5- to 6-membered heterocyclic groups;

[0098] Among them C 3-6 Cycloalkyl, phenyl or 5- to 6-membered heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy, -C(O)OH, -C(O)O-(C 1-4 Alkyl), -NR A R B 、-(C1-4 alkyl)-NR A R B 、C 3-7 cycloalkyl and 5 to 6 membered heterocyclyl; and wherein R A and R B are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0099] a is an integer from 0 to 3;

[0100] Each R 2 independently selected from the group consisting of chloro, fluoro, methyl, and methoxy;

[0101] R A and R B are each independently selected from the group consisting of hydrogen and halogen; alternatively, R A and R B Together with the carbon atom to which they are attached, they form an oxo group;

[0102] R C Selected from the group consisting of: hydrogen and C1-4 alkyl;

[0103] R D Selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 1-4 alkoxy;

[0104] R E Selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0105] Q is selected from the group consisting of:

[0106]

[0107] in

[0108] R 4 Selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0109] R 5 Selected from the group consisting of hydrogen, halogen and C 1-4 alkyl;

[0110] selected from the group consisting of phenyl, 5-6 membered heteroaryl and 9 to 10 membered heterocyclyl;

[0111] b is an integer from 0 to 1;

[0112] R 6 Select from the group consisting of: C 3-8 Cycloalkyl, -O-(C 1-2 Alkylene)-C 3-8 Cycloalkyl, -C(O)-(C 3-8 Cycloalkyl), -NH-(C 3-8 Cycloalkyl), -NH-C(O)-(C 3-8 Cycloalkyl), -C(O)-NH-(C 3-8 Cycloalkyl), 4-6 membered heterocycloalkyl, -O-(C 1-2 alkylene)-(4-6 membered heterocycloalkyl), -C(O)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(O)-NH-(4-6 membered heterocycloalkyl), -NH-C(O)-(4-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -O-(C 1-2alkylene)-(5-6 membered heteroaryl), -C(O)-(5-6 membered heteroaryl), -NH-(5-6 membered heteroaryl), -NH-C(O)-(5-6 membered heteroaryl), -C(O)-NH-(5-6 membered heteroaryl), 2-oxa-6-azaspiro[3.3]hept-6-yl, 6-oxa-2-azaspiro[3.4]oct-2-yl and 7-oxa-2-azaspiro[3.5]non-2-yl;

[0113] Among them C 3-8 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, whether alone or as part of a substituent group, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-4 Alkyl, hydroxy, oxo, cyano and NR P R Q ; where R P and R Q are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0114] c is an integer from 0 to 3;

[0115] Each R 7 independently selected from the group consisting of halogen, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxy substituted C 1-6 Alkyl, hydroxy substituted fluorinated C 1-2 Alkyl, cyano substituted C 1-2 Alkyl, C 1-4 Alkoxy, fluorinated C 1-2 Alkoxy, hydroxy substituted C 1-4 Alkoxy, -(C 1-2 Alkylene)-O-(C 1-4 alkyl), oxo, -C(O)OH, -C(O)O-(C 1-2 Alkyl), -NR K R L 、-NR K -(hydroxy substituted C 1-4 Alkyl), -NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -C(O)-NR K R L 、-C(O)-NR K -O-(C 1-4 Alkyl), -C(O)-NR K -(C 1-2 Alkylene)-O-(C 1-2Alkyl), -(C 1-2 Alkylene)-C(O)-NR K R L 、-NR K -C(O)-(C 1-4 Alkyl), -NR K -C(O)-(fluorinated C 1-2 Alkyl), -NR K -C(O)O-(C 1-4 Alkyl), -NR K -C(O)-C 3-6 Cycloalkyl, -(C 1-2 Alkylene)-NR K -C(O)-(C 1-4 Alkyl), -(C 1-2 Alkylene)-NR K -C(O)O-(C 1-4 Alkyl), -(C 1-2 Alkylene)-OC(O)-(amino substituted C 1-4 Alkyl), -NR K -SO2-(C 1-4 Alkyl), -C(O)-NR K -SO2-(C 1-2 alkyl), -(C1-2 alkylene)-OP(O)(OH)2 and -(C 1-2 Alkylene)-O-(C 1-2 Alkylene)-P(O)(OH)2; wherein R K and RL are each independently selected from hydrogen and C 1-4 alkyl;

[0116] And as When the heterocyclyl, heteroaryl or heterocycloalkyl group present in any part of the group contains a nitrogen atom, the heterocyclyl, heteroaryl or heterocycloalkyl group may be further substituted to form an N-oxide;

[0117] The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and both R 2 When the group is 2-fluoro and 3-chloro, then Q is not

[0118] and stereoisomers, isotopomers and pharmaceutically acceptable salts thereof.

[0119] In some embodiments, the present invention relates to compounds of formula (I), wherein

[0120] R 1 Selected from the group consisting of: halogen, C1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 wherein the phenyl group or the 5- to 6-membered heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy and fluorinated C 1-4 alkoxy;

[0121] a is an integer from 0 to 2;

[0122] Each R 2 independently selected from the group consisting of chloro, fluoro, and methyl;

[0123] R A and R B are each independently selected from the group consisting of hydrogen and halogen; alternatively, R A and R B Together with the carbon atom to which they are attached, they form an oxo group;

[0124] R C Selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0125] R D Selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 1-4 alkoxy;

[0126] R E Selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0127] Q is selected from the group consisting of: in

[0128] R 4 Selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0129] R 5 Selected from the group consisting of hydrogen, halogen and C 1-4 alkyl;

[0130] b is an integer from 0 to 1;

[0131] R 6 Select from the group consisting of: C 3-6 Cycloalkyl, -O-(C 1-2 Alkylene)-C3-6 Cycloalkyl, -NH-(C 3-8 Cycloalkyl), -NH-C(O)-(C 3-8 Cycloalkyl), 4-6 membered heterocycloalkyl, -O-(C 1-2 alkylene)-(4-6 membered heterocycloalkyl), -C(O)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(O)-NH-(4-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -O-(C 1-2 alkylene)-(5-6 membered heteroaryl), -NH-C(O)-(5-6 membered heteroaryl) and 2-oxa-6-azaspiro[3.3]hept-6-yl; wherein C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, whether alone or as part of a substituent group, are optionally substituted with one to two substituents independently selected from the group consisting of halogen, C 1-2 Alkyl, hydroxy, oxo, cyano and NR P R Q ; where R P and R Q are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0132] c is an integer from 0 to 2;

[0133] Each R 7 independently selected from the group consisting of halogen, C 1-2 Alkyl, fluorinated C 1-2 Alkyl, hydroxy substituted C 1-6 Alkyl, hydroxy substituted fluorinated C 1-2 Alkyl, cyano substituted C 1-2 Alkyl, C 1-4 Alkoxy, fluorinated C 1-2 Alkoxy, hydroxy substituted C 1-4 Alkoxy, -(C 1-2 Alkylene)-O-(C 1-4 alkyl), oxo, -C(O)OH, -C(O)O-(C 1-2 Alkyl), -NR K R L 、-NR K -(hydroxy substituted C 1-4 Alkyl), -NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -C(O)-NR K R L 、-C(O)-NR K -O-(C1-4 Alkyl), -C(O)-NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -(C 1-2 Alkylene)-C(O)-NR K R L 、-NR K -C(O)-(C 1-4 Alkyl), -NR K -C(O)-(fluorinated C 1-2 Alkyl), -NR K -C(O)O-(C 1-4 Alkyl), -NR K -C(O)-C 3-5 Cycloalkyl, -(C 1-2 Alkylene)-NR K -C(O)-(C 1-4 Alkyl), -(C 1-2 Alkylene)-NR K -C(O)O-(C 1-4 Alkyl), -(C 1-2 Alkylene)-OC(O)-(amino substituted C 1-4 Alkyl), -NR K -SO2-(C 1-2 Alkyl), -C(O)-NR K -SO2-(C 1-2 Alkyl), -(C 1-2 Alkylene)-OP(O)(OH)2 and -(C 1-2 Alkylene)-O-(C 1-2 Alkylene)-P(O)(OH)2; wherein R K and R L are each independently selected from hydrogen and C 1-4 alkyl;

[0134] The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and both R 2 When the group is 2-fluoro and 3-chloro, then Q is not

[0135] and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts.

[0136] In some embodiments, the present invention relates to compounds of formula (I), wherein

[0137] R 1 Selected from the group consisting of: fluorinated C 1-2Alkyl, fluorinated C 1-2 Alkoxy and 5-membered nitrogen-containing heteroaryl; wherein the 5-membered nitrogen-containing heteroaryl is optionally halogenated or fluorinated 1-2 Alkyl substitution;

[0138] a is an integer from 1 to 2;

[0139] Each R 2 independently selected from the group consisting of chloro, fluoro, and methyl;

[0140] R A and R B are each independently selected from the group consisting of hydrogen and halogen; alternatively, R A and R B Together with the carbon atom to which they are attached, they form an oxo group;

[0141] R C Selected from the group consisting of: hydrogen and C 1-2 alkyl;

[0142] R D Selected from the group consisting of: hydrogen, C 1-2 Alkyl and C 1-2 alkoxy;

[0143] R E Selected from the group consisting of: hydrogen and C 1-2 alkyl;

[0144] Q is selected from the group consisting of: in

[0145] R 4 Selected from the group consisting of: hydrogen and C 1-2 alkyl;

[0146] R 5 Selected from the group consisting of hydrogen, halogen and C 1-2 alkyl;

[0147] selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, and 9- to 10-membered heterocyclyl;

[0148] b is an integer from 0 to 1;

[0149] R 6 Select from the group consisting of: C 3-5 Cycloalkyl, -NH-C(O)-C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C 1-2alkylene)-(4-6 membered heterocycloalkyl), -C(O)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(O)-NH-(5-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -O-(C 1-2 alkylene)-(5-6 membered heteroaryl), -NH-C(O)-(5-6 membered heteroaryl) and 2-oxa-6-azaspiro[3.3]hept-6-yl; wherein C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, whether alone or as part of a substituent group, are optionally substituted with one to two substituents independently selected from the group consisting of halogen, C 1-2 Alkyl, hydroxy, oxo, cyano and NR P R Q ; where R P and R Q are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0150] c is an integer from 0 to 2;

[0151] Each R 7 independently selected from the group consisting of halogen, C 1-2 Alkyl, fluorinated C 1-2 Alkyl, hydroxy substituted C 1-6 Alkyl, hydroxy substituted fluorinated C 1-2 Alkyl, cyano substituted C 1-2 Alkyl, C 1-4 Alkoxy, fluorinated C 1-2 Alkoxy, hydroxy substituted C 1-4 Alkoxy, -(C 1-2 Alkylene)-O-(C 1-4 alkyl), oxo, -C(O)OH, -C(O)O-(C 1-2 Alkyl), -NR K R L 、-NR K -(hydroxy substituted C 1-4 Alkyl), -NRK-(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -C(O)-NR K R L 、-C(O)-NR K -O-(C 1-4 Alkyl), -C(O)-NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -(C 1-2 Alkylene)-C(O)-NRK R L 、-NR K -C(O)-(C 1-4 Alkyl), -NR K -C(O)-(fluorinated C 1-2 Alkyl), -NR K -C(O)O-(C 1-4 Alkyl), -NR K -C(O)-C 3-5 Cycloalkyl, -(C 1-2 Alkylene)-NR K -C(O)-(C 1-4 Alkyl), -(C 1-2 Alkylene)-NR K -C(O)O-(C 1-4 Alkyl), -(C 1-2 Alkylene)-OC(O)-(amino substituted C 1-4 Alkyl), -NR K -SO2-(C 1-2 Alkyl), -C(O)-NR K -SO2-(C 1-2 Alkyl), -(C 1-2 Alkylene)-OP(O)(OH)2 and -(C 1-2 Alkylene)-O-(C 1-2 Alkylene)-P(O)(OH)2; wherein R K and R L are each independently selected from hydrogen and C 1-2 alkyl;

[0152] And as When the heterocyclyl, heteroaryl or heterocycloalkyl group present in any part of the group contains a nitrogen atom, the heterocyclyl, heteroaryl or heterocycloalkyl group may be further substituted to form an N-oxide;

[0153] The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and both R 2 When the group is 2-fluoro and 3-chloro, then Q is not

[0154] and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts.

[0155] In some embodiments, the present invention relates to compounds of formula (I), wherein

[0156] R 1Selected from the group consisting of difluoromethyl, difluoro-methoxy, 2,2,2-trifluoro-ethoxy, pyrazol-5-yl, imidazol-5-yl, 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl;

[0157] a is an integer from 1 to 2;

[0158] Each R 2 independently selected from the group consisting of 2-fluoro, 3-chloro, 5-chloro, and 3-methyl;

[0159] R A and R B are each independently selected from the group consisting of: hydrogen and fluorine; alternatively, R A and R B Together with the carbon atom to which they are attached, they form an oxo group;

[0160] R C selected from the group consisting of: hydrogen, deuterated and methyl;

[0161] R D selected from the group consisting of hydrogen, deuterated, methyl, S*-methyl, R*-methyl, S-methoxy, and R-methoxy;

[0162] R E selected from the group consisting of: hydrogen and methyl;

[0163] Q is selected from the group consisting of: in

[0164] R 4 selected from the group consisting of: hydrogen and methyl;

[0165] R 5 selected from the group consisting of hydrogen, deuterated, fluoro, chloro, bromo, and methyl;

[0166] Select from the group consisting of:

[0167] 2-methoxy-phenyl, 2-(isopropoxy)-phenyl, 3-fluoro-4-carboxy-phenyl, 2-amino-phenyl, 2-(dimethyl-amino)-phenyl, 2-(amino-carbonyl)-phenyl, 2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-3-(amino-carbonyl)-phenyl, 3-(amino-carbonyl)-4-fluoro-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 2-(methyl-amino-carbonyl)-phenyl, 2-(dimethyl-amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)-phenyl, 2-( phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 2-(methoxy-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 4-(1R-(methyl-carbonyl-amino)-ethyl)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl, 2-(methyl-sulfonyl-amino)-phenyl, 4-( Oxazolidin-3-yl-2-one)-phenyl;

[0168] 2-Carboxy-thiophen-5-yl, 2-carboxy-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-4-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-5-yl, 3-(cyclopropyl-carbonyl-amino)-thiophen-2-yl, 2-(methyl-sulfonyl-amino-carbonyl)-3-fluoro-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 4-chloro-pyrazol-3-yl, 3-fluoro-pyrazol-4-yl, 3-chloro-pyrazol-4-yl, 3-methoxy-pyrazol-4-yl, 3-(trifluoromethyl)-pyrrol-4-yl )-pyrazol-4-yl, 5-chloro-pyrazol-4-yl, 1-methyl-3-(cyclopropyl-carbonyl-amino)-pyrazol-4-yl, 1-methyl-4-(cyclopropyl-carbonyl-amino)-pyrazol-5-yl, imidazol-2-yl, 2-(trifluoro-methyl)-imidazol-4-yl, 1-methyl-imidazol-2-yl, 4-(hydroxy-methyl)-thiazol-2-yl, 2-(hydroxy-methyl)-thiazol-4-yl, 2-(amino-carbonyl)-thiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-5-yl, 1-methyl-(1,2,4-triazol-3-yl), 1-methyl-1,2,3-triazol-5-yl;

[0169] 3-Fluoro-pyridin-4-yl-2-one, 3-fluoro-pyridin-4-yl, 2-fluoro-5-chloro-pyridin-4-yl, 2-(difluoromethoxy)-pyridin-4-yl, 2-(trifluoro-methyl)-pyridin-4-yl, 2-(cyano-methyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-carboxy-3-fluoro-pyridin-4-yl, 2-(methoxy-carbonyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-d2-methyl)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-ethoxy)-pyridin-4-yl, 2-(2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin- 4-yl, 2-(2-hydroxy-2-methyl-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-chloro-6-(hydroxy-methyl)-pyridin-3-yl, 2-fluoro-6-(hydroxy-methyl)-pyridin-3-yl, 2-(hydroxy-d2-methyl)-3-chloro-pyridin-4-yl, 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-2,2-difluoro- -ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 2-(3-hydroxy-3-methyl-n-butyl)-3-fluoro-pyridin-3-yl, 2-(1,1-difluoro-2-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(1S*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 4-amino-pyridin-3-yl, 2-chloro-6-amino-pyridin-3-yl, 3-chloro-6-amino-pyridin-4-yl, 2-amino-3-methyl-pyridin -4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-amino-6-(trifluoro-methyl)-pyridin-5-yl, 2-(methyl-amino)-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin-3-yl, 2-fluoro-6-(dimethyl-amino)-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-amino-3-methoxy-pyridin-4-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(1,1-dimethyl-2-hydroxy-ethyl-amino)-3-fluoro-pyridin-4-yl,2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2R*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deutero-6-amino-pyridin-3-yl, 2-fluoro-5-deutero-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(N-ethyl-N-2-hydroxy-ethyl-amino)-3-fluoro- Pyridin-4-yl, 2-(amino-carbonyl)-pyridin-4-yl, 2-(amino-carbonyl)-pyridin-5-yl, 2-(amino-carbonyl)-3-fluoro-pyridin-3-yl, 2-chloro-6-(amino-carbonyl)-pyridin-3-yl, 2-(2-methoxy-ethyl-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(amino-carbonyl-methyl)-3-fluoro-pyridin-4-yl, 3-(trifluoromethyl-carbonyl-amino)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-pyridin-4-yl, 3-chloro-6-(methyl-carbonyl-amino)-pyridin-4-yl, 5-(methoxy-carbonyl-amino)-pyridin- 2-yl, 2-(methoxy-carbonyl-amino)-pyridin-5-yl, 2-(methoxy-carbonyl-amino)-pyridin-4-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 2-(ethoxy-carbonyl-amino)-pyridin-3-yl, 4-(ethoxy-carbonyl-amino)-pyridin-3-yl, 2-(ethoxy-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 3-(methyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(1S-amino-isopropyl-carbonyl-oxy 2-(1-Hydroxy-1-methyl)-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-pyridin-4-yl,3-(Cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(Cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(oxetan-3-yl)-3-fluoro-pyridin-4-yl, 2-(3-cyano-oxetan-3-yl)-3-fluoro-pyridin-4-yl, 2-(azetidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(3-cyano-azetidin-1-yl)-3 -fluoro-pyridin-4-yl, 2-(pyrrolidin-1-yl-2-one)-3-fluoro-pyridin-4-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(3S-hydroxy-piperidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(pyrazol-1-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-2-yl, 2-(pyrazol-5-yl)-pyridin-5-yl -4-yl, 2-(pyrazol-5-yl)-3-fluoro-pyridin-4-yl, 2-(5-amino-pyrazol-1-yl)-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(5-amino-pyrazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-pyridin-4-yl, 2-(imidazol-2-yl)-3-fluoro- Pyridin-4-yl, 2-(1,2,3-triazol-1-yl)-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 2-(1,2,3-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(1,3,4-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(1,2,4-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(, Oxazolidin-3-yl-2-one)-3-fluoro-pyridin-4-yl, 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3-fluoro-pyridin-4-yl, 2-(di Alkyl-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1R*- Oxazol-2-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S*- Oxazol-2-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S-(1,3,4- oxadiazole-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(3,3-difluoro-azetidin-1-yl-carbonyl)-3-fluoro-pyridin-4-yl, 2-fluoro-6-(bicyclo[1.1.1]pentyl-amino)-pyridin-3-yl, 2-(bicyclo[1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, 2-(bicyclo[1.1.1]pentyl-amino-carbonyl)-3-fluoro-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(3-methyl-isoxadiazole-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(3,3-difluoro-azetidin-1-yl-carbonyl)-3-fluoro-pyridin-4-yl, 2-fluoro-6-(bicyclo[1.1.1]pentyl-amino)-pyridin-3-yl, 2-(bicyclo[1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, Oxazol-5-yl-carbonyl-amino)-3-fluoro-pyridin-4-yl, pyridin-4-yl-2-one, pyridin-4-yl-N-oxide, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl-N-oxide;

[0170] Indol-3-yl, indol-6-yl, indol-5-yl, indol-5-yl-2-one, 7-fluoro-indol-6-yl, indazol-5-yl, indazol-4-yl, 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, indolin-5-yl-2-one, 6-methyl-indolin-7-yl-2-one, benzimidazol-5-yl, 2-methyl-benzimidazol-6-yl, benzimidazol-5-yl-2-one, 1-methyl-benzimidazol-6-yl-2-one, 1-methyl-benzimidazol-5-yl-2-one, 3-amino-benzisodazole oxazol-5-yl, benzo oxazol-6-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 6-methyl-quinoxalin-5-yl-2(1H)-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 2,3-dihydrofuro[2,3-b]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-c ]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 5-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[3,2-c]pyridin-3-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl and 1H-pyrazolo[3,4-b]pyridin-5-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 2,3-dihydro-[1,4]dihydro- Ino[2,3-b]pyridin-8-yl and 7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl-7-ol;

[0171] and wherein one or both of the following are optionally deuterated: (i) in R 1 a hydrogen atom bound to the phenyl ring at the meta position of (ii) and a hydrogen atom bound to the 8a position of 2,3,8,8a-tetrahydroindole-5(1H)-one;

[0172] The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and both R 2 When the group is 2-fluoro and 3-chloro, then Q is not

[0173] and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts.

[0174] In some embodiments, the present invention relates to compounds of formula (I), wherein

[0175] R 1 Selected from the group consisting of 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl;

[0176] a is an integer from 1 to 2;

[0177] Each R 2 independently selected from the group consisting of: 2-fluoro and 3-chloro;

[0178] R A and R B Each is hydrogen;

[0179] R C selected from the group consisting of: hydrogen and methyl;

[0180] R D selected from the group consisting of hydrogen, methyl, S*-methyl, R*-methyl, S-methoxy, and R-methoxy;

[0181] R E is hydrogen;

[0182] Q is selected from the group consisting of: in

[0183] R 4 is hydrogen;

[0184] R 5 selected from the group consisting of hydrogen, deuterated, fluoro, chloro, bromo, and methyl;

[0185] Select from the group consisting of:

[0186] 2-methoxy-phenyl, 2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-3-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)-phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 2-(methoxy-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl;

[0187] 2-carboxy-thiophen-5-yl, 2-carboxy-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-4-yl, 3-(cyclopropyl-carbonyl-amino)-thiophen-2-yl, 2-(methyl-sulfonyl-amino-carbonyl)-3-fluoro-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3-fluoro-pyrazol-4-yl, 3-chloro-pyrazol-4-yl, 3-methoxy-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 5-chloro-pyrazol-4-yl, 2-(amino-carbonyl)-thiazol-5-yl;

[0188] 3-Fluoro-pyridin-4-yl-2-one, 3-fluoro-pyridin-4-yl, 2-(difluoromethoxy)-pyridin-4-yl, 2-(trifluoro-methyl)-pyridin-4-yl, 2-(cyano-methyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-carboxy-3-fluoro-pyridin-4-yl, 2-(methoxy-carbonyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-d2-methyl)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-ethoxy)-pyridin-4-yl, 2-(2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-2-methyl- 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 1R*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 2-(3-hydroxy-3-methyl-n-butyl)-3-fluoro-pyridin-3-yl, 2-(1,1-difluoro-2-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(1S*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 3-chloro-6-amino-pyridin-4-yl, 2-amino-3-methyl-pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin- 4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-amino-3-methoxy-pyridin-4-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(1,1-dimethyl-2-hydroxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl,3-trifluoro-2R*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated-6-amino-pyridin-3-yl,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(N-ethyl-N-2-hydroxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(amino-carbonyl)-pyridin-5-yl, 2-(amino-carbonyl)-3-fluoro-pyridin-3-yl, 2-(2-methoxy-ethyl-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(amino-carbonyl-methyl)-3-fluoro-pyridin-4-yl, 3-(trifluoromethyl-carbonyl-amino)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-pyridin-4-yl, 5-(methoxy)-6-(methyl-amino)-pyridin-3-yl, 2-(Methyl-carbonyl-amino)-pyridin-2-yl, 2-(methoxy-carbonyl-amino)-pyridin-5-yl, 2-(methoxy-carbonyl-amino)-pyridin-4-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 2-(ethoxy-carbonyl-amino)-pyridin-3-yl, 2-(ethoxy-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 2-(1S-amino-isopropyl-carbonyl-oxo-methyl)-3-fluoro-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(phosphono- 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(oxetan-3-yl)-3-fluoro-pyridin-4-yl, 2-(azetidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, (3-Cyano-azetidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(3S-hydroxy-piperidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(pyrazol-1-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-3-fluoro-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-pyridin-4-yl, 2-(imidazol-2-yl)-3-fluoro-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 2-(1,2,5-triazol-1-yl)-pyridin-4-yl,4-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(, Oxazolidin-3-yl-2-one)-3-fluoro-pyridin-4-yl, 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3-fluoro-pyridin-4-yl, 2-(di Alkyl-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S*- Oxazol-2-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S-(1,3,4- oxadiazole-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(bicyclo[1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(3-methyl-isoxadiazole)-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(bicyclo[1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, Oxazol-5-yl-carbonyl-amino)-3-fluoro-pyridin-4-yl, pyridin-4-yl-2-one;

[0189] Indol-3-yl, indol-6-yl, indol-5-yl, indol-5-yl-2-one, 7-fluoro-indol-6-yl, indazol-5-yl, indazol-4-yl, 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, indolin-5-yl-2-one, 6-methyl-indolin-7-yl-2-one, benzimidazol-5-yl, 2-methyl-benzimidazol-6-yl, benzimidazol-5-yl-2-one, 1-methyl-benzimidazol-6-yl-2-one, 1-methyl-benzimidazol-5-yl-2-one, 3-amino-benzisodazole oxazol-5-yl, benzo oxazol-6-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 6-methyl-quinoxalin-5-yl-2(1H)-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 2,3-dihydrofuro[2,3-b]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2, 3-b]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[3,2-c]pyridin-3-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 2,3-dihydro-[1,4]dihydro- Ino[2,3-b]pyridin-8-yl and 7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl-7-ol;

[0190] and wherein one or both of the following are optionally deuterated: (i) in R 1 a hydrogen atom bound to the phenyl ring at the meta position of (ii) and a hydrogen atom bound to the 8a position of 2,3,8,8a-tetrahydroindole-5(1H)-one;

[0191] The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and both R 2 When the group is 2-fluoro and 3-chloro, then Q is not

[0192] and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts.

[0193] In some embodiments, the present invention relates to compounds of formula (I), wherein

[0194] R 1 Selected from the group consisting of 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl;

[0195] a is an integer from 1 to 2;

[0196] Each R 2 independently selected from the group consisting of: 2-fluoro and 3-chloro;

[0197] R A and R B Each is hydrogen;

[0198] R C selected from the group consisting of: hydrogen and methyl;

[0199] R D selected from the group consisting of hydrogen, methyl, S*-methyl, and R-methoxy;

[0200] R E is hydrogen;

[0201] Q is selected from the group consisting of: in

[0202] R 4is hydrogen;

[0203] R 5 selected from the group consisting of hydrogen, deuterated, fluorinated and chlorinated;

[0204] Select from the group consisting of:

[0205] 2-Fluoro-4-(amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)-phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl;

[0206] 2-Carboxy-thiophen-5-yl, 2-carboxy-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-4-yl, 3-(cyclopropyl-carbonyl-amino)-thiophen-2-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3-chloro-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 5-chloro-pyrazol-4-yl, 1-methyl-4-(cyclopropyl-carbonyl-amino)-pyrazol-5-yl, 2-(amino-carbonyl)-thiazol-5-yl;

[0207] 2-carboxy-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-ethoxy)-pyridin-4-yl, 2-(2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-2-methyl-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(hydroxy-d2-methyl)-3-chloro-pyridin-4-yl, 2 -(1R-(Hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 2-(3-hydroxy-3-methyl-n-butyl)-3-fluoro-pyridin-3-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 2-fluoro- 6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-amino-3-methoxy-pyridin-4-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-( methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-amino-carbonyl)-3-fluoro-pyridin-4-yl, 3-(trifluoromethyl-carbonyl-amino)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-pyridin-4-yl, 5-(methoxy-carbonyl-amino)-pyridin-2-yl, 2-(methoxy-carbonyl- amino)-pyridin-5-yl, 2-(methoxy-carbonyl-amino)-pyridin-4-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(ethoxy-carbonyl-amino)-pyridin-3-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(phosphono-oxy-methyl)-3-fluoro-pyridin-4 -yl, 2-(phosphono-methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(3-cyano-azetidin-1-yl)-3- Fluoro-pyridin-4-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(pyrazol-1-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-3-fluoro-pyridin-4-yl, 2-(imidazol-2-yl)-3-fluoro-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 2-(di, Alkyl-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, pyridin-4-yl-2-one;

[0208] Indol-5-yl-2-one, 7-fluoro-indol-6-yl, indazol-5-yl, 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, benzimidazol-5-yl, 2-methyl-benzimidazol-6-yl, benzimidazol-5-yl-2-one, 1-methyl-benzimidazol-6-yl-2-one, 1-methyl-benzimidazol-5-yl-2-one, benzo oxazol-6-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 2,3-dihydrofuro[2,3-b]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 1H-pyrrolo[2,3 -b]pyridin-4-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one and 2,3-dihydro-[1,4]dihydro- Ino[2,3-b]pyridin-8-yl;

[0209] and wherein one or both of the following are optionally deuterated: (i) in R 1 a hydrogen atom bound to the phenyl ring at the meta position of (ii) and a hydrogen atom bound to the 8a position of 2,3,8,8a-tetrahydroindole-5(1H)-one;

[0210] The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and both R 2 When the group is 2-fluoro and 3-chloro, then Q is not

[0211] and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts.

[0212] In some embodiments, the present invention relates to compounds of formula (I), wherein

[0213] R 1 Selected from the group consisting of 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl;

[0214] a is an integer from 1 to 2;

[0215] Each R 2 independently selected from the group consisting of: 2-fluoro and 3-chloro;

[0216] R A and R B Each is hydrogen;

[0217] R C selected from the group consisting of: hydrogen and methyl;

[0218] R D selected from the group consisting of: hydrogen, methyl, and R-methoxy;

[0219] R E is hydrogen;

[0220] Q is selected from the group consisting of: in

[0221] R 4 is hydrogen;

[0222] R 5 selected from the group consisting of hydrogen, deuterated, fluorinated and chlorinated;

[0223] Select from the group consisting of:

[0224] 2-Fluoro-4-(amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)-phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl;

[0225] 2-Carboxy-thiophen-5-yl, 2-carboxy-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3-chloro-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 1-methyl-4-(cyclopropyl-carbonyl-amino)-pyrazol-5-yl, 2-(amino-carbonyl)-thiazol-5-yl;

[0226] 2-carboxy-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin- 3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deutero-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-amino-pyridin- 3-yl, 2-fluoro-4,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 5-(methoxy-carbonyl-amino)-pyridin-2-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(phosphono-oxy-methyl)-3-fluoro-pyridin-4 -yl, 2-(1-hydroxy-cyclopropyl-1-yl)-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl;

[0227] 3-(Methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, benzimidazol-5-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one and 2,3-dihydro-[1,4]dihydro- Ino[2,3-b]pyridin-8-yl;

[0228] and wherein one or both of the following are optionally deuterated: (i) in R 1 a hydrogen atom bound to the phenyl ring at the meta position of (ii) and a hydrogen atom bound to the 8a position of 2,3,8,8a-tetrahydroindole-5(1H)-one;

[0229] The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and both R 2 When the group is 2-fluoro and 3-chloro, then Q is not

[0230] and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts.

[0231] In some embodiments, the present invention relates to compounds of formula (I), wherein

[0232] R 1 Selected from the group consisting of: 4-chloro-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl;

[0233] a is an integer from 1 to 2;

[0234] Each R 2 independently selected from the group consisting of: 2-fluoro and 3-chloro;

[0235] R A and R B Each is hydrogen;

[0236] R C is hydrogen;

[0237] R D is hydrogen;

[0238] R E is hydrogen;

[0239] Q is selected from the group consisting of: in

[0240] R 4 is hydrogen;

[0241] R 5 selected from the group consisting of hydrogen, deuterated, fluorinated and chlorinated;

[0242] Select from the group consisting of:

[0243] 4-(Methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl;

[0244] 2-carboxy-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 2-(amino-carbonyl)-thiazol-5-yl;

[0245] 2-Carboxy-3-fluoro-pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n- propyl-amino)-3-fluoro-pyridin-4-yl, 2-fluoro-4,5-dideutero-6-amino-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl;

[0246] 3-(Methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, benzimidazol-5-yl-2-one, 2H-quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one and 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one;

[0247] and wherein one or both of the following are optionally deuterated: (i) in R 1 a hydrogen atom bound to the phenyl ring at the meta position of (ii) and a hydrogen atom bound to the 8a position of 2,3,8,8a-tetrahydroindole-5(1H)-one;

[0248] The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and both R 2 When the group is 2-fluoro and 3-chloro, then Q is not

[0249] and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts.

[0250] In some embodiments, the present invention relates to compounds of formula (I), wherein R 1is 1,2,3,4-tetrazolyl-1-yl; a is 2; two R 2 is 2-fluoro and 3-chloro; R A and R B Each is hydrogen; R C is hydrogen; R D is hydrogen; R E is hydrogen; and Q is selected from the group consisting of: where R 4 is hydrogen; R 5 selected from the group consisting of: hydrogen and chlorine; and Selected from the group consisting of: 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(amino-carbonyl)-thiophen-5-yl, 2-(amino-carbonyl)-thiazol-5-yl, 2-chloro-6-amino-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 3-amino-indazol-6-yl, 2H-quinolin-6-yl-2-one, 1H-pyrrolo[2,3-b]pyridin-4-yl and 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one;

[0251] and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts.

[0252] In some embodiments, the present invention relates to compounds of formula (I), wherein R 1 Selected from the group consisting of: halogen, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 wherein the phenyl group or the 5- to 6-membered heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy and fluorinated C 1-4 In some embodiments, the present invention relates to compounds of formula (I), wherein R 1 Selected from the group consisting of: fluorinated C 1-2 Alkyl, fluorinated C 1-2 Alkoxy and 5-membered nitrogen-containing heteroaryl; wherein the 5-membered nitrogen-containing heteroaryl is optionally halogenated or fluorinated 1-2 Alkyl substitution.

[0253] In some embodiments, the present invention relates to compounds of formula (I), wherein R 1is selected from the group consisting of difluoromethyl, difluoro-methoxy, 2,2,2-trifluoro-ethoxy, pyrazol-5-yl, imidazol-5-yl, 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl. In some embodiments, the present invention relates to compounds of formula (I) wherein R 1 is selected from the group consisting of 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl. In some embodiments, the present invention relates to compounds of formula (I), wherein R 1 is selected from the group consisting of 4-chloro-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl. In some embodiments, the present invention relates to compounds of formula (I), wherein R 1 It is 1,2,3,4-tetrazolyl-1-yl.

[0254] In some embodiments, the present invention relates to compounds of formula (I), wherein a is an integer from 0 to 2. In some embodiments, the present invention relates to compounds of formula (I), wherein a is an integer from 1 to 2. In some embodiments, the present invention relates to compounds of formula (I), wherein a is 0. In some embodiments, the present invention relates to compounds of formula (I), wherein a is 1. In some embodiments, the present invention relates to compounds of formula (I), wherein a is 2.

[0255] In some embodiments, the present invention relates to compounds of formula (I), wherein each R 2 In some embodiments, the present invention relates to compounds of formula (I), wherein each R 2 In some embodiments, the present invention relates to compounds of formula (I), wherein each R 2 In some embodiments, the present invention relates to compounds of formula (I), wherein each R 2 Independently selected from the group consisting of 2-fluoro and 3-chloro.

[0256] In some embodiments, the present invention relates to compounds of formula (I), wherein a is 2, and both R 2 The groups are 2-fluoro and 3-chloro.

[0257] In some embodiments, the present invention relates to compounds of formula (I), wherein R Ais selected from the group consisting of hydrogen and halogen. In some embodiments, the present invention relates to compounds of formula (I), wherein R A is selected from the group consisting of hydrogen and fluorine. In some embodiments, the present invention relates to compounds of formula (I), wherein R A is selected from the group consisting of hydrogen (or deuterated) and fluorine. In some embodiments, the present invention relates to compounds of formula (I), wherein R A is hydrogen (or deuterated). In some embodiments, the present invention relates to compounds of formula (I), wherein R A In some embodiments, the present invention relates to compounds of formula (I), wherein R A In some embodiments, the present invention relates to compounds of formula (I), wherein R A In some embodiments, the present invention relates to compounds of formula (I), wherein R A For fluorine.

[0258] In some embodiments, the present invention relates to compounds of formula (I), wherein R B is selected from the group consisting of hydrogen and halogen. In some embodiments, the present invention relates to compounds of formula (I), wherein R B is selected from the group consisting of hydrogen and fluorine. In some embodiments, the present invention relates to compounds of formula (I), wherein R B is hydrogen (or deuterated) and fluorine. In some embodiments, the present invention relates to compounds of formula (I), wherein R B is hydrogen (or deuterated). In some embodiments, the present invention relates to compounds of formula (I), wherein R B In some embodiments, the present invention relates to compounds of formula (I), wherein R B In some embodiments, the present invention relates to compounds of formula (I), wherein R B In some embodiments, the present invention relates to compounds of formula (I), wherein R B For fluorine.

[0259] In some embodiments, the present invention relates to compounds of formula (I), wherein R A and R B In some embodiments, the present invention relates to compounds of formula (I), wherein R A and R B Each is a deuterated group.

[0260] In some embodiments, the present invention relates to compounds of formula (I), wherein R A and R B Together with the carbon atom to which they are attached, they form an oxo group.

[0261] In some embodiments, the present invention relates to compounds of formula (I), wherein R C Selected from the group consisting of: hydrogen and C 1-2 In some embodiments, the present invention relates to compounds of formula (I), wherein R C is selected from the group consisting of hydrogen (or deuterated) and methyl. In some embodiments, the present invention relates to compounds of formula (I), wherein R C is hydrogen (or deuterated). In some embodiments, the present invention relates to compounds of formula (I), wherein R C is selected from the group consisting of hydrogen and methyl. In some embodiments, the present invention relates to compounds of formula (I), wherein R C is selected from the group consisting of: methyl and ethyl. In some embodiments, the present invention relates to compounds of formula (I), wherein R C In some embodiments, the present invention relates to compounds of formula (I), wherein R C In some embodiments, the present invention relates to compounds of formula (I), wherein R C It is a methyl group.

[0262] In some embodiments, the present invention relates to compounds of formula (I), wherein R D Selected from the group consisting of: hydrogen, C 1-2 Alkyl and C 1-2 In some embodiments, the present invention relates to compounds of formula (I), wherein R D is selected from the group consisting of hydrogen (or deuterated), methyl and methoxy. In some embodiments, the present invention relates to compounds of formula (I), wherein R D is hydrogen (or deuterated). In some embodiments, the present invention relates to compounds of formula (I), wherein R D In some embodiments, the present invention relates to compounds of formula (I), wherein R D In some embodiments, the present invention relates to compounds of formula (I), wherein R D is selected from the group consisting of: methyl and methoxy. In some embodiments, the present invention relates to compounds of formula (I), wherein R D In some embodiments, the present invention relates to compounds of formula (I), wherein R D It is a methoxy group.

[0263] In some embodiments, the present invention relates to compounds of formula (I), wherein R Dis selected from the group consisting of hydrogen (or deuterated), methyl, S*-methyl, R*-methyl, methoxy, S-methoxy and R-methoxy. In some embodiments, the present invention relates to compounds of formula (I), wherein R D is selected from the group consisting of hydrogen (or deuterated), methyl, S*-methyl, R*-methyl, S-methoxy and R-methoxy. In some embodiments, the present invention relates to compounds of formula (I), wherein R D is selected from the group consisting of hydrogen, methyl, S*-methyl, R*-methyl, S-methoxy and R-methoxy. In some embodiments, the present invention relates to compounds of formula (I), wherein R D is selected from the group consisting of hydrogen, methyl, S*-methyl and R-methoxy. In some embodiments, the present invention relates to compounds of formula (I), wherein R D is selected from the group consisting of hydrogen, methyl and R-methoxy. In some embodiments, the present invention relates to compounds of formula (I), wherein R D In some embodiments, the present invention relates to compounds of formula (I), wherein R D It is a deuterated group.

[0264] In some embodiments, the present invention relates to compounds of formula (I), wherein R E Selected from the group consisting of: hydrogen and C 1-2 In some embodiments, the present invention relates to compounds of formula (I), wherein R E is selected from the group consisting of hydrogen and methyl. In some embodiments, the present invention relates to compounds of formula (I), wherein R E In some embodiments, the present invention relates to compounds of formula (I), wherein R E It is a methyl group.

[0265] In some embodiments, the present invention relates to compounds of formula (I), wherein R A and R B In some embodiments, the present invention relates to compounds of formula (I), wherein R C and R D In some embodiments, the present invention relates to compounds of formula (I), wherein R A 、R B and R E In some embodiments, the present invention relates to compounds of formula (I), wherein R C 、R D and R E In some embodiments, the present invention relates to compounds of formula (I), wherein R A 、RB 、R C and R D In some embodiments, the present invention relates to compounds of formula (I), wherein R A 、R B 、R C 、R D and R E In some embodiments, the present invention relates to compounds of formula (I), wherein R A 、R B 、R C 、R D or R E One of them is not hydrogen.

[0266] In some embodiments, the present invention relates to compounds of formula (I), wherein R 4 Selected from the group consisting of: hydrogen and C 1-2 In some embodiments, the present invention relates to compounds of formula (I), wherein R 4 is selected from the group consisting of hydrogen and methyl. In some embodiments, the present invention relates to compounds of formula (I), wherein R 4 In some embodiments, the present invention relates to compounds of formula (I), wherein R 4 It is a methyl group.

[0267] In some embodiments, the present invention relates to compounds of formula (I), wherein R 5 Selected from the group consisting of hydrogen, halogen and C 1-2 In some embodiments, the present invention relates to compounds of formula (I), wherein R 5 In some embodiments, the present invention relates to compounds of formula (I), wherein R 5 In some embodiments, the present invention relates to compounds of formula (I), wherein R 5 is selected from the group consisting of fluorine and chlorine. In some embodiments, the present invention relates to compounds of formula (I), wherein R 5 In some embodiments, the present invention relates to compounds of formula (I), wherein R 5 C 1-2 In some embodiments, the present invention relates to compounds of formula (I), wherein R 5 It is a methyl group.

[0268] In some embodiments, the present invention relates to compounds of formula (I), wherein R 5 is selected from the group consisting of hydrogen, deuterated, fluoro, chloro, bromo and methyl. In some embodiments, the present invention relates to compounds of formula (I), wherein R5 is selected from the group consisting of hydrogen (or deuterated), fluorine and chlorine. In some embodiments, the present invention relates to compounds of formula (I), wherein R 5 Selected from the group consisting of hydrogen (or deuterated) and chlorine.

[0269] In some embodiments, the present invention relates to compounds of formula (I), wherein In some embodiments, the present invention relates to compounds of formula (I), wherein In some embodiments, the present invention relates to a compound of formula (I), wherein In some embodiments, the present invention relates to compounds of formula (I), wherein In some embodiments, the present invention relates to compounds of formula (I), wherein is a 9- to 10-membered heterocyclyl. In some embodiments, the present invention relates to a compound of formula (I), wherein In some embodiments, the present invention relates to compounds of formula (I), wherein It is a 10-membered heterocyclic group.

[0270] In some embodiments, the present invention relates to compounds of formula (I), wherein b is 0. In some embodiments, the present invention relates to compounds of formula (I), wherein b is 1.

[0271] In some embodiments, the present invention relates to compounds of formula (I), wherein R 6 Select from the group consisting of: C 3-6 Cycloalkyl, -O-(C1-2 alkylene)-C 3-6 Cycloalkyl, -NH-(C 3-8 Cycloalkyl), -NH-C(O)-(C 3-8 Cycloalkyl), 4-6 membered heterocycloalkyl, -O-(C 1-2 alkylene)-(4-6 membered heterocycloalkyl), -C(O)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(O)-NH-(4-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -O-(C 1-2 alkylene)-(5-6 membered heteroaryl), -NH-C(O)-(5-6 membered heteroaryl) and 2-oxa-6-azaspiro[3.3]hept-6-yl; wherein C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, whether alone or as part of a substituent group, are optionally substituted with one to two substituents independently selected from the group consisting of halogen, C 1-2 Alkyl, hydroxy, oxo, cyano and NRP R Q ; where R P and R Q are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl.

[0272] In some embodiments, the present invention relates to compounds of formula (I), wherein R 6 Select from the group consisting of: C 3-5 Cycloalkyl, -NH-C(O)-C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C 1-2 alkylene)-(4-6 membered heterocycloalkyl), -C(O)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(O)-NH-(5-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -O-(C 1-2 alkylene)-(5-6 membered heteroaryl), -NH-C(O)-(5-6 membered heteroaryl) and 2-oxa-6-azaspiro[3.3]hept-6-yl; wherein C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, whether alone or as part of a substituent group, are optionally substituted with one to two substituents independently selected from the group consisting of halogen, C 1-2 Alkyl, hydroxy, oxo, cyano and NR P R Q ; where R P and R Q are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl.

[0273] In some embodiments, the present invention relates to compounds of formula (I), wherein c is an integer from 0 to 2. In some embodiments, the present invention relates to compounds of formula (I), wherein c is an integer from 0 to 1. In some embodiments, the present invention relates to compounds of formula (I), wherein c is an integer from 1 to 2. In some embodiments, the present invention relates to compounds of formula (I), wherein c is 0. In some embodiments, the present invention relates to compounds of formula (I), wherein c is 1. In some embodiments, the present invention relates to compounds of formula (I), wherein c is 2.

[0274] In some embodiments, the present invention relates to compounds of formula (I), wherein each R 7 independently selected from the group consisting of halogen, C 1-2 Alkyl, fluorinated C 1-2 Alkyl, hydroxy substituted C 1-6 Alkyl, hydroxy substituted fluorinated C 1-2 Alkyl, cyano substituted C1-2 Alkyl, C 1-4 Alkoxy, fluorinated C 1-2 Alkoxy, hydroxy substituted C 1-4 Alkoxy, -(C 1-2 Alkylene)-O-(C 1-4 alkyl), oxo, -C(O)OH, -C(O)O-(C 1-2 Alkyl), -NR K RL, -NR K -(hydroxy substituted C 1-4 Alkyl), -NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -C(O)-NR K RL, -C(O)-NR K -O-(C 1-4 Alkyl), -C(O)-NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -(C 1-2 Alkylene)-C(O)-NR K R L 、-NR K -C(O)-(C 1-4 Alkyl), -NR K -C(O)-(fluorinated C 1-2 Alkyl), -NR K -C(O)O-(C 1-4 Alkyl), -NR K -C(O)-C3-5 cycloalkyl, -(C 1-2 Alkylene)-NR K -C(O)-(C 1-4 Alkyl), -(C 1-2 Alkylene)-NR K -C(O)O-(C 1-4 Alkyl), -(C 1-2 Alkylene)-OC(O)-(amino substituted C 1-4 Alkyl), -NR K -SO2-(C 1-2 Alkyl), -C(O)-NR K -SO2-(C 1-2 Alkyl), -(C 1-2 Alkylene)-OP(O)(OH)2 and -(C 1-2 Alkylene)-O-(C 1-2 Alkylene)-P(O)(OH)2; wherein R K and R Lare each independently selected from hydrogen and C 1-4 alkyl.

[0275] In some embodiments, the present invention relates to compounds of formula (I), wherein each R 7 independently selected from the group consisting of halogen, C 1-2 Alkyl, fluorinated C 1-2 Alkyl, hydroxy substituted C 1-6 Alkyl, hydroxy substituted fluorinated C 1-2 Alkyl, cyano substituted C 1-2 Alkyl, C 1-4 Alkoxy, fluorinated C 1-2 Alkoxy, hydroxy substituted C 1-4 Alkoxy, -(C 1-2 Alkylene)-O-(C 1-4 alkyl), oxo, -C(O)OH, -C(O)O-(C 1-2 Alkyl), -NR K RL, -NR K -(hydroxy substituted C 1-4 Alkyl), -NRK-(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -C(O)-NR K R L 、-C(O)-NR K -O-(C 1-4 Alkyl), -C(O)-NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -(C 1-2 Alkylene)-C(O)-NR K R L 、-NR K -C(O)-(C 1-4 Alkyl), -NR K -C(O)-(fluorinated C 1-2 Alkyl), -NR K -C(O)O-(C 1-4 Alkyl), -NR K -C(O)-C 3-5 Cycloalkyl, -(C 1-2 Alkylene)-NR K -C(O)-(C 1-4 Alkyl), -(C 1-2 Alkylene)-NR K -C(O)O-(C 1-4 Alkyl), -(C 1-2 Alkylene)-OC(O)-(amino substituted C 1-4Alkyl), -NR K -SO2-(C 1-2 Alkyl), -C(O)-NR K -SO2-(C 1-2 Alkyl), -(C 1-2 Alkylene)-OP(O)(OH)2 and -(C 1-2 Alkylene)-O-(C 1-2 Alkylene)-P(O)(OH)2; wherein R K and R L are each independently selected from hydrogen and C 1-2 alkyl.

[0276] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of 2-methoxy-phenyl, 2-(isopropoxy)-phenyl, 3-fluoro-4-carboxy-phenyl, 2-amino-phenyl, 2-(dimethyl-amino)-phenyl, 2-(amino-carbonyl)-phenyl, 2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-3-(amino-carbonyl)-phenyl, 3-(amino-carbonyl)-4-fluoro-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 2-(methyl-amino-carbonyl)-phenyl, 2-(dimethyl-amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)- phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 2-(methoxy-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 4-(1R-(methyl-carbonyl-amino)-ethyl)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl, 2-(methyl-sulfonyl-amino)-phenyl, 4-( oxazolidin-3-yl-2-one)-phenyl, 2-carboxy-thiophen-5-yl, 2-carboxy-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-4-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-5-yl, 3-(cyclopropyl-carbonyl-amino)-thiophen-2-yl, 2-(methyl-sulfonyl-amino-carbonyl)-3-fluoro-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 4-chloro-pyrazol-3-yl, 3-fluoro-pyrazol-4-yl, 3-chloro-pyrazol-4-yl, 3-methoxy-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 5- Chloro-pyrazol-4-yl, 1-methyl-3-(cyclopropyl-carbonyl-amino)-pyrazol-4-yl, 1-methyl-4-(cyclopropyl-carbonyl-amino)-pyrazol-5-yl, imidazol-2-yl, 2-(trifluoro-methyl)-imidazol-4-yl, 1-methyl-imidazol-2-yl, 4-(hydroxy-methyl)-thiazol-2-yl, 2-(hydroxy-methyl)-thiazol-4-yl, 2-(amino-carbonyl)-thiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-5-yl, 1-methyl-(1,2,4-triazol-3-yl), 1-methyl-1,2,3-triazol-5-yl, 3-fluoro-pyridin-4-yl-2-one, 3-fluoro-pyridin-4-yl, 2-fluoro-5-chloro-pyridin-4 -yl, 2-(difluoromethoxy)-pyridin-4-yl, 2-(trifluoro-methyl)-pyridin-4-yl, 2-(cyano-methyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-carboxy-3-fluoro-pyridin-4-yl, 2-(methoxy-carbonyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-d2-methyl)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-ethoxy)-pyridin-4-yl, 2-(2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-2-methyl-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-chloro-6-( 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl,2-(3-Hydroxy-3-methyl-n-butyl)-3-fluoro-pyridin-3-yl, 2-(1,1-difluoro-2-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(1S*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 4-amino-pyridin-3-yl, 2-chloro-6-amino-pyridin-3-yl, 3-chloro-6-amino-pyridin-4-yl, 2-amino-3-methyl-pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-amino-6-(trifluoro-methyl)-pyridin-3-yl 2-(1,1-dimethyl-2-hydroxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-propyl)-3-fluoro-pyridin-4-yl, ... -n-propyl)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2R*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deuterated 6-amino-pyridin-3-yl, 2-fluoro-5-deuterated 6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated 6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated 6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(N-ethyl-N-2-hydroxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(amino-carbonyl)-pyridin-4-yl, 2-(amino-carbonyl)-pyridin-5-yl, 2-(amino-carbonyl)-pyridin- 2-(2-methoxy-ethyl-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(amino-carbonyl-methyl)-3-fluoro-pyridin-4-yl, 3-(trifluoromethyl-carbonyl-amino)-pyridin-4-yl, 3-(3-methyl-carbonyl-amino)-pyridin-4-yl, 3-chloro-6-(methyl-carbonyl-amino)-pyridin-4-yl, 5-(methoxy-carbonyl-amino)-pyridin-2-yl, 2-(methoxy-carbonyl-amino)-pyridin-5-yl, 2-(methoxy-carbonyl-amino)-pyridin-4-yl,2-(Methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 2-(ethoxy-carbonyl-amino)-pyridin-3-yl, 4-(ethoxy-carbonyl-amino)-pyridin-3-yl, 2-(ethoxy-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 3-(methyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(1S-amino-isopropyl-carbonyl-oxo-methyl)-3-fluoro-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, acyl-amino)-3-fluoro-pyridin-4-yl, 2-(phosphono-oxy-methyl)-3-fluoro-pyridin-4-yl, 2-(phosphono-methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-3-chloro-pyridin-4-yl, 2-(2-cyano-cyclopropyl-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2 -(oxetane-3-yl)-3-fluoro-pyridin-4-yl, 2-(3-cyano-oxetane-3-yl)-3-fluoro-pyridin-4-yl, 2-(azetidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(3-cyano-azetidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(pyrrolidin-1-yl-2-one)-3-fluoro-pyridin-4-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(3S-hydroxy-piperidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(pyrazol-1-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-2-yl, 2-(pyrazol-5-yl)-pyridin-4-yl, 2-(Pyrazol-5-yl)-3-fluoro-pyridin-4-yl, 2-(5-amino-pyrazol-1-yl)-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(5-amino-pyrazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-pyridin-4-yl, 2-(imidazol-2-yl)-3-fluoro-pyridin-4-yl, 2-(1,2,3-triazol-1-yl)-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 2-(1,2,3-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(1,3,4-triazol-1-yl)-3-fluoro-pyridin-4-yl,2-(1,2,4-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(, Oxazolidin-3-yl-2-one)-3-fluoro-pyridin-4-yl, 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3-fluoro-pyridin-4-yl, 2-(di Alkyl-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1R*- Oxazol-2-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S*- Oxazol-2-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S-(1,3,4- oxadiazole-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(3,3-difluoro-azetidin-1-yl-carbonyl)-3-fluoro-pyridin-4-yl, 2-fluoro-6-(bicyclo[1.1.1]pentyl-amino)-pyridin-3-yl, 2-(bicyclo[1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, 2-(bicyclo[1.1.1]pentyl-amino-carbonyl)-3-fluoro-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(3-methyl-isoxadiazole-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(3,3-difluoro-azetidin-1-yl-carbonyl)-3-fluoro-pyridin-4-yl, 2-fluoro-6-(bicyclo[1.1.1]pentyl-amino)-pyridin-3-yl, 2-(bicyclo[1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, oxazol-5-yl-carbonyl-amino)-3-fluoro-pyridin-4-yl, pyridin-4-yl-2-one, pyridin-4-yl-N-oxide, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl-N-oxide, indol-3-yl, indol-6-yl, indol-5-yl, indol-5-yl-2-one, 7-fluoro-indol-6-yl, indazol-5-yl, indazol-4-yl, 3-( methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, indolin-5-yl-2-one, 6-methyl-indolin-7-yl-2-one, benzimidazol-5-yl, 2-methyl-benzimidazol-6-yl, benzimidazol-5-yl-2-one, 1-methyl-benzimidazol-6-yl-2-one, 1-methyl-benzimidazol-5-yl-2-one, 3-amino-benzisodazole oxazol-5-yl, benzo oxazol-6-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 6-methyl-quinoxalin-5-yl-2(1H)-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 2,3-dihydrofuro[2,3-b]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-c ]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 5-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[3,2-c]pyridin-3-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl and 1H-pyrazolo[3,4-b]pyridin-5-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 2,3-dihydro-[1,4]dihydro- quino[2,3-b]pyridin-8-yl and 7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl-7-ol.

[0277] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of: 2-methoxy-phenyl, 2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-3-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)-phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 2-(methoxy-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl, 2-carboxy-thiophene -5-yl, 2-carboxy-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-4-yl, 3-(cyclopropyl-carbonyl-amino)-thiophen-2-yl, 2-(methyl-sulfonyl-amino-carbonyl)-3-fluoro-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3-fluoro-pyrazol-4-yl, 3-chloro-pyrazol-4-yl, 3-methoxy-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 5-chloro-pyrazol-4-yl, 2-(amino-carbonyl)-thiazol-5-yl, 3-fluoro-pyridin-4-yl-2-one, 3-fluoro-pyridin-4-yl-2-one, pyridin-4-yl, 2-(difluoromethoxy)-pyridin-4-yl, 2-(trifluoro-methyl)-pyridin-4-yl, 2-(cyano-methyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-carboxy-3-fluoro-pyridin-4-yl, 2-(methoxy-carbonyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-d2-methyl)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-ethoxy)-pyridin-4-yl, 2-(2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-2-methyl-n-propyl-oxy)-3-fluoro-pyridin- 4-yl, 2-chloro-6-(hydroxy-methyl)-pyridin-3-yl, 2-fluoro-6-(hydroxy-methyl)-pyridin-3-yl, 2-(hydroxy-d2-methyl)-3-chloro-pyridin-4-yl, 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 2-(3-hydroxy-3-methyl-n-butyl)-3-fluoro-pyridin-3-yl, 2-(1,1-difluoro-2-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(1S*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R *-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 3-chloro-6-amino-pyridin-4-yl, 2-amino-3-methyl-pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin-3-yl yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-amino-3-methoxy-pyridin-4-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(1,1-dimethyl-2-hydroxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy- n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2R*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(N-ethyl-N-2-hydroxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(amino-carbonyl)-pyridin-5-yl, 2-(amino-carbonyl)-3-fluoro-pyridin-3-yl, 2-(2-methoxy-ethyl-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(amino-carbonyl-methyl)-3-fluoro-pyridin-4-yl, 3-(trifluoromethyl-carbonyl-amino)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-pyridin-4-yl, 5-(methoxy)-6-(methyl-amino)-pyridin-3-yl, 2-(Methyl-carbonyl-amino)-pyridin-2-yl, 2-(methoxy-carbonyl-amino)-pyridin-5-yl, 2-(methoxy-carbonyl-amino)-pyridin-4-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 2-(ethoxy-carbonyl-amino)-pyridin-3-yl, 2-(ethoxy-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 2-(1S-amino-isopropyl-carbonyl-oxo-methyl)-3-fluoro-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(phosphono- 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(oxetan-3-yl)-3-fluoro-pyridin-4-yl, 2-(azetidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, (3-Cyano-azetidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(3S-hydroxy-piperidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(pyrazol-1-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-3-fluoro-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-pyridin-4-yl, 2-(imidazol-2-yl)-3-fluoro-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 2-(1,2,5-triazol-1-yl)-pyridin-4-yl,4-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(, Oxazolidin-3-yl-2-one)-3-fluoro-pyridin-4-yl, 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3-fluoro-pyridin-4-yl, 2-(di Alkyl-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S*- Oxazol-2-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S-(1,3,4- oxadiazole-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(bicyclo[1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(3-methyl-isoxadiazole)-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(bicyclo[1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, oxazol-5-yl-carbonyl-amino)-3-fluoro-pyridin-4-yl, pyridin-4-yl-2-one, indol-3-yl, indol-6-yl, indol-5-yl, indol-5-yl-2-one, 7-fluoro-indol-6-yl, indazol-5-yl, indazol-4-yl, 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, indolin-5-yl-2-one, 6-methyl-indolin-7-yl-2-one, benzimidazol-5-yl, 2-methyl-benzimidazol-6-yl, benzimidazol-5-yl-2-one, 1-methyl-benzimidazol-6-yl-2-one, 1-methyl-benzimidazol-5-yl-2-one, 3-amino-benzisodazole oxazol-5-yl, benzo oxazol-6-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 6-methyl-quinoxalin-5-yl-2(1H)-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 2,3-dihydrofuro[2,3-b]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2, 3-b]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[3,2-c]pyridin-3-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 2,3-dihydro-[1,4]dioxadiazine quino[2,3-b]pyridin-8-yl and 7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl-7-ol.

[0278] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of 2-fluoro-4-(amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)-phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl, 2-carboxy-thiophen-5-yl, 2-carboxy-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl , 2-(amino-carbonyl)-3-fluoro-thiophen-4-yl, 3-(cyclopropyl-carbonyl-amino)-thiophen-2-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3-chloro-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 5-chloro-pyrazol-4-yl, 1-methyl-4-(cyclopropyl-carbonyl-amino)-pyrazol-5-yl, 2-(amino-carbonyl)-thiazol-5-yl, 2-carboxy-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-ethoxy)-pyridin-4-yl, 2-(2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-2- 2-(2-Methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(2-methyl-3-fluoro-6-amino-pyridin-3-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3 ... -yl, 2-fluoro-6-(methyl-amino)-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-amino-3-methoxy-pyridin-4-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deutero-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-amino-carbonyl)-3-fluoro-pyridin-4-yl, 3-(trifluoromethyl-carbonyl-amino)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-pyridin-4-yl, 5-(methoxy-carbonyl-amino)-pyridin-2-yl, 2-(methoxy-carbonyl- amino)-pyridin-5-yl, 2-(methoxy-carbonyl-amino)-pyridin-4-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(ethoxy-carbonyl-amino)-pyridin-3-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(phosphono-oxy-methyl)-3-fluoro-pyridin-4 -yl, 2-(phosphono-methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(3-cyano-azetidin-1-yl)-3- Fluoro-pyridin-4-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(pyrazol-1-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-3-fluoro-pyridin-4-yl, 2-(imidazol-2-yl)-3-fluoro-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 2-(di, (alkyl-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, pyridin-4-yl-2-one, indol-5-yl-2-one, 7-fluoro-indol-6-yl, indazol-5-yl, 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, benzimidazol-5-yl, 2-methyl-benzimidazol-6-yl, benzimidazol-5-yl-2-one, 1-methyl-benzimidazol-6-yl-2-one, 1-methyl-benzimidazol-5-yl-2-one, benzo oxazol-6-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 2,3-dihydrofuro[2,3-b]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 1H-pyrrolo[2,3 -b]pyridin-4-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one and 2,3-dihydro-[1,4]dihydro- Ino[2,3-b]pyridin-8-yl.

[0279] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of 2-fluoro-4-(amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)-phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl, 2-carboxy-thiophen-5-yl, 2-carboxy-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 3-(trifluoro-methyl)-thiophene. -pyrrol-4-yl, 3-chloro-pyrazole-4-yl, 3-(trifluoromethyl)-pyrazole-4-yl, 1-methyl-4-(cyclopropyl-carbonyl-amino)-pyrazole-5-yl, 2-(amino-carbonyl)-thiazol-5-yl, 2-carboxy-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin -3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deutero-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 5-(methoxy-carbonyl-amino)-pyridin-2-yl, 2-(Methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(phosphono-oxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, benzimidazol-5-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1,4-dihydro-2H-benzo[d][1,3], Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one and 2,3-dihydro-[1,4]dihydro- Ino[2,3-b]pyridin-8-yl.

[0280] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of: 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-carboxy-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 2-(amino-carbonyl)-thiazol-5-yl, 2-carboxy-3-fluoro-pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2- hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-fluoro-4,5-dideutero-6-amino-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, benzimidazol-5-yl-2-one, 2H-quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one and 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one.

[0281] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of: 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(amino-carbonyl)-thiophen-5-yl, 2-(amino-carbonyl)-thiazol-5-yl, 2-chloro-6-amino-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 3-amino-indazol-6-yl, 2H-quinolin-6-yl-2-one, 1H-pyrrolo[2,3-b]pyridin-4-yl and 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one.

[0282] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of 2-methoxy-phenyl, 2-(isopropoxy)-phenyl, 3-fluoro-4-carboxy-phenyl, 2-amino-phenyl, 2-(dimethyl-amino)-phenyl, 2-(amino-carbonyl)-phenyl, 2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-3-(amino-carbonyl)-phenyl, 3-(amino-carbonyl)-4-fluoro-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 2-(methyl-amino-carbonyl)-phenyl, 2-(dimethyl-amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)- phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 2-(methoxy-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 4-(1R-(methyl-carbonyl-amino)-ethyl)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl, 2-(methyl-sulfonyl-amino)-phenyl and 4-( Oxazolidin-3-yl-2-one)-phenyl.

[0283] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of 2-methoxy-phenyl, 2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-3-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)-phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 2-(methoxy-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl and 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl. In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of 2-fluoro-4-(amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)-phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl and 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl. In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of 4-(methoxy-carbonyl-amino)-phenyl and 2-(cyclopropyl-carbonyl-amino)-phenyl.

[0284] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of: 2-carboxyl-thiophen-5-yl, 2-carboxyl-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-4-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-5-yl, 3-(cyclopropyl-carbonyl-amino)-thiophen-2-yl, 2-(methyl-sulfonyl-amino-carbonyl)-3-fluoro-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 4-chloro-pyrazol-3-yl, 3-fluoro-pyrazol-4-yl, 3-chloro-pyrazol-4-yl, 3-methoxy-pyrazol-4-yl, 3-(cyclopropyl-carbonyl-amino)-thiophen-2-yl, -(trifluoromethyl)-pyrazol-4-yl, 5-chloro-pyrazol-4-yl, 1-methyl-3-(cyclopropyl-carbonyl-amino)-pyrazol-4-yl, 1-methyl-4-(cyclopropyl-carbonyl-amino)-pyrazol-5-yl, imidazol-2-yl, 2-(trifluoro-methyl)-imidazol-4-yl, 1-methyl-imidazol-2-yl, 4-(hydroxy-methyl)-thiazol-2-yl, 2-(hydroxy-methyl)-thiazol-4-yl, 2-(amino-carbonyl)-thiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-5-yl, 1-methyl-(1,2,4-triazol-3-yl) and 1-methyl-1,2,3-triazol-5-yl.

[0285] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of: 2-carboxy-thiophen-5-yl, 2-carboxy-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-4-yl, 3-(cyclopropyl-carbonyl-amino)-thiophen-2-yl, 2-(methyl-sulfonyl-amino-carbonyl)-3-fluoro-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3-fluoro-pyrazol-4-yl, 3-chloro-pyrazol-4-yl, 3-methoxy-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 5-chloro-pyrazol-4-yl and 2-(amino-carbonyl)-thiazol-5-yl. In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of: 2-carboxy-thiophene-5-yl, 2-carboxy-3-fluoro-thiophene-5-yl, 2-(amino-carbonyl)-thiophene-4-yl, 2-(amino-carbonyl)-thiophene-5-yl, 2-(amino-carbonyl)-3-fluoro-thiophene-4-yl, 3-(cyclopropyl-carbonyl-amino)-thiophene-2-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3-chloro-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 5-chloro-pyrazol-4-yl, 1-methyl-4-(cyclopropyl-carbonyl-amino)-pyrazol-5-yl and 2-(amino-carbonyl)-thiazol-5-yl.

[0286] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of: 2-carboxyl-thiophen-5-yl, 2-carboxyl-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3-chloro-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 1-methyl-4-(cyclopropyl-carbonyl-amino)-pyrazol-5-yl and 2-(amino-carbonyl)-thiazol-5-yl. In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of 2-carboxy-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl and 2-(amino-carbonyl)-thiazol-5-yl.

[0287] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of: 3-fluoro-pyridin-4-yl-2-one, 3-fluoro-pyridin-4-yl, 2-fluoro-5-chloro-pyridin-4-yl, 2-(difluoromethoxy)-pyridin-4-yl, 2-(trifluoro-methyl)-pyridin-4-yl, 2-(cyano-methyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-carboxy-3-fluoro-pyridin-4-yl, 2-(methoxy-carbonyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-d2-methyl)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-ethoxy)-pyridin-4-yl, 2-(2-hydroxy-n-propyl-oxy) -3-fluoro-pyridin-4-yl, 2-(2-hydroxy-2-methyl-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-chloro-6-(hydroxy-methyl)-pyridin-3-yl, 2-fluoro-6-(hydroxy-methyl)-pyridin-3-yl, 2-(hydroxy-d2-methyl)-3-chloro-pyridin-4-yl, 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-2-methyl-n-propyl-oxy)-3-fluoro-pyridin-4-yl , 2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 2-(3-hydroxy-3-methyl-n-butyl)-3-fluoro-pyridin-3-yl, 2-(1,1-difluoro-2-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(1S*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 4-amino-pyridin-3-yl, 2-chloro-6-amino-pyridin-3-yl, 3-chloro-6-amino-pyridin-4-yl, 2-amino-3-methyl -pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-amino-6-(trifluoro-methyl)-pyridin-5-yl, 2-(methyl-amino)-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin-3-yl, 2-fluoro-6-(dimethyl-amino)-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-amino-3-methoxy-pyridin-4-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(1,1-dimethyl-2-hydroxy-ethyl-amino)-3-fluoro-pyridin-4-yl,2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2R*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deutero-6-amino-pyridin-3-yl, 2-fluoro-5-deutero-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(N-ethyl-N-2-hydroxy-ethyl-amino)-3-fluoro- Pyridin-4-yl, 2-(amino-carbonyl)-pyridin-4-yl, 2-(amino-carbonyl)-pyridin-5-yl, 2-(amino-carbonyl)-3-fluoro-pyridin-3-yl, 2-chloro-6-(amino-carbonyl)-pyridin-3-yl, 2-(2-methoxy-ethyl-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(amino-carbonyl-methyl)-3-fluoro-pyridin-4-yl, 3-(trifluoromethyl-carbonyl-amino)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-pyridin-4-yl, 3-chloro-6-(methyl-carbonyl-amino)-pyridin-4-yl, 5-(methoxy-carbonyl-amino)-pyridin- 2-yl, 2-(methoxy-carbonyl-amino)-pyridin-5-yl, 2-(methoxy-carbonyl-amino)-pyridin-4-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 2-(ethoxy-carbonyl-amino)-pyridin-3-yl, 4-(ethoxy-carbonyl-amino)-pyridin-3-yl, 2-(ethoxy-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 3-(methyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(1S-amino-isopropyl-carbonyl-oxy 2-(1-Hydroxy-1-methyl)-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-methyl)-pyridin-4-yl,3-(Cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(Cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(oxetan-3-yl)-3-fluoro-pyridin-4-yl, 2-(3-cyano-oxetan-3-yl)-3-fluoro-pyridin-4-yl, 2-(azetidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(3-cyano-azetidin-1-yl)-3 -fluoro-pyridin-4-yl, 2-(pyrrolidin-1-yl-2-one)-3-fluoro-pyridin-4-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(3S-hydroxy-piperidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(pyrazol-1-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-2-yl, 2-(pyrazol-5-yl)-pyridin-5-yl -4-yl, 2-(pyrazol-5-yl)-3-fluoro-pyridin-4-yl, 2-(5-amino-pyrazol-1-yl)-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(5-amino-pyrazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-pyridin-4-yl, 2-(imidazol-2-yl)-3-fluoro- Pyridin-4-yl, 2-(1,2,3-triazol-1-yl)-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 2-(1,2,3-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(1,3,4-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(1,2,4-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(, Oxazolidin-3-yl-2-one)-3-fluoro-pyridin-4-yl, 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3-fluoro-pyridin-4-yl, 2-(di Alkyl-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1R*- Oxazol-2-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S*- Oxazol-2-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S-(1,3,4- oxadiazole-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(3,3-difluoro-azetidin-1-yl-carbonyl)-3-fluoro-pyridin-4-yl, 2-fluoro-6-(bicyclo[1.1.1]pentyl-amino)-pyridin-3-yl, 2-(bicyclo[1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, 2-(bicyclo[1.1.1]pentyl-amino-carbonyl)-3-fluoro-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(3-methyl-isoxadiazole-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(3,3-difluoro-azetidin-1-yl-carbonyl)-3-fluoro-pyridin-4-yl, 2-fluoro-6-(bicyclo[1.1.1]pentyl-amino)-pyridin-3-yl, 2-(bicyclo[1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, oxazol-5-yl-carbonyl-amino)-3-fluoro-pyridin-4-yl, pyridin-4-yl-2-one, pyridin-4-yl-N-oxide and 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl-N-oxide.

[0288] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of: 3-fluoro-pyridin-4-yl-2-one, 3-fluoro-pyridin-4-yl, 2-(difluoromethoxy)-pyridin-4-yl, 2-(trifluoro-methyl)-pyridin-4-yl, 2-(cyano-methyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-carboxy-3-fluoro-pyridin-4-yl, 2-(methoxy-carbonyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-d2-methyl)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-ethoxy)-pyridin-4-yl, 2-(2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(2- 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl yl, 2-(1R*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 2-(3-hydroxy-3-methyl-n-butyl)-3-fluoro-pyridin-3-yl, 2-(1,1-difluoro-2-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(1S*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 3-chloro-6-amino-pyridin-4-yl, 2-amino-3-methyl-pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro- pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-amino-3-methoxy-pyridin-4-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(1,1-dimethyl-2-hydroxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl,3-trifluoro-2R*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated-6-amino-pyridin-3-yl,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(N-ethyl-N-2-hydroxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(amino-carbonyl)-pyridin-5-yl, 2-(amino-carbonyl)-3-fluoro-pyridin-3-yl, 2-(2-methoxy-ethyl-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(amino-carbonyl-methyl)-3-fluoro-pyridin-4-yl, 3-(trifluoromethyl-carbonyl-amino)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-pyridin-4-yl, 5-(methoxy)-6-(methyl-amino)-pyridin-3-yl, 2-(Methyl-carbonyl-amino)-pyridin-2-yl, 2-(methoxy-carbonyl-amino)-pyridin-5-yl, 2-(methoxy-carbonyl-amino)-pyridin-4-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 2-(ethoxy-carbonyl-amino)-pyridin-3-yl, 2-(ethoxy-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 2-(1S-amino-isopropyl-carbonyl-oxo-methyl)-3-fluoro-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(phosphono- 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(oxetan-3-yl)-3-fluoro-pyridin-4-yl, 2-(azetidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, (3-Cyano-azetidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(3S-hydroxy-piperidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(pyrazol-1-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-3-fluoro-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-pyridin-4-yl, 2-(imidazol-2-yl)-3-fluoro-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 2-(1,2,5-triazol-1-yl)-pyridin-4-yl,4-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(, Oxazolidin-3-yl-2-one)-3-fluoro-pyridin-4-yl, 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3-fluoro-pyridin-4-yl, 2-(di Alkyl-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S*- Oxazol-2-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S-(1,3,4- oxadiazole-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(bicyclo[1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(3-methyl-isoxadiazole)-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(bicyclo[1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, Oxazol-5-yl-carbonyl-amino)-3-fluoro-pyridin-4-yl and pyridin-4-yl-2-one.

[0289] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of: 2-carboxyl-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-fluoro-6-(methyl)- -amino)-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deutero-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-amino 2-(Methyl-amino)-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 5-(methoxy-carbonyl-amino)-pyridin-2-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(phosphono-oxy-methyl)-3-fluoro-pyridin- -4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-4-yl and 1-(1,2,5-triazol-1-yl)-pyridin-4-yl.

[0290] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of: 2-carboxy-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-ethoxy)-pyridin-4-yl, 2-(2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-2-methyl-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-2-methyl-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(hydroxy-2-methyl)-3-chloro- Pyridin-4-yl, 2-(1R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 2-(3-hydroxy-3-methyl-n-butyl)-3-fluoro-pyridin-3-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl , 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-amino-3-methoxy-pyridin-4-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2 -(methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-amino-carbonyl)-3-fluoro-pyridin-4-yl, 3-(trifluoromethyl-carbonyl-amino)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-pyridin-4-yl, 5-(methoxy-carbonyl-amino)-pyridin-2-yl, 2-(methoxy-carbonyl- amino)-pyridin-5-yl, 2-(methoxy-carbonyl-amino)-pyridin-4-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(ethoxy-carbonyl-amino)-pyridin-3-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(phosphono-oxy-methyl)-3-fluoro-pyridin-4 -yl, 2-(phosphono-methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(3-cyano-azetidin-1-yl)-3- Fluoro-pyridin-4-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(pyrazol-1-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-3-fluoro-pyridin-4-yl, 2-(imidazol-2-yl)-3-fluoro-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 2-(di, Alkyl-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl and pyridin-4-yl-2-one.

[0291] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of: 2-carboxy-3-fluoro-pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl- 2-Hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-fluoro-4,5-dideutero-6-amino-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-pyridin-4-yl and 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl.

[0292] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of indol-3-yl, indol-6-yl, indol-5-yl, indol-5-yl-2-one, 7-fluoro-indol-6-yl, indazol-5-yl, indazol-4-yl, 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, indolin-5-yl-2-one, 6-methyl-indolin-7-yl-2-one, benzimidazol-5-yl, 2-methyl-benzimidazol-6-yl, benzimidazol-5-yl-2-one, 1-methyl-benzimidazol-6-yl-2-one, 1-methyl-benzimidazol-5-yl-2-one, 3-amino-benzisodazole oxazol-5-yl, benzo oxazol-6-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 6-methyl-quinoxalin-5-yl-2(1H)-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 2,3-dihydrofuro[2,3-b]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-c ]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 5-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[3,2-c]pyridin-3-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl and 1H-pyrazolo[3,4-b]pyridin-5-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 2,3-dihydro-[1,4]dihydro- quino[2,3-b]pyridin-8-yl and 7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl-7-ol.

[0293] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of indol-3-yl, indol-6-yl, indol-5-yl, indol-5-yl-2-one, 7-fluoro-indol-6-yl, indazol-5-yl, indazol-4-yl, 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, indolin-5-yl-2-one, 6-methyl-indolin-7-yl-2-one, benzimidazol-5-yl, 2-methyl-benzimidazol-6-yl, benzimidazol-5-yl-2-one, 1-methyl-benzimidazol-6-yl-2-one, 1-methyl-benzimidazol-5-yl-2-one, 3-amino-benzisodazole oxazol-5-yl, benzo oxazol-6-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 6-methyl-quinoxalin-5-yl-2(1H)-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 2,3-dihydrofuro[2,3-b]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2, 3-b]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[3,2-c]pyridin-3-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 2,3-dihydro-[1,4]dihydro- quino[2,3-b]pyridin-8-yl and 7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl-7-ol.

[0294] In some embodiments, the present invention relates to compounds of formula (I), wherein Selected from the group consisting of indol-5-yl-2-one, 7-fluoro-indol-6-yl, indazol-5-yl, 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, benzimidazol-5-yl, 2-methyl-benzimidazol-6-yl, benzimidazol-5-yl-2-one, 1-methyl-benzimidazol-6-yl-2-one, 1-methyl-benzimidazol-5-yl-2-one, benzo oxazol-6-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 2,3-dihydrofuro[2,3-b]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 1H-pyrrolo[2,3 -b]pyridin-4-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one and 2,3-dihydro-[1,4]dihydro- In some embodiments, the present invention relates to a compound of formula (I), wherein Selected from the group consisting of: 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, benzimidazol-5-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-copper and 2,3-dihydro-[1,4]dihydro- In some embodiments, the present invention relates to a compound of formula (I), wherein Selected from the group consisting of: 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, benzimidazol-5-yl-2-one, 2H-quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one and 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one.

[0295] In some embodiments, the present invention relates to compounds of formula (I), wherein one or more, preferably one to two, more preferably one, heterocyclyl, heteroaryl or heterocycloalkyl containing a nitrogen atom (as a substituent group (preferably R 5 In some embodiments, the present invention relates to compounds of formula (I), wherein any one or more (preferably one to two, more preferably one) heterocyclyl, heteroaryl or heterocycloalkyl as a nitrogen atom containing Where any part of the group is present, the heterocyclyl, heteroaryl or heterocycloalkyl group may be further substituted to form an N-oxide.

[0296] In some embodiments, the present invention relates to compounds of formula (I), wherein one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, etc.) hydrogen atoms are replaced by deuterium.

[0297] In some embodiments, the present invention relates to compounds of formula (I), wherein the compound of formula (I) In some embodiments, the present invention relates to compounds of formula (I), wherein the hydrogen atoms of the compound of formula (I) are replaced by deuterium. Part 4 (ie R 1 In some embodiments, the present invention relates to compounds of formula (I), wherein the hydrogen atom at the meta position of the compound of formula (I) is replaced by deuterium. The portion is selected from the group consisting of:

[0298] In some embodiments, the present invention relates to compounds of formula (I), wherein R 5 In some embodiments, the present invention relates to compounds of formula (I), wherein R A and R B In some embodiments, the present invention relates to compounds of formula (I), wherein R C and R D In some embodiments, the present invention relates to compounds of formula (I), wherein R A 、R B 、R C and R D Each is a deuterated group.

[0299] In some embodiments, the present invention relates to compounds of formula (I), wherein the hydrogen at position 8a of 2,3,8,8a-tetrahydroindole-5(1H)-one is replaced by deuterium. In some embodiments, the present invention relates to compounds of formula (I), wherein RA 、R B 、R C and R D One or more of the groups is a deuterated group, wherein the hydrogen atom at the 8a position of 2,3,8,8a-tetrahydroindoleazin-5(1H)-one is replaced by deuterium.

[0300] In some embodiments, the present invention relates to compounds of formula (I), wherein R 5 In some embodiments, the present invention relates to compounds of formula (I), wherein R 5 It is a deuterated group, and the hydrogen atom at the 8a position of 2,3,8,8a-tetrahydroindoleazin-5(1H)-one is substituted with deuterium.

[0301] In some embodiments, the present invention relates to compounds of formula (I), wherein the compound of formula (I) Part 4 (ie R 1 The hydrogen atom at the meta position of 2,3,8,8a-tetrahydroindole-5(1H)-one and the hydrogen atom at the 8a position of 2,3,8,8a-tetrahydroindole-5(1H)-one are each replaced by deuterium. In some embodiments, the present invention relates to a compound of formula (I), wherein the The portion is selected from the group consisting of: wherein each hydrogen atom at the 8a position of 2,3,8,8a-tetrahydroindole-5(1H)-one is substituted by deuterium.

[0302] In some embodiments, the present invention relates to compounds of formula (I), wherein one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, etc.), preferably one to six, more preferably one to three hydrogen atoms on the Q portion of the compound of formula (I) are replaced by deuterium.

[0303] In some embodiments, the present invention relates to a compound of formula (I) selected from the group consisting of:

[0304]

[0305]

[0306] and their isotopologues and pharmaceutically acceptable salts.

[0307] In some embodiments, the present invention relates to compounds of formula (Ix)

[0308]

[0309] and their tautomers, stereoisomers, isotopomers and pharmaceutically acceptable salts or solvates. In some embodiments, the present invention relates to a compound of formula (Iy)

[0310]

[0311] Also known as (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindole-5(1H)-one and its tautomers, isotopomers and pharmaceutically acceptable salts or solvates. In some embodiments, the present invention relates to a compound of formula (Iz)

[0312]

[0313] Also known as (3S,8aS)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindole-5(1H)-one and its tautomers, isotopomers and pharmaceutically acceptable salts or solvates.

[0314] Those skilled in the art will recognize that, depending on the substituent groups, the compounds of the present invention may contain one or more stereocenters, including, for example, the stereocenters represented by the "*" symbol in the structure of Formula (I) shown below:

[0315]

[0316] Unless otherwise indicated, the asterisk ("*") stereocenter at the bridge carbon atom of the 2,3,8,8a-tetrahydroindole-5(1H)-one structure shall be referred to as a "ring" stereocenter. Those skilled in the art will further recognize that where a compound of Formula (I) exists in stereoisomeric excess of one of the corresponding ring stereoisomers, then the compound may alternatively be referred to as the corresponding atropisomer.

[0317] Unless otherwise stated, the same as R A and R B The asterisk ("*") stereocenter at the carbon atom of the bound 2,3,8,8a-tetrahydroindole-5(1H)-one structure shall be referred to as "R A / R B ″stereocenter; with R C and R D The asterisk ("*") stereocenter at the carbon atom of the bound 2,3,8,8a-tetrahydroindole-5(1H)-one structure shall be referred to as "R C / R D″stereocenter; with R E The asterisk ("*") stereocenter at the carbon atom of the bound 2,3,8,8a-tetrahydroindole-5(1H)-one structure shall be referred to as "R E "Stereocenter; The asterisk ("*") stereocenter at the carbon atom of the 2,3,8,8a-tetrahydroindole-5(1H)-one structure to which the Q substituent group is bound shall be referred to as a "Q" stereocenter.

[0318] In some embodiments, the present invention relates to compounds of formula (I), wherein the cyclic stereocenter is present as a racemic mixture. In some embodiments, the present invention relates to compounds of formula (I), wherein the cyclic stereocenter is present in enantiomeric excess of the corresponding R-enantiomer. In some embodiments, the present invention relates to compounds of formula (I), wherein the cyclic stereocenter is present in enantiomeric excess of the corresponding S-enantiomer.

[0319] In some embodiments, the present invention relates to compounds of formula (I), wherein the ring stereocenter is present in a stereoisomeric excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% of the R-enantiomer or the S-enantiomer. Preferably, the compound of formula (I) is present in a stereoisomeric excess of greater than or equal to about 80%, preferably greater than or equal to about 90%, more preferably greater than or equal to about 93%, more preferably greater than or equal to about 95%, more preferably greater than or equal to about 97%, more preferably greater than or equal to about 98%, more preferably greater than or equal to about 99% of the ring stereocenter.

[0320] In some embodiments, the present invention relates to compounds of formula (I), wherein R A / R B The stereocenter exists as a racemic mixture. In some embodiments, the present invention relates to compounds of formula (I), wherein R A / R B The stereocenter is present in enantiomeric excess of the corresponding R-enantiomer. In some embodiments, the present invention relates to compounds of formula (I), wherein R A / R B The stereocenter is present in enantiomeric excess of the corresponding S-enantiomer.

[0321] In some embodiments, the present invention relates to compounds of formula (I), wherein R A / R BThe stereocenter is present in a stereoisomeric excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% of the R-enantiomer or the S-enantiomer. Preferably, the compound of formula (I) is present in a stereoisomeric excess of greater than or equal to about 80%, preferably greater than or equal to about 90%, more preferably greater than or equal to about 93%, more preferably greater than or equal to about 95%, more preferably greater than or equal to about 97%, more preferably greater than or equal to about 98%, more preferably greater than or equal to about 99% of the R-enantiomer. A / R B The stereoisomer at the stereocenter is present in excess.

[0322] In some embodiments, the present invention relates to compounds of formula (I), wherein R C / R D The stereocenter exists as a racemic mixture. In some embodiments, the present invention relates to compounds of formula (I), wherein R C / R D The stereocenter is present in enantiomeric excess of the corresponding R-enantiomer. In some embodiments, the present invention relates to compounds of formula (I), wherein R C / R D The stereocenter is present in enantiomeric excess of the corresponding S-enantiomer.

[0323] In some embodiments, the present invention relates to compounds of formula (I), wherein R C / R D The stereocenter is present in a stereoisomeric excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% of the R-enantiomer or the S-enantiomer. Preferably, the compound of formula (I) is present in a stereoisomeric excess of greater than or equal to about 80%, preferably greater than or equal to about 90%, more preferably greater than or equal to about 93%, more preferably greater than or equal to about 95%, more preferably greater than or equal to about 97%, more preferably greater than or equal to about 98%, more preferably greater than or equal to about 99% of the R-enantiomer. C / R D The stereoisomer at the stereocenter is present in excess.

[0324] In some embodiments, the present invention relates to compounds of formula (I), wherein R E The stereocenter exists as a racemic mixture. In some embodiments, the present invention relates to compounds of formula (I), wherein R EThe stereocenter is present in enantiomeric excess of the corresponding R-enantiomer. In some embodiments, the present invention relates to compounds of formula (I), wherein R E The stereocenter is present in enantiomeric excess of the corresponding S-enantiomer.

[0325] In some embodiments, the present invention relates to compounds of formula (I), wherein R E The stereocenter is present in a stereoisomeric excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% of the R-enantiomer or the S-enantiomer. Preferably, the compound of formula (I) is present in a stereoisomeric excess of greater than or equal to about 80%, preferably greater than or equal to about 90%, more preferably greater than or equal to about 93%, more preferably greater than or equal to about 95%, more preferably greater than or equal to about 97%, more preferably greater than or equal to about 98%, more preferably greater than or equal to about 99% of the R-enantiomer. E The stereoisomer at the stereocenter is present in excess.

[0326] In some embodiments, the present invention relates to compounds of formula (I), wherein the Q stereocenter is present as a racemic mixture. In some embodiments, the present invention relates to compounds of formula (I), wherein the Q stereocenter is present in enantiomeric excess of the corresponding R-enantiomer. In some embodiments, the present invention relates to compounds of formula (I), wherein the Q stereocenter is present in enantiomeric excess of the corresponding S-enantiomer.

[0327] In some embodiments, the present invention relates to compounds of formula (I), wherein the Q stereocenter is present in a stereoisomeric excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% of the R-enantiomer or the S-enantiomer. Preferably, the compound of formula (I) is present in a stereoisomeric excess of greater than or equal to about 80%, preferably greater than or equal to about 90%, more preferably greater than or equal to about 93%, more preferably greater than or equal to about 95%, more preferably greater than or equal to about 97%, more preferably greater than or equal to about 98%, more preferably greater than or equal to about 99% of the ring stereocenter.

[0328] In certain embodiments, the present invention relates to compounds of formula (I), wherein the ring stereocenter is present in excess as the R-configured stereoisomer and the Q stereocenter is present in excess as the S-configured stereoisomer.

[0329] Additional embodiments of the present invention include compounds of Formula (I), (II), (III), and / or (IV) wherein the asterisk ("*") denotes a stereogenic center (i.e., a ring, R A / R B 、R C / R D 、R E , Q, etc.) are each independently present as a racemic mixture or in excess as a stereoisomer in the corresponding R-stereoorientation or S-stereoorientation. Those skilled in the art will recognize that, similarly, additional embodiments of the present invention include compounds of Formula (I), compounds of Formula (II), compounds of Formula (III), and / or compounds of Formula (IV), wherein the asterisk ("*") indicates a stereocenter (i.e., ring, R A / R B 、R C / R D 、R E , Q, etc.) in any combination of stereoconfigurations and any combination of stereoisomeric excesses.

[0330] Additional embodiments of the present invention include those in which the substituents selected for one or more of the variables defined herein (i.e., a, R 1 、R 2 、R A 、R B 、R C 、R D 、R E , Q, etc.) are independently selected from any individual substituent or any subset of substituents selected from the complete list as defined herein. Additional embodiments of the present invention include those in which the substituents (a, R, etc.) selected for one or more of the variables defined herein are 1 、R 2 、R A 、R B 、R C 、R D 、R E , Q, etc.) are independently selected to correspond to any one of the embodiments as defined herein.

[0331] In some embodiments, the present invention is directed to any single compound or subset of compounds independently selected from the list of representative compounds in Tables 1 and 2 below.

[0332] Representative compounds of formula (I) of the present invention are listed in Tables 1 and 2 below. Unless otherwise specified, R 2 The positions of the groups are listed in the table below using the following numbering scheme:

[0333]

[0334] Make R 1 The substituent is bonded to the 6-position of the phenyl group, and R 2 The substituent is bonded to the 2-position, 3-position, 4-position and / or 5-position of the phenyl group.

[0335] In the tables below, where one column lists the stereoorientation of a particular stereocenter (as indicated by the column title), "RAC" shall indicate that the compound was prepared as a racemic mixture at the designated stereocenter. The S* and R* designations shall indicate that, although the compound was prepared in stereoisomer excess of one of the corresponding stereoisomers at the designated stereocenter, the exact stereoconfiguration has not been determined. The S and R designations shall indicate that the compound was prepared in stereoisomer excess of the corresponding S or R stereoisomer at the designated stereocenter, with the exact stereoconfiguration as indicated.

[0336] Table 1: Representative compounds of formula (I)

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368] Table 2: Representative compounds of formula (I)

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377] As used herein, the "*" symbol or notation shall denote the presence of a stereogenic center.

[0378] If the compounds according to the present invention have at least one chiral center, they may exist in enantiomeric forms accordingly. If the compounds have two or more chiral centers, they may also exist in diastereomeric forms. It should be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. It should also be understood that atropisomers (specific types of stereoisomers caused by steric hindrance or other obstacles to rotation) are also encompassed within the scope of the present invention.

[0379] Preferably, where the compound exists as an enantiomer, the enantiomer is present in an enantiomeric excess of greater than or equal to about 80%, more preferably, in an enantiomeric excess of greater than or equal to about 90%, still more preferably, in an enantiomeric excess of greater than or equal to about 95%, still more preferably, in an enantiomeric excess of greater than or equal to about 98%, and most preferably, in an enantiomeric excess of greater than or equal to about 99%. Similarly, where the compound exists as diastereomers or stereoisomers, the diastereomers or stereoisomers are present in greater than or equal to about 80% diastereomer or stereoisomer excess, more preferably greater than or equal to about 90% diastereomer or stereoisomer excess, still more preferably greater than or equal to about 95% diastereomer or stereoisomer excess, still more preferably greater than or equal to about 98% diastereomer or stereoisomer excess, and most preferably greater than or equal to about 99% diastereomer or stereoisomer excess.

[0380] In some embodiments, the present invention relates to one of the R-enantiomer or the S-enantiomer (in the case of R indicated by "*") 3 In some embodiments of the present invention, the compound of formula (I) is present in an enantiomeric excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% of one of the R-enantiomer or the S-enantiomer (in the case of R-enantiomers indicated by "*"). 3 Preferably, the compound of formula (I), the compound of formula (II), the compound of formula (III) and / or the compound of formula (IV) is present in an enantiomeric excess of greater than or equal to about 80%, preferably greater than or equal to about 90%, more preferably greater than or equal to about 93%, more preferably greater than or equal to about 95%, more preferably greater than or equal to about 97%, more preferably greater than or equal to about 98%, more preferably greater than or equal to about 99% of one of the R-enantiomer or the S-enantiomer (in the case of R indicated by "*") 3 The enantiomeric excess of the stereogenic center) is present.

[0381] In some embodiments, the present invention relates to compounds of formula (I), (II), (III), and / or (IV) in a diastereomeric or stereoisomer excess of one of the possible diastereomers or stereoisomers. In some embodiments of the present invention, the compounds of formula (I), (II), (III), and / or (IV) are present in a diastereomeric or stereoisomer excess of one of the possible diastereomers or stereoisomers of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%. Preferably, the compound of formula (I), the compound of formula (II), the compound of formula (III) and / or the compound of formula (IV) is present in a diastereomeric or stereoisomer excess of one of the possible diastereomers or stereoisomers of greater than or equal to about 80%, preferably greater than or equal to about 90%, more preferably greater than or equal to about 93%, more preferably greater than or equal to about 95%, more preferably greater than or equal to about 97%, more preferably greater than or equal to about 98%, more preferably greater than or equal to about 99%.

[0382] In addition, some crystalline forms of the compound of the present invention can exist in polymorphic form, and are equally intended to be included in the present invention. In addition, some compounds of the present invention can form solvates (i.e. hydrates) with water or form solvates with common organic solvents, and such solvates are also intended to be included in the scope of the present invention.

[0383] As used herein, unless otherwise indicated, the term "isotopologue" shall mean a molecule that differs only in its isotopic composition. More specifically, an isotopologue of a molecule differs from the parent molecule in that the former contains at least one atom that is an isotope (i.e., has a different number of neutrons than the parent atom). For example, isotopologues of water include, but are not limited to: "light water" (HOH or HO); "semi-heavy water" (HDO or H2O), which contains deuterium isotopes in equal proportions to protium; "half-heavy water" (HDO or H2O), which contains deuterium isotopes in equal proportions to protium; and "half-heavy water" (HDO or H2O). 1 H 2 HO); "heavy water" (d2O or 2 H2O); "super heavy water" or tritiated water (T2O or 3 H2O), in which the hydrogen atoms are replaced by tritium ( 3 H) isotope substitution; two heavy-oxygen water isotopologues (H2 18 O and H2 17 O) and isotopologues, in which hydrogen and oxygen atoms can each be independently replaced by an isotope (e.g., doubly labeled water isotopologue d2 18 O) Replacement.

[0384] Within the scope of the present invention, any one or more elements (especially when referred to in relation to compounds of formula (I)) are intended to include all isotopes or isotopic mixtures of said elements (naturally occurring or synthetically prepared) in their natural abundance or in their isotopically enriched form. For example, a reference to hydrogen includes within its scope 1 H. 2 H(D) and 3 H(T). Similarly, references to carbon and oxygen include within their scope 12 C. 13 C and 14 C and 16 O and 18 O. Isotopes may be radioactive or non-radioactive. The radiolabeled compound of formula (I) may contain one or more radioactive isotopes selected from the group consisting of: 3 H. 11 C. 18 F. 122 I. 123 I. 12 5I, 131 I. 75 Br, 76 Br, 77 Br and 82 Br. Preferably, the radioisotope is selected from the group consisting of 3 H. 11 C and 18 F's group.

[0385] As used herein, unless otherwise indicated, the term "isotope" shall mean an isomer containing isotopic atoms, the same number of each isotope of each element but in different positions. Isotopes include both constitutional isomers and stereoisomers based solely on isotopic position. For example, CH3CHDCH3 and CH3CH2CH2D are a pair of constitutional isotopomers of n-propane; while (R)-CH3CHDOH and (S)-CH3CHDOH or (Z)-CH3CH=CHD and (E)-CH3CH=CHD are examples of isotopic stereoisomers of ethanol and n-propylene, respectively.

[0386] Those skilled in the art will recognize that compounds of formula (I) wherein R 4 and R 5 When each is hydrogen, the compound of formula (I) may exist as any one or any mixture of its corresponding tautomers (i.e. structural isomers that can be readily converted into each other), as shown below

[0387]

[0388] Those skilled in the art will further recognize that compounds of formula (II), compounds of formula (III), and compounds of formula (IV) may similarly exist as any one or any mixture of their corresponding tautomers. The present invention is intended to include any compound described herein that exists as any one of its corresponding tautomeric forms or as a mixture of its tautomeric forms.

[0389] The present invention is intended to include the compounds described herein, including all isomers thereof (including but not limited to stereoisomers, enantiomers, diastereomers, tautomers, isotopomers, atropisomers, etc.).

[0390] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a "phenyl-(C1-C6 alkylene)-amino-carbonyl-(C1-C6 alkylene)-" substituent refers to a radical of the formula

[0391]

[0392] As used herein, unless otherwise indicated, the term "isolated form" shall mean that the compound is present in a form separated from any solid mixture with another compound, from a solvent system, or from the biological environment. In one embodiment of the invention, the compound of formula (I), the compound of formula (II), the compound of formula (III), or the compound of formula (IV) is present in an isolated form.

[0393] As used herein, unless otherwise indicated, the term "substantially pure form" shall mean that the mole percentage of impurities in the isolated compound is less than about 5 mole%, preferably less than about 2 mole%, more preferably less than about 0.5 mole%, and most preferably less than about 0.1 mole%. In one embodiment of the present invention, the compound of formula (I), the compound of formula (II), the compound of formula (III), or the compound of formula (IV) is present in substantially pure form.

[0394] As used herein, unless otherwise indicated, the term "substantially free of corresponding salt forms" when used to describe a compound of formula (I) shall mean that the mole percentage of corresponding salt forms in the isolated base of formula (I) is less than about 5 mole%, preferably less than about 2 mole%, more preferably less than about 0.5 mole%, and most preferably less than about 0.1 mole%. In one embodiment of the invention, the compound of formula (I), the compound of formula (II), the compound of formula (III), or the compound of formula (IV) is present in a form that is substantially free of corresponding salt forms.

[0395] 2. General Synthesis Scheme

[0396] The compound of formula (I) of the present invention can be prepared as described in the general synthesis scheme and the examples herein, and selection and substitution of suitable reagents and conditions are as will be fully within the skill range of those skilled in the art. In addition, the preparation of any raw materials used in the subsequent schemes and synthesis examples herein is fully within the skill range of those skilled in the art.

[0397] Those skilled in the art will further recognize that by selecting and substituting appropriate starting reagents (and then following or applying the methods described in the subsequent general synthetic schemes and examples herein), compounds of formula (I) (and any intermediates, such as compounds of formula (M1)) can be prepared as racemates and then separated into their corresponding stereoisomers (according to known methods, such as chiral separation or SFC), or can be prepared as stereoisomer-enriched or pure stereoisomers.

[0398] The intermediates in the synthesis of the compound of formula (I) of the present invention include compounds of formula (M1)

[0399]

[0400] Among them A 1 Selected from C 1-4 Alkyl, preferably methyl or ethyl. Some compounds of formula (M1) are known or can be prepared according to known methods, as will be recognized by those skilled in the art.

[0401] Compounds of formula (M1) can be prepared, for example, as described in Scheme 1 below.

[0402]

[0403] Thus, a suitably substituted compound of formula (V) wherein A 1 C 1-4 alkyl, preferably methyl or ethyl, and wherein pG 1 is a suitably selected nitrogen protecting group such as Boc, benzyl, PMB, etc.), which is a known compound or a compound prepared by a known method (e.g., as described in the Examples that follow herein), and (1.0 M lithium triethylborohydride in THF), which is a known solution, is reacted under the following conditions: in an appropriately selected solvent such as THF, 1,4-diethylborohydride at a reduced temperature, for example, at about -78 ° C; and then reacting with an appropriately selected catalyst such as p-TsOH, etc. under the following conditions: in an appropriately selected solvent such as MeOH, etc.; to obtain the corresponding compound of formula (VI).

[0404] Compounds of formula (VI) are reacted with appropriately substituted compounds of formula (VII) (e.g., wherein R A and RB When each is hydrogen, the compound of formula (VII) is allyltrimethylsilane), which is a known compound, reacts under the following conditions: in the presence of a suitably selected Lewis acid such as BF3.Et2O, TiCl4, etc.; in a suitably selected solvent such as diethyl ether, THF, DCM, etc.; at a reduced temperature, for example at about -40°C; to obtain the corresponding compound of formula (VIII).

[0405] The compound of formula (VIII) is deprotected according to known methods to obtain the corresponding compound of formula (IX). For example, the compound of formula (VIII) can be reacted with an appropriately selected acid such as HCl under the following conditions: in an appropriately selected solvent such as 1,4-dihydro-1,4-dihydro-2-nitropropene; In alkane.

[0406] The compound of formula (IX) is reacted with acryloyl chloride (which is a known compound) under the following conditions: in the presence of an appropriately selected organic amine base such as TEA, pyridine, DIEA, etc.; in an appropriately selected solvent such as THF, DCM, DMF, etc.; at a reduced temperature, for example at about -78°C; to obtain the corresponding compound of formula (X).

[0407] The compound of formula (X) is reacted with an appropriately selected catalyst such as the second generation Grubb catalyst, the third generation Grubb catalyst, etc. under the following conditions: in an appropriately selected solvent such as DCM, THF, toluene, etc.; at an elevated temperature, for example at about 45°C; to obtain the corresponding compound of formula (XI).

[0408] The compound of formula (XI) is reacted with an appropriately selected hydroboration agent such as bis(pinacolato)diboron under the following conditions: in the presence of an appropriately selected copper reagent such as CuCl; in the presence of an appropriately selected ligand such as BINAP; in the presence of an appropriately selected base such as NaOt-Bu; in an appropriately selected solvent or a mixture of solvents such as a mixture of THF and methanol; and then reacted with a peroxide such as 30% H2O2 to obtain the corresponding compound of formula (XII).

[0409] The compound of formula (XII) is reacted with an appropriately selected oxidizing agent such as PCC, Dess-Martin periodinane (DMP), etc., in an appropriately selected solvent such as DCM, EtOAc, etc., to give the corresponding compound of formula (M1).

[0410] Compounds of formula (M1) can alternatively be prepared as described in Scheme 2 below.

[0411]

[0412] Thus, for example, an appropriately substituted compound of formula (VIII) prepared as described in Scheme 1 above is reacted with an appropriately selected oxidizing agent or system such as a mixture of OsO4 and NaIO4, O3, etc., in an appropriately selected solvent or mixture of solvents such as a mixture of THF and water, DCM, etc.; at about room temperature; to give the corresponding compound of formula (XIII).

[0413] The compound of formula (XIII) is reacted with ethyl acetate (which is a known compound) under the following conditions: in the presence of a suitably selected base such as LiHMDS, LiN(Pr-i)2, NaOEt, etc.; in a suitably selected solvent such as THF, toluene, EtOAc, etc.; at a reduced temperature, for example at about -78°C; to give the corresponding compound of formula (XIV).

[0414] The compound of formula (XIV) is reacted with an appropriately selected oxidizing agent such as a mixture of DMSO / (COCl)2, Dess-Martin periodinane (DMP), PCC, etc. under the following conditions: in an appropriately selected solvent such as DCM, EtOAc, etc.; at about room temperature; to obtain the corresponding compound of formula (XV).

[0415] The compound of formula (XV) is reacted with an appropriately selected acid such as HCl, TFA, etc. under the following conditions: in an appropriately selected solvent such as 1,4-dichlorobenzene then reacting with an appropriately selected base such as NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , etc. under the following conditions: in an appropriately selected solvent such as toluene, xylene, etc.; at an elevated temperature, for example, at about 110° C.; to give the corresponding compound of formula (M1).

[0416] Those skilled in the art will recognize that although the methods of Schemes 1 and 2 above describe the preparation of a racemic mixture of a compound of formula (M1), the methods can also be used to prepare specific stereoisomers by using stereoisomer-enriched starting materials, or by separating the prepared racemic mixture of a compound of formula (M1) and isolating the corresponding stereoisomers according to known methods (e.g., by chiral separation, SFC, etc.).

[0417] Some compounds of formula (M1), for example, wherein R A 、R B 、R C 、R D and R E Compounds of formula (M1), each of which is hydrogen, may alternatively be prepared as described in Scheme 3 below.

[0418]

[0419]

[0420] Thus, an appropriately substituted compound of formula (V) (which is a known compound or a compound prepared by a known method) is reacted with ethyl acetate (which is a known compound) under the following conditions: in the presence of an appropriately selected base such as LiHMDS, LiN(Pr-i)2, NaOEt, etc.; in an appropriately selected solvent such as THF, PhMe, EtOH, etc.; at a reduced temperature, for example at about -78°C; to give the corresponding compound of formula (XVI).

[0421] The compound of formula (XVI) is reacted with an appropriately selected organic base such as TFA, HCl, etc.; deprotection and ring closure are achieved; and the corresponding compound of formula (XVII) is obtained.

[0422] The compound of formula (XVII) is reacted with H2 under the following conditions: in the presence of a suitably selected catalyst such as PtO2, Pd, Ni, Pd(OH)2, etc.; in a suitably selected solvent such as HOAc, EtOH, DCM, etc.; to obtain the corresponding compound of formula (XVIII).

[0423] The compound of formula (XVIII) is reacted with ethyl 3-chloro-3-oxopropionate (which is a known compound) under the following conditions: in the presence of an appropriately selected organic amine base such as DIPEA, TEA, pyridine, etc.; in an appropriately selected solvent such as DCM, THF, etc.; to obtain the corresponding compound of formula (XIX).

[0424] The compound of formula (XIX) is reacted with an appropriately selected base such as NaOEt, NaOMe, NaH, etc. in an appropriately selected solvent such as EtOH, MeOH, DMF, etc. to give the corresponding compound of formula (XX).

[0425] The compound of formula (XX) is reacted with an appropriately selected reagent such as an aqueous solution of oxalic acid, a 10% aqueous solution of AcOH, an aqueous solution of HCl (pH about 2) or a mixture of ACN / water under the following conditions: at an elevated temperature, for example at about 110° C.; to obtain the corresponding compound of formula (M1a).

[0426] Those skilled in the art will recognize that although the method of Scheme 3 above describes the preparation of a specific stereoisomer of a compound of formula (M1), the method of Scheme 3 can also be used to prepare a racemic mixture of a compound of formula (M1) and alternative specific stereoisomers by using a starting material enriched in an appropriately selected racemate or stereoisomer, or by preparing a racemate of a compound of formula (M1) and then separating the corresponding stereoisomer according to known methods (e.g., by chiral separation, SFC, etc.).

[0427] Appropriately substituted compounds of formula (M1) can be reacted as described in the Schemes and Examples that follow herein to provide compounds of formula (I) of the present invention.

[0428] where R 4 is hydrogen and R 5 Some compounds of formula (I) that are hydrogen can be prepared as described in Scheme 4 below.

[0429]

[0430] Thus, for example, a suitably substituted compound of formula (M1b) (wherein A 1 C 1-4 alkyl, preferably methyl or ethyl), with an appropriately selected oxygen protecting agent such as 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide, trifluoromethanesulfonic anhydride, etc., under the following conditions: in the presence of an appropriately selected organic amine base such as TEA, pyridine, DIEA, etc.; in an appropriately selected solvent such as DCM, THF, etc.; to obtain the corresponding compound of formula (XXI), wherein PG 2 is the corresponding oxygen protecting group.

[0431] Compounds of formula (XXI) are reacted with appropriately substituted compounds of formula (XXII) which are known compounds or compounds prepared by known methods and wherein -B(OR)2 is, for example, -B(OH)2, -B(OCH3)2, etc.) under the following conditions: in the presence of a properly selected coupling agent such as Pd(dppf)Cl2, Pd(PPh3)4, Pd(OAc)2, etc.; in the presence of a properly selected base such as K2CO3, Cs2CO3, K3PO4, etc.; in the presence of a properly selected solvent or a mixture of solvents such as 1,4-dihydro- In a mixture of alkanes and water, DMF, toluene / water, etc.; at an elevated temperature (such as about 80° C.); the corresponding compound of formula (XXIII) is obtained.

[0432] Compounds of formula (XXII) are reacted with appropriately substituted compounds of formula (XXIII) (which are known compounds, compounds prepared by known methods, or compounds prepared as described in the Examples that follow herein), wherein LG 1 The reaction is carried out under the following conditions: in the presence of a properly selected base such as Cs2CO3, K2CO3, Na2CO3, etc.; in the presence of a properly selected solvent such as DMF, ACN, 1,4-dichlorobenzene, etc. at about room temperature; to obtain the corresponding compound of formula (XXIV).

[0433] The compound of formula (XXIV) is reacted with an appropriately selected reagent such as NH4OAc, etc. under the following conditions: in the presence of an appropriately selected acid such as AcOH, etc.; in an appropriately selected solvent such as toluene, xylene, etc.; at an elevated temperature, for example at about 110°C; to obtain the corresponding compound of formula (Ia).

[0434] where R 5 Compounds of formula (I) which are halogen can be prepared from the corresponding compounds of formula (Ia) by reacting with an appropriately selected halogenating agent such as NCS (for chlorine), NBS (for bromine), NIS (for iodine), Selectfluor (for fluorine), etc. in an appropriately selected solvent such as DCM, DCE, ACN, THF, Et2O, etc.

[0435] where R 5 C 1-4 Alkyl compounds of formula (I) can be prepared similarly as described above in Scheme 4 by reacting a compound of formula (XXII) with an appropriately substituted analog of a compound of formula (XXIII), such as a compound of formula (XXIII-ALT),

[0436]

[0437] The resulting intermediate is then reacted as described in Scheme 4 to achieve ring closure.

[0438] Those skilled in the art will recognize that although Scheme 4 describes the preparation of specific stereoisomers of compounds of formula (I), the methods described therein are applicable to the preparation of racemic mixtures and alternative stereoisomers of compounds of formula (I). The racemates and / or alternative stereoisomers can be prepared by using starting materials enriched in an appropriately selected racemate or stereoisomer, or by preparing the racemate of the desired compound of formula (I) and then separating the corresponding stereoisomer according to known methods (e.g., by chiral separation, SFC, etc.).

[0439] where R1 The compound of formula (I) which is 1,2,3,4-tetrazolyl-1-yl may alternatively be composed of 1 The corresponding compound of formula (Ia) where NH 2 is prepared as described in Scheme 5 below.

[0440]

[0441] Thus, for example, an appropriately substituted compound of formula (Ib) prepared as described above in Scheme 4 is reacted with an appropriately selected reagent such as TMSN3, NaN3, etc. under the following conditions: in the presence of trimethoxymethane, etc.; in an appropriately selected solvent such as AcOH, etc.; at elevated temperature, for example at about 80°C; to give the corresponding compound of formula (Ic).

[0442] where R 1 Compounds of formula (I) which are 1,2,3,4-tetrazolyl-1-yl may alternatively be prepared by: 1 The compound of formula (XXII) wherein NH2 (ie, the compound of formula (XXIIa))

[0443]

[0444] With a suitable reagent such as TMSN3, NaN3, etc. under the following conditions: in the presence of trimethoxymethane, etc.; in a suitably selected solvent such as AcOH, etc.; at an elevated temperature, for example, at about 80 ° C; as described in the above scheme 5; to obtain the corresponding compound of formula (XXV)

[0445]

[0446] This compound of formula (XXV) is then substituted for the compound of formula (XXII) in Scheme 4 above and reacted as described therein; yielding the corresponding compound of formula (Ic).

[0447] Compounds of formula (XXII) may alternatively be prepared as described in Scheme 6 below.

[0448]

[0449] Thus, appropriately substituted compounds of formula (M1b), which are known compounds or compounds prepared as described in the Schemes or Examples herein, wherein A 1 C 1-4alkyl, preferably methyl or ethyl), with an appropriately selected oxygen protecting agent such as 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide, trifluoromethanesulfonic anhydride, etc., under the following conditions: in the presence of an appropriately selected organic amine base such as TEA, pyridine, DIEA, etc.; in an appropriately selected solvent such as DCM, THF, etc.; to obtain the corresponding compound of formula (XXI), wherein PG 2 is the corresponding oxygen protecting group.

[0450] The compound of formula (XXI) is reacted with bis(pinacolato)diboron (which is a known compound) under the following conditions: in the presence of a suitably selected coupling agent such as Pd(dppf)Cl2, Pd(PPh3)4, Pd(OAc)2, etc.; in the presence of a suitably selected base such as KOAc, potassium ethylhexanoate (n-BuCH(Et)CO2K), etc.; in the presence of a suitably selected solvent or a mixture of solvents such as 1,4-diboron in a mixture of alkanes and water, DMF, toluene / water, etc.; at an elevated temperature (such as about reflux temperature); to give the corresponding compound of formula (XXVI).

[0451] Compounds of formula (XXVI) are reacted with appropriately substituted compounds of formula (XXVII), which are known compounds, compounds prepared by known methods, or compounds prepared as described in the Examples that follow herein, wherein LG 2 The reaction is carried out under the following conditions: in the presence of a suitable coupling agent such as Pd(dppf)Cl2, Pd(PPh3)4, Pd(OAc)2, etc.; in the presence of a suitable base such as K2CO3, Cs2CO3, K3PO4, etc.; in the presence of a suitable solvent or a mixture of solvents such as 1,4-dihydro-1,4-diol in a mixture of alkane and water, DMF, toluene / water, etc.; at an elevated temperature (eg, reflux temperature); to obtain the corresponding compound of formula (XXII).

[0452] Those skilled in the art will recognize that although Scheme 6 describes the preparation of a specific stereoisomer of a compound of formula (XXII), the methods described therein are applicable to the preparation of racemic mixtures and alternative stereoisomers of compounds of formula (XXII). The racemates and / or alternative stereoisomers may be prepared by using a starting material enriched in an appropriately selected racemate or stereoisomer, or by preparing a racemate of a compound of formula (XXII) and then separating the corresponding stereoisomer according to known methods (e.g., by chiral separation).

[0453] where R 1Compounds of formula (XXII) which are 4-trifluoromethyl-1,2,3-triazol-1-yl may alternatively be prepared as described in Scheme 7 below.

[0454]

[0455] Thus, for example, a compound prepared as described in the Schemes and Examples herein wherein R 1 A compound of formula (XXIIa) suitably substituted with NH2 is reacted with an appropriately selected reagent such as TMSN3, NaN3, etc. under the following conditions: in the presence of an appropriately selected reagent such as tert-butyl nitrite, NaNO2 / HCl, etc.; in an appropriately selected solvent such as acetonitrile, EtOH, heptane, etc.; at about 0°C to room temperature; to obtain the corresponding compound of formula (XXVIH).

[0456] The compound of formula (XXVIII) is reacted with 4,4,4-trifluorobut-2-ynoic acid (which is a known compound) under the following conditions: in the presence of an appropriately selected reagent such as Cu2O, CuCl, etc.; in an appropriately selected solvent such as acetonitrile, DCM, etc.; at an elevated temperature, for example at about reflux temperature; to obtain the corresponding compound of formula (XXIIb).

[0457] Those skilled in the art will recognize that the compound of formula (XXIIb) can then be further substituted for the compound of formula (XXII) in Scheme 4 above and reacted as described therein to provide a compound wherein R 1 The corresponding compound of formula (I) is 4-trifluoromethyl-1,2,3-triazol-1-yl. Those skilled in the art will further recognize that, wherein R 1 Compounds of formula (I) which are 4-trifluoromethyl-1,2,3-triazol-1-yl may alternatively be prepared by: 1 An appropriately substituted compound of formula (Ia) which is NH2 is substituted for the compound of formula (XXII) in Scheme 7 above and reacted as described therein.

[0458] Those skilled in the art will further recognize that, although Scheme 7 describes the preparation of a racemate of a compound of Formula (XXIIb), the methods described therein can be applied to the preparation of specific stereoisomers of a compound of Formula (XXIIb). Such alternative stereoisomers can be prepared by using a starting material enriched in an appropriately selected stereoisomer, or by preparing a racemic compound and then separating the corresponding stereoisomer according to known methods (e.g., by chiral separation, SFC, etc.).

[0459] Certain compounds of formula (I) can alternatively be prepared as described in Scheme 8 below.

[0460]

[0461] Thus, an appropriately substituted compound of formula (XXII), prepared, for example, as described in the Schemes and Examples herein, is reacted with an appropriately selected reagent such as DABAL, BH3.Me2S, etc., in an appropriately selected solvent such as DCM, THF, etc., at a reduced temperature, for example at -78°C, to give the corresponding compound of formula (XXIX).

[0462] The compound of formula (XXIX) is reacted with an appropriately selected reagent such as NH3.H2O under the following conditions: in the presence of an appropriately selected reagent such as glyoxal; in an appropriately selected solvent such as methanol; at about room temperature; to obtain the corresponding compound of formula (XXX).

[0463] The compound of formula (XXX) is reacted with an appropriately selected iodine source such as NIS, I2, etc. under the following conditions: in an appropriately selected solvent such as DCM, etc.; at about room temperature; and then reacted with an appropriately selected reagent such as Na2SO3, etc. under the following conditions: in an appropriately selected solvent or a mixture of solvents such as a mixture of ethanol / water, etc.; at an elevated temperature, for example, at about 95°C; to obtain the corresponding compound of formula (XXXI).

[0464] The compound of formula (XXXI) is reacted with a suitably substituted compound of formula (XXXII) (which is a known compound, a compound prepared by a known method, or a compound prepared as described herein, wherein BPin is bis(pinacolato)diboron) under the following conditions: in the presence of a suitably selected palladium catalyst such as Pd(dppf)Cl2, Pd(PPh3)4, etc.; in the presence of a suitably selected base such as K2CO3, Cs2CO3, etc.; in the presence of a suitably selected solvent or mixture of solvents such as 1,4-diboron in a mixture of alkane / water, toluene / water, etc.; at elevated temperature, for example at reflux temperature; to obtain the corresponding compound of formula (Ia).

[0465] Those skilled in the art will recognize that in the process described in Scheme 8 above, wherein R 1 The NH2 group is preferably protected with an appropriately selected nitrogen protecting group (e.g., BOC, etc.) and subsequently deprotected at an appropriate point in the synthesis. Those skilled in the art will further recognize that the synthesis as described in Scheme 8 can be modified at any appropriate step to achieve the desired effect. 1 Any (intermediate or final) compound of NH2 is converted into one in which R 1For the corresponding compounds, for example, 1,2,3,4-tetrazol-1-yl, 4-trifluoromethyl-1,2,3-triazol-1-yl, etc., the reaction procedures and conditions described in the schemes and examples herein are applied.

[0466] Those skilled in the art will further recognize that although Scheme 8 describes the preparation of specific stereoisomers of compounds of Formula (Ia), the methods described therein are applicable to the preparation of racemic mixtures and alternative stereoisomers of compounds of Formula (Ia). The racemates and / or alternative stereoisomers can be prepared by using starting materials enriched in appropriately selected racemates or stereoisomers, or by preparing racemates of compounds of Formula (Ia) and then separating the corresponding stereoisomers according to known methods (e.g., by chiral separation, SFC, etc.).

[0467] Compounds of formula (XXIII) are known compounds, compounds that can be prepared by known methods and / or compounds that can be prepared as described herein. 2 Compounds of formula (XXIII) which are, for example, bromo, can be prepared as described in Scheme 9 below.

[0468]

[0469] Thus, a suitably substituted compound of formula (XXXIII) (which is a known compound or a compound prepared by a known method) wherein LG 3 is a properly selected leaving group such as Br, I, OTf, etc.), and is reacted with dibutyl (1-ethoxyvinyl) (pentyl) stannane (which is a known compound) under the following conditions: in the presence of a properly selected coupling agent such as Pd (dppf) Cl2, Pd (PPh3) Cl2, Pd (PPh3) 4, etc.; in the presence of a properly selected solvent such as 1,4-dimethoxybenzylamine. at elevated temperatures, for example, at about 90° C. to 100° C.; to give the corresponding compound of formula (XXXIV).

[0470] The compound of formula (XXXIV) is reacted with an appropriately selected bromine source such as NBS, HBr, Br2, pyridine HBr, etc. under the following conditions: in an appropriately selected solvent or a mixture of solvents such as THF / water, DCM, 1,4-dichlorobenzene, In a mixture of alkane / water, etc.; at about room temperature; to obtain the corresponding compound of formula (XXIIIa). Those skilled in the art will recognize that the bromine source is, for example, a mixture of HBr and Br2, pyridine HBr, etc.; and then the reaction of the compound of formula (XXXIV) with the bromine source is completed in the presence of an appropriately selected acid such as AcOH, etc. 1Compounds of formula (XXIII) which are I can be prepared analogously according to known methods by reacting appropriately substituted compounds of formula (XXXIV) with a suitably selected iodine source.

[0471] Alternatively, a compound of formula (XXXIII) (which is a known compound or a compound prepared by a known method, wherein LG 3 is -C(O)Cl), reacted with an appropriately selected reagent such as trimethylsilyldiazomethane (TMSCHN2) or the like under the following conditions: in an appropriately selected solvent such as acetonitrile or the like; then reacted with an appropriately selected bromine source such as HBr / water, Br2, NBS or the like under the following conditions: at about room temperature; to obtain the corresponding compound of formula (XXIIIa).

[0472] Those skilled in the art will recognize that any substituent group and / or any portion of a substituent group (e.g. R 1 , Q etc.) can be incorporated into the desired compound of formula (I) in any order by applying the appropriate reaction steps in the desired order (e.g., reaction steps under the reaction conditions described in the Schemes and Examples herein).

[0473] Those skilled in the art will further recognize that the various substituent groups and / or functional groups on the substituent groups (e.g., -OH, -NH2, etc.) can be protected prior to any of the above reaction steps and then deprotected in subsequent steps of the synthesis, as desired or necessary.

[0474] Those skilled in the art will further recognize that any starting material, intermediate or compound of Formula (I), (II), (III) or (IV) of the present invention can be prepared as a racemate or a stereoisomer-enriched compound by selecting and substituting the appropriate stereoisomer in the processes described herein, or by preparing a racemic mixture and then separating the stereoisomers according to known methods (e.g., by chiral separation, SFC, etc.).

[0475] As used herein, as more generally provided for in this written specification, terms such as "react" and "reacting" are used to refer to a chemical entity in either: (a) the actual enumerated form of such chemical entity, and (b) any form of such chemical entity in the medium in which the compound is contemplated at the time of naming.

[0476] Those skilled in the art will recognize that, unless otherwise indicated, the reaction steps are carried out according to known methods under appropriate conditions to provide the desired products. Those skilled in the art will further recognize that, in the description and claims given herein, where a reagent or reagents are Gender / TypeWhen a reagent (e.g., a base, a solvent, etc.) is mentioned in more than one step of the method, each reagent is independently selected for each reaction step and can be the same as or different from one another. For example, when two steps of the method list an organic base or an inorganic base as a reagent, the organic base or inorganic base selected for the first step can be the same as or different from the organic base or inorganic base of the second step. In addition, those skilled in the art will recognize that when the reaction steps of the present invention can be carried out in a variety of solvents or solvent systems, the reaction steps can also be carried out in a mixture of suitable solvents or solvent systems.

[0477] Those skilled in the art will recognize that where a reaction step of the present invention can be carried out in a variety of solvents or solvent systems, the reaction step can also be carried out in a mixture of suitable solvents or solvent systems.

[0478] Those skilled in the art will further recognize that a reaction or process step as described herein is allowed to proceed for a sufficient period of time until the reaction is complete, as determined by any method known to those skilled in the art, such as chromatography (e.g., HPLC). As used herein, a "completed reaction or process step" shall mean that the reaction mixture contains significantly reduced amounts of starting materials / reagents and significantly reduced amounts of desired product compared to the amounts of each present at the start of the reaction.

[0479] In order to provide a more concise description, some quantitative expressions appearing herein are not modified by the term "about". It should be understood that, regardless of whether the term "about" is explicitly used, each quantity appearing herein is intended to refer to the actual value and also to refer to the approximate value of these values ​​that can be reasonably estimated by a person skilled in the art, including the approximate value of these values ​​caused by experimental and / or measurement conditions.

[0480] To provide a more concise description, some quantitative expressions herein are described as a range from about X amount to about Y amount. It should be understood that when a range is described, the range is not limited to the upper and lower limits described, but should include the entire range from about X amount to about Y amount or any amount or range therein.

[0481] Examples of suitable solvents, bases, reaction temperatures and other reaction parameters and components are given in the detailed description that follows. Those skilled in the art will recognize that listing such examples is not intended and should not be construed as limiting in any way the invention as set forth in the claims appended hereto.

[0482] As used herein, unless otherwise indicated, the term "leaving group" shall mean a charged or uncharged atom or group that leaves during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.

[0483] In any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules concerned. This may be achieved by conventional protecting groups, such as those described in "Protective Groups in Organic Chemistry", edited by JFW McOmie, Plenum Press, 1973; and TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.

[0484] As used herein, unless otherwise indicated, the term "nitrogen protecting group" shall mean a group that can be attached to a nitrogen atom to protect the nitrogen atom from participating in a reaction and that can be easily removed after the reaction. Suitable nitrogen protecting groups include, but are not limited to: carbamates, i.e., groups represented by the formula -C(O)OR, where R is, for example, methyl, ethyl, tert-butyl, benzyl, phenethyl, CH2=CH-CH2-, etc.; amides, i.e., groups represented by the formula -C(O)-R', where R' is, for example, methyl, phenyl, trifluoromethyl, etc.; N-sulfonyl derivatives, i.e., groups represented by the formula -SO2-R", where R" is, for example, tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-Zmethylchroman-6-yl, 2,3,6-trimethyl-4-methoxybenzene, etc. Other suitable nitrogen protecting groups can be found in texts such as TW Greene and PGM Wuts, " Protective Groups in Organic Synthesis ″, John Wiley & Sons, 1991.

[0485] As used herein, unless otherwise indicated, the term "oxygen protecting group" shall mean a group that can be attached to an oxygen atom to protect the oxygen atom from participating in a reaction and that can be easily removed after the reaction. Suitable oxygen protecting groups include, but are not limited to, acetyl, benzoyl, tert-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like. Other suitable oxygen protecting groups can be found in texts such as TW Greene and PGM Wuts, " Protective Groups in Organic Synthesi s″, John Wiley & Sons, 1991.

[0486] If the method for preparing the compound according to the present invention produces a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography.Compound can be prepared in racemic form, or can be synthesized by enantiomer specificity or prepared by splitting a single enantiomer.For example, by standard techniques, as by forming a salt with an optically active acid (such as (-)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid) to form a diastereomeric pair, then fractional crystallization and regeneration free alkali, the compound is split into their component enantiomers.These compounds can also be separated by chromatographic separation and removal of chiral auxiliary agents by forming diastereomeric esters or amides.Alternatively, chiral HPLC column can be used to split the compound.

[0487] Alternatively, chiral HPLC can be used to determine the enantiomeric excess (%ee) by comparison with a standard. Enantiomeric excess can be calculated as follows:

[0488] [(R mole - S mole) / (R mole + S mole)] × 100%

[0489] Wherein R mol and S mol are the number of R mol fractions and the number of S mol fractions in the mixture such that R mol + S mol = 1. The enantiomeric excess can also be calculated alternatively from the specific rotation of the desired enantiomer and the prepared mixture as follows:

[0490] ee=([α-obs] / [α-max])×100.

[0491] The present invention includes within its scope prodrugs of the compounds of the invention. Generally speaking, such prodrugs will be functional derivatives of the compounds that are readily converted into the desired compound in vivo. Thus, in the therapeutic methods of the present invention, the term "administering" shall encompass the use of a specifically disclosed compound or an unspecified compound to treat the various disorders described, wherein the unspecified compound may be converted into the specified compound in vivo after administration to the patient. For example, conventional procedures for selecting and preparing suitable prodrug derivatives are described in "Design of Prodrugs", edited by H. Bundgaard, Elsevier, 1985.

[0492] 3. Practicality

[0493] The compounds of the present invention are useful for the treatment and / or prevention of thromboembolic disorders, inflammatory disorders, and diseases or conditions in which factor XIa and / or plasma kallikrein activity is implicated.

[0494] In some embodiments, the present invention relates to methods for treating and / or preventing thromboembolic disorders, comprising administering to a patient in need of such treatment and / or prevention a therapeutically effective amount of at least one of the compounds as described herein, or stereoisomers, isotopomers, or pharmaceutically acceptable salts thereof.

[0495] As used herein, the term "thromboembolic disorder" includes arterial cardiovascular thromboembolic disorder, venous cardiovascular thromboembolic disorder, or cerebrovascular thromboembolic disorder, as well as thromboembolic disorder in the chambers of the heart or in the peripheral circulation. As used herein, the term "thromboembolic disorder" also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndromes, atrial fibrillation, first or recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by medical implants, devices, or surgeries in which blood is exposed to artificial surfaces that promote thrombosis. Medical implants or devices include, but are not limited to, prosthetic valves / artificial valves, indwelling catheters, stents, blood oxygenators, shunts, vascular access ports, ventricular assist devices, and artificial hearts or heart chambers, as well as vascular grafts. Surgeries include, but are not limited to, cardiopulmonary bypass, percutaneous coronary intervention, and hemodialysis. In some embodiments, the term "thromboembolic disorder" includes acute coronary syndrome, stroke, deep vein thrombosis, and pulmonary embolism. In some embodiments, "thromboembolic disorder" includes hereditary angioedema (HAE) and diabetic macular edema (DME).

[0496] In some embodiments, the present invention relates to methods for treating and / or preventing inflammatory disorders, comprising administering to a patient in need of such treatment and / or prevention a therapeutically effective amount of a compound of the present invention, or at least one of its stereoisomers, isotopomers, or pharmaceutically acceptable salts. Examples of inflammatory disorders include, but are not limited to, sepsis, acute respiratory distress syndrome, and systemic inflammatory response syndrome.

[0497] In some embodiments, the present invention relates to methods for treating and / or preventing diseases or conditions in which plasma kallikrein activity is implicated, comprising administering to a patient in need of such treatment and / or prevention a therapeutically effective amount of a compound of the present invention or at least one of its stereoisomers, isotopomers, or pharmaceutically acceptable salts. Diseases or conditions in which plasma kallikrein activity is implicated include, but are not limited to, impaired vision, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, and cardiopulmonary bypass surgery.

[0498] In some embodiments, the present invention provides a method for treating a primary prevention of a thromboembolic disorder. In some embodiments, the present invention provides a method for treating a primary prevention of a thromboembolic disorder, wherein the thromboembolic disorder is selected from the group consisting of unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by a medical implant, device, or surgery in which blood is exposed to an artificial surface that promotes thrombosis. In another embodiment, the present invention provides a method for treating a primary prevention of a thromboembolic disorder, wherein the thromboembolic disorder is selected from the group consisting of an acute coronary syndrome, stroke, venous thrombosis, and thrombosis caused by a medical implant and device.

[0499] In some embodiments, the present invention provides a method for the secondary prevention of thromboembolic disorders. In some embodiments, the present invention provides a method for the secondary prevention of thromboembolic disorders. Wherein the thromboembolic disorder is selected from unstable angina, acute coronary syndrome, atrial fibrillation, recurrent myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism and thrombosis caused by medical implants, devices or surgeries in which blood is exposed to artificial surfaces that promote thrombosis. In another embodiment, the present invention provides a method for the secondary prevention of thromboembolic disorders, wherein the thromboembolic disorder is selected from acute coronary syndrome, stroke, atrial fibrillation and venous thrombosis.

[0500] Those skilled in the art will recognize that, where the present invention relates to a method of prevention, a subject in need thereof (i.e., a subject in need of prevention) shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease, or condition to be prevented. In addition, a subject in need thereof may also be a subject (preferably a mammal, more preferably a human) who does not exhibit any symptoms of the disorder, disease, or condition to be prevented, but is considered by a physician, clinician, or other medical professional to be at risk of developing the disorder, disease, or condition. For example, due to the subject's medical history, including but not limited to family history, a predisposing constitution, coexisting (comorbid) disorders or conditions, genetic testing, and the like, the subject may be considered to be at risk of developing the disorder, disease, or condition (and therefore in need of prevention or preventative treatment).

[0501] The compounds of the present invention are preferably administered alone to a mammal in a therapeutically effective amount. However, the compounds of the present invention may also be administered to a mammal in a therapeutically effective amount in combination with an additional therapeutic agent as defined below. When administered in combination, the combination of compounds is preferably a synergistic combination, but not necessarily a synergistic combination. For example, synergy may occur when the effect of the compound (in this case, inhibition of the desired target) when administered in combination is superior to the additive effect of the compound when administered alone as a single agent. Generally speaking, synergy is most evident at suboptimal concentrations of the compound. Synergy can be in the form of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of the combination compared to the individual components. Possible beneficial results of treatment using a synergistic combination include, but are not limited to: (a) improving the efficacy of the therapeutic effect, (b) being able to reduce the administered dose while improving or maintaining efficacy (which in turn can lead to reduced toxicity and / or adverse side effects), (c) minimizing or slowing the development of drug resistance, and (d) selective synergy (or efficacy synergy) with the host (toxicity antagonism) for the biological target.

[0502] In some embodiments of the present invention, the compound of formula (I), the compound of formula (II), the compound of formula (III) and / or the compound of formula (IV) may be administered in combination with one or more anticoagulants, antithrombin agents, antiplatelet agents, fibrinolytic agents, lipid-lowering agents, antihypertensive agents and / or anti-ischemic agents. Suitable examples include, but are not limited to, warfarin, heparin, aprotinin, synthetic pentasaccharides, boroarginine derivatives, boropeptides, heparin, hirudin, argatroban, thromboxane-A2-receptor antagonists, thromboxane-A2-synthase inhibitors, PDE-III inhibitors, PDE V inhibitors, ADP receptor antagonists, purinergic receptor P2Y1 antagonists, purinergic receptor P2Y12 antagonists, tissue plasminogen activator and its modified forms, anistreplase, urokinase, streptokinase, tenecteplase, lanteplase, PAI-I inhibitors, α-2-antiplasmin inhibitors, anisoyl plasminogen streptokinase activator complex, HMG-CoA reductase inhibitors, squalene synthetase inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors, MTP inhibitors, lipoxygenase synthase inhibitors, cholesterol absorption inhibitors, cholesterol ester transfer protein inhibitors, alpha adrenergic blockers, beta adrenergic blockers, calcium channel blockers, diuretics, renin inhibitors, angiotensin converting enzyme inhibitors, angiotensin-II-receptor antagonists, ET receptor antagonists, dual ET / A11 antagonists, neutral endopeptidase inhibitors, vasopeptidase inhibitors, Class I agents, Class II agents, Class III agents, Class IV agents, Iach inhibitors, Ikur inhibitors and cardiac glycosides.

[0503] "Combination administration" or "combination therapy" means that a compound of the invention and one or more additional therapeutic agents are administered simultaneously or sequentially to a subject (preferably a mammal, more preferably a human) to be treated. When administered in combination, each component can be administered simultaneously or sequentially in any order at different time points. Thus, each component can be administered separately but sufficiently close in time to provide the desired therapeutic effect. Chou, "Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies", Pharmacol Rev., 2006, Vol. 58, pp. 621-681.

[0504] 4. Pharmaceutical Compositions

[0505] The present invention also includes pharmaceutical compositions containing a compound of formula (I), a compound of formula (II), a compound of formula (III) and / or a compound of formula (IV) and a pharmaceutically acceptable carrier. Pharmaceutical compositions containing the compounds as active ingredients can be prepared by intimately mixing one or more of the compounds of the present invention described herein with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Depending on the desired route of administration (e.g., oral administration, parenteral administration), the carrier can take a variety of forms. Therefore, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, colorants, etc.; for solid oral preparations such as powders, capsules and tablets, suitable carriers and additives include starch, sugar, diluents, granulating agents, lubricants, binders, disintegrants, etc. Solid oral preparations can also be coated with substances such as sugar or coated with enteric coatings to regulate the main absorption sites. For parenteral administration, the carrier will generally consist of sterile water, and other ingredients may be added to increase solubility or preservatives. Injectable suspensions or solutions can also be prepared using aqueous vehicles together with suitable additives.

[0506] To prepare the pharmaceutical composition of the present invention, one or more compounds of the present invention as active ingredients are intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a variety of forms depending on the desired dosage form for administration (e.g., oral administration, or parenteral administration such as intramuscular administration). When preparing a composition in an oral dosage form, any available pharmaceutical medium can be used. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, and the like; for solid oral preparations such as, for example, powders, capsules, caplets, capsule lozenges and tablets, suitable carriers and additives include starch, sugar, diluents, granulating agents, lubricants, binders, disintegrants, and the like. Due to their ease of administration, tablets and capsules represent the most advantageous oral unit dosage form, and in this case, solid pharmaceutical carriers are obviously used. If desired, tablets can be sugar-coated or enteric-coated by standard techniques. For parenteral administration, the carrier will generally include sterile water, but may also include other ingredients, for example, for purposes such as helping to dissolve or preserve. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents, etc. can be used. Every dosage unit of the pharmaceutical composition of the present invention (for example, every tablet, every capsule, every powder, every injection, every teaspoon, etc.) will include the amount of the active ingredient necessary to deliver the above-mentioned effective dose. Every unit dosage unit of the pharmaceutical composition herein (for example, every tablet, every capsule, every powder, every injection, every suppository, every teaspoon, etc.) will contain about 0.01 mg to about 1000 mg or any amount or scope therein, and can be about 0.05 mg / day to about 1000 mg / day or any amount or scope therein, about 0.1 mg / day to about 500 mg / day or any amount or scope therein, preferably about 1 mg / day to about 300 mg / day or any amount or scope therein) for use.

[0507] However, the dosage may vary depending on the needs of the patient, the severity of the condition being treated and the compound being used. Daily administration or post-cyclical dosing may be used.

[0508] Preferably, these compositions are in unit dosage form, such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, automatic injection devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition can be provided in a manner suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound (such as a decanoate) can be suitable for providing a long-acting preparation for intramuscular injection. To prepare a solid composition such as a tablet, the main active ingredient is mixed with a pharmaceutical carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformulation composition containing a uniform mixture of the compound of the invention or a pharmaceutically acceptable salt thereof. When these preformulated compositions are referred to as uniform, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equivalent dosage forms, such as tablets, pills, and capsules. The solid preformulated composition is then subdivided into the above-mentioned unit dosage form containing the active ingredient of the present invention of about 0.01 mg to about 1,000 mg or any amount or scope thereof. The tablet or pill of this novel composition can be coated or otherwise compounded to obtain a dosage form with the advantage of a long-lasting effect. For example, a tablet or pill can comprise an inner dosage form component and an outer dosage form component, the latter being in the form of a coating above the former. These two components can be separated by an enteric layer, which plays a role in preventing disintegration in the stomach and allows the inner component to enter the duodenum intact or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, and such materials include a variety of polymeric acid materials together with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0509] Liquid preparations that can be incorporated into the novel compositions of the present invention for oral or injectable administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersants or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, gum arabic, alginates, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, or gelatin.

[0510] The methods of treating and / or preventing thromboembolic disorders described herein may also be performed using a pharmaceutical composition comprising any compound as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain from about 0.01 mg to about 1000 mg or any amount or range thereof of the compound, preferably from about 0.05 mg to about 300 mg or any amount or range thereof of the compound, more preferably from about 0.1 mg to about 100 mg or any amount or range thereof of the compound, more preferably from about 0.1 mg to about 50 mg or any amount or range thereof of the compound; and may be prepared in any form suitable for the selected mode of administration. Carriers include necessary and inert pharmaceutical excipients, including but not limited to binders, suspending agents, lubricants, flavorings, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (including immediate release, timed release, and sustained release formulations, respectively), granules, and powders; and liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions. Useful forms for parenteral administration include sterile solutions, emulsions and suspensions.

[0511] Advantageously, the compounds of the present invention can be used in a single daily dose, or the total daily dose can be used in divided doses twice, three times or four times a day. In addition, the compounds of the present invention can be used in an intranasal form by topical use of a suitable intranasal vehicle, or by a transdermal patch well known to those of ordinary skill in the art. In order to use in the form of a transdermal delivery system, the dosage administration will certainly be continuous rather than discontinuous throughout the dosage regimen.

[0512] For example, for oral administration in the form of tablets or capsules, the active pharmaceutical ingredient can be combined with an oral, nontoxic, pharmaceutically acceptable inert carrier (such as ethanol, glycerol, water, etc.). In addition, when needed or necessary, suitable binders, lubricants, disintegrants and coloring agents can also be incorporated into the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural gums and synthetic gums (such as gum arabic, tragacanth) or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0513] Liquid forms may include suspending or dispersing agents with appropriate flavors, such as synthetic and natural gums, for example, gum tragacanth, gum arabic, methylcellulose, etc. For parenteral administration, sterile suspensions and solutions are desirable. When intravenous administration is desired, isotonic preparations, which typically contain suitable preservatives, are employed.

[0514] To prepare the pharmaceutical composition of the present invention, the active ingredient, the compound of formula (I), the compound of formula (II), the compound of formula (III) and / or the compound of formula (IV), is intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a variety of forms depending on the desired formulation form for administration (e.g., oral administration or parenteral administration). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in the "Pharmaceuticals of the United States" published by the American Pharmaceutical Association and the British Pharmaceutical Association. The Handbook of Pharmaceutical Excipients Methods for formulating pharmaceutical compositions are described in various publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded ″, Volumes 1-3, edited by Lieberman et al.;″ Pharmaceutical Dosage Forms:Parenteral Medications ”, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms:Disperse Systems ″, Volumes 1-2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[0515] The compounds of this invention may be administered in any of the aforementioned compositions and according to dosage regimens established in the art whenever treatment or prevention of a thromboembolic disorder, an inflammatory disorder, or a disease or condition in which plasma kallikrein activity is implicated is required.

[0516] The daily dose of product can change in the wide range of about 0.01mg to about 1,000mg in each adult every day, or changes in any amount or scope therein.For oral administration, compositions is preferably provided in the tablet form containing 0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,15.0,25.0,50.0,100,150,200,250 and 500 milligrams of active ingredient, for regulating dosage according to the symptom of patient to be treated.The medicine of effective dose can provide with the dosage level of about 0.005mg / kg body weight / day to about 10mg / kg body weight / day or any amount or scope therein usually. This range is preferably from about 0.01 mg / kg body weight to about 5.0 mg / kg body weight per day, or any amount or range therein, more preferably from about 0.1 mg / kg body weight to about 1.0 mg / kg body weight per day, or any amount or range therein, more preferably from about 0.1 mg / kg body weight to about 0.5 mg / kg body weight per day, or any amount or range therein. The compound can be administered on a regimen of 1 to 4 times per day.

[0517] The optimal dosage to be administered can be readily determined by one skilled in the art, and the optimal dosage will vary with the specific compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors related to the specific patient being treated, including patient age, weight, diet, and time of administration, will result in the need to adjust the dosage.

[0518] Those skilled in the art will recognize that both in vivo and in vitro assays using appropriate, known and accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a disorder.

[0519] Those skilled in the art will further recognize that human clinical trials (including first-in-human, dose-ranging and efficacy trials) in healthy patients and / or those suffering from disorders can be accomplished according to methods well known in the clinical and medical arts.

[0520] 5. Combination therapy

[0521] One or more additional pharmacologically active agents may be administered in combination with the compounds of the present invention. One or more additional active agents are intended to mean one or more pharmaceutically active agents that are active in vivo, including prodrugs that are converted into pharmaceutically active forms different from the compound of formula (I) after administration, and also include free acids, free bases, and pharmaceutically acceptable salts of the additional active agents (when such forms are commercially available or otherwise chemically feasible). Generally speaking, any suitable one or more additional active agents (including but not limited to antihypertensive agents, additional diuretics, antiatherosclerotic agents (such as lipid-modified compounds), antidiabetic agents, and / or antiobesity agents) can be used in any combination with a compound of formula (I), a compound of formula (II), a compound of formula (III), and / or a compound of formula (IV) in a single dose formulation (fixed dose drug combination), or can be administered to a patient in one or more separate dosage formulations that allow simultaneous or sequential administration of the active agents (co-administered separate active agents).

[0522] Examples of additional active agents that can be used include, but are not limited to, angiotensin converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, movipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril); angiotensin II receptor antagonists also known as angiotensin receptor blockers or ARBs (e.g., losartan (i.e., ), valsartan, candesartan, olmesartan, telmesartan, eprosartan, irbesartan, and any of these drugs used in combination with hydrochlorothiazide, such as diuretics, such as hydrochlorothiazide (HCTZ); potassium-sparing diuretics, such as amiloride hydrochloride, spironolactone, eplerenone, triazolam, each with or without HCTZ; neutral endopeptidase inhibitors (e.g., enkephalinase inhibitors and phosphonodipeptides); aldosterone antagonists; aldosterone synthase inhibitors; renin inhibitors, such as urea derivatives of dipeptides and tripeptides (see U.S. Pat. No. 5,116,835), amino acids and their derivatives (U.S. Pat. Nos. 5,095,119 and 5,104,869), amino acid chains linked by non-peptide bonds (U.S. Pat. No. 5,114,937), dipeptide derivatives and tripeptide derivatives (U.S. Pat. No. 5,106,835), peptidylaminodiols (U.S. Pat. Nos. 5,063,208 and 4,845,079), and peptidyl β-aminoacylaminodiol carbamates (U.S. Pat. No. 5,089,471); and , various other peptide analogs are disclosed in the following U.S. Patents: 5,071,837; 5,064,965; 5,063,207; 5,036,054; 5,036,053; 5,034,512 and 4,894,437; and small molecule renin inhibitors include diol sulfonamides and sulfinyl groups (U.S. Patent 5,098,924), N-morpholino derivatives (U.S. Patent 5,055,466), N-heterocyclic alcohols (U.S. Patent 4,885,92) and pyrrolidinones (U.S. Patent 5,075,451); in addition, pepsin inhibitor derivatives (U.S. Patent 4,980,283) and fluoro and chloro derivatives of sterone-containing peptides (U.S. Patent 5,066,643); enakiren; RO42-5892 (CAS Reg. No. 126222-34-2, also known as remikiren); A 65317 (CAS Reg. No. 119625-78-4); CP80794 (CAS Reg. No. 119625-78-4, also known as traskiren); ES 1005 (CAS Reg. No. 115404-79-0); ES8891 (CAS Reg. No. 129445-88-1); SQ 34017 (CAS Reg. No. 695226-77-8); Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamide hemifumarate); endothelin receptor antagonists; vasodilators (e.g., nitroprusside); calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, felodipine, gallopamil, niludipine, nimodipine, nicardipine); potassium channel activators (e.g., nicorandil, pinacidil, chromankalim, minoxidil, aprilkalim, loprazolam); sympathomimetic agents;beta-adrenergic blocking agents (e.g., acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartrate, nadolol, propranolol, sotalol, timolol); alpha-adrenergic blocking agents (e.g., doxazosin, prazosin, or alpha-methyldopa); central alpha-adrenergic agonists; peripheral vasodilators (e.g., hydralazine); lipid-lowering agents, such as HMG-CoA reductase inhibitors (such as simvastatin and lovastatin, which are sold as lactone prodrugs as; and and used as inhibitors after administration), and pharmaceutically acceptable salts of dihydroxy-secolic acid HMG-CoA reductase inhibitors, such as atorvastatin (particularly as calcium salts sold), rosuvastatin (especially as calcium salts sold), pravastatin (especially as sodium salt) and fluvastatin (especially as cholesterol absorption inhibitors, such as ezetimibe and ezetimibe in combination with any other lipid-lowering agent (such as the above-mentioned HMG-CoA reductase inhibitors), and in particular with simvastatin or in combination with atorvastatin calcium; immediate-release or controlled-release forms of niacin, particularly with DP antagonists such as lapritor and / or niacin in combination with an HMG-CoA reductase inhibitor; immediate-release or controlled-release forms of niacin, particularly with a DP antagonist such as lapritor and / or niacin used in combination with HMG-CoA reductase inhibitors; niacin receptor agonists (such as acipimox and acifuran), and niacin receptor partial agonists; metabolism-altering agents, including insulin sensitizers and related compounds used to treat diabetes such as biguanides (e.g., metformin), glinides (e.g., repaglinide, nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide, glyburide, tolbutamide), thiazolidinediones (also known as glitazones, such as pioglitazone, rosiglitazone), alpha-glucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl peptidase inhibitors (e.g., sitagliptin), Alogliptin, vildagliptin, saxagliptin, linagliptin, dulagliptin, gemagliptin), ergot alkaloids (e.g., bromocriptine), combination drugs such as (sitagliptin and metformin), as well as injectable diabetes drugs such as exenatide and pramlintide acetate; or used together with other drugs that are beneficial for the prevention or treatment of the above diseases, including but not limited to diazoxide; and including the free acid, free base and pharmaceutically acceptable salt forms of the above active agents where chemically feasible. Alternatively or in addition, compounds that can be administered in combination with the compounds of the present invention include but are not limited to anticoagulants, antithrombin agents, antiplatelet agents, fibrinolytics, hypolipidemic agents, antihypertensive agents and anti-ischemic agents.

[0523] Anticoagulants (or coagulation inhibitors) that can be used in combination with the compounds of the present invention include warfarin, heparin (unfractionated heparin or any commercially available low molecular weight heparin, such as enoxaparin and dalteparin), aprotinin, synthetic pentasaccharide inhibitors of factor Xa (such as fondaparinux and idroparinux), direct factor Xa inhibitors (such as rivaroxaban, apixaban, betrixaban, edoxaban, omixaban), direct acting thrombin inhibitors (including hirudin, dabigatran, argatroban, simelagatran, melagatran, lepirudin, desirudin and bivalirudin), and other factor Vila inhibitors, Villa inhibitors, Dca inhibitors, Xa inhibitors, XIa inhibitors, fibrinogen receptor antagonists (including abciximab, efifibatide and tirofiban), TAFI inhibitors and other inhibitors known in the art. Factor Dca inhibitors include synthetic active site blocking competitive inhibitors, oral inhibitors and RNA aptamers. These are described in Howard, EL, Becker, KC, Rusconi, CP, Becker, RC. Factor Ixa inhibitors as novel anticoagulants. Arterioscler Thromb Vasc Biol, 2007, 27: 722-727.

[0524] As used herein, the term "antiplatelet agent" or "platelet inhibitor" refers to an agent that inhibits platelet function, for example, by inhibiting platelet aggregation, adhesion, or granule secretion. Such agents include, but are not limited to, various known nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamic acid, chrysene sulfonate, dapoxetine ... The present invention also provides the pharmaceutically acceptable salt or prodrug of NSAIDS.In NSAIDS, aspirin (acetylsalicylic acid or ASA) and piroxicam are preferred.Other suitable platelet inhibitors include IIb / IIIa antagonists (such as tirofiban, efifibatide and abciximab), thromboxane-A2-receptor antagonists (such as ifitroban), thromboxane-A2-synthetase inhibitors, phosphodiesterase-III (PDE-III) inhibitors (such as dipyridamole, cilostazol) and PDEV inhibitors (such as sildenafil), and their pharmaceutically acceptable salt or prodrug.

[0525] As used herein, the term "antiplatelet agent" or "platelet inhibitor" is also intended to include ADP (adenosine diphosphate) receptor antagonists, preferably antagonists of the purinergic receptors P2Y1 and P2Y12, with P2Y12 being even more preferred. Preferred P2Y12 receptor antagonists include ticlopidine, prasugrel, clopidogrel, enogrelide, ticagrelor, and cangrelor, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are also preferred compounds because they are known to be gentle on the gastrointestinal tract in use. The compounds of the present invention can also be administered in combination with aprotinin.

[0526] As used herein, the term "thrombin inhibitor" or "antithrombin agent" refers to an inhibitor of the serine protease thrombin. Various thrombin-mediated processes are disrupted by inhibiting thrombin, such as thrombin-mediated platelet activation (i.e., for example, platelet aggregation, and / or granule secretion of plasminogen activator inhibitor-I and / or serotonin), endothelial cell activation, inflammatory response and / or fibrin formation. Many thrombin inhibitors are known to those skilled in the art, and these inhibitors are expected to be used in combination with the compounds of the present invention. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparin, hirudin, dabigatran and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal α-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and their corresponding isothioureas. Analogs. As used herein, the term "hirudin" includes suitable derivatives or analogs of hirudin, referred to herein as leech peptides, such as hirudin disulfate.

[0527] The term "thrombin receptor antagonists," also known as protease-activated receptor (PAR) antagonists or PAR-1 antagonists, are useful in treating thrombotic, inflammatory, atherosclerotic, and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role. Thrombin receptor antagonist peptides have been identified based on structure-activity studies involving amino acid substitutions on the thrombin receptor. In Bernatowicz et al., J Med. Chem., Vol. 39, pp. 4879-4887 (1996), tetrapeptides and pentapeptides such as N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH2 and N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-NH2 are disclosed as effective thrombin receptor antagonists. Peptide thrombin receptor antagonists are also disclosed in WO 94 / 03479. Substituted tricyclic thrombin receptor antagonists are disclosed in U.S. Patents 6,063,847, 6,326,380 and WO 01 / 96330. Other thrombin receptor antagonists include those disclosed in U.S. Patents 7,304,078; 7,235,567; 7,037,920; 6,645,987; and European Patents EP1495018 and EP1294714.

[0528] As used herein, the term thrombolytic or fibrinolytic agent refers to an agent that dissolves a blood clot (thrombus). Such agents include tissue plasminogen activator (TPA, natural or recombinant) and its modified forms, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanteplase (nPA), factor Vila inhibitors, PAI-I inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), alpha-2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complexes, including their pharmaceutically acceptable salts or prodrugs. As used herein, the term anistreplase refers to anisoylated plasminogen streptokinase activator complexes. As used herein, the term urokinase is intended to refer to both double-chain urokinase and single-chain urokinase, the latter also referred to herein as prourokinase. Examples of suitable antiarrhythmic agents for use in combination with the compounds of the invention include: Class I agents (such as propafenone); Class II agents (such as carvedilol and propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as diltiazem and verapamil); Iach inhibitors and Ikur inhibitors (e.g., compounds such as those disclosed in WO 01 / 40231).

[0529] 6. Definitions

[0530] As used herein, unless otherwise indicated, "halogen" shall mean chlorine, bromine, fluorine and iodine, preferably bromine, fluorine or chlorine, more preferably fluorine or chlorine.

[0531] As used herein, unless otherwise indicated, the term "oxo" shall mean a functional group of the structure =0 (ie, a substituent oxygen atom attached to another atom through a double bond).

[0532] As used herein, unless otherwise indicated, "C X-Y "Alkyl" (wherein X and Y are integers, whether used alone as a substituent group or as part of a substituent group) includes straight and branched chains containing X to Y carbon atoms. For example, C 1-4 Alkyl groups include straight and branched chains having 1 to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0533] As used herein, unless otherwise indicated, the term "-(C X-Y Alkylene)-" and "-C X-Y "Alkylene-" (wherein X and Y are integers) shall mean any C X-Y Alkyl carbon chain, wherein the C X-Y The alkyl chain is divalent and further bonded via two points of attachment, preferably via the two terminal carbon atoms.

[0534] As used herein, unless otherwise indicated, the term "fluorinated C 1-4 "Alkyl" shall mean any C alkyl group as defined above substituted by one or more fluoro groups, preferably one to three fluoro groups. 1-4 Suitable examples include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2-CF3, -CF2-CH3, -CH2-CH2-CH2F, -CH2-CH2-CF3, -C(CH3)2CF3, -C(CF3)3, and the like.

[0535] As used herein, unless otherwise indicated, the term "hydroxy substituted C 1-4 "Alkyl" shall mean any C alkyl group as defined above substituted with one or more hydroxyl groups (-OH), preferably one to three, more preferably one to two hydroxyl groups. 1-4 Suitable examples include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH(OH)CH2OH, -CH2CH2CH2OH, -C(CH2OH)3, and the like.

[0536] As used herein, unless otherwise indicated, the term "hydroxy-substituted fluorinated C 1-4"Alkyl" shall mean any fluorinated C 2 -alkyl group as defined above further substituted with one or more hydroxyl groups (-OH), preferably one to three, more preferably one to two hydroxyl groups. 1-4 Suitable examples include, but are not limited to, -CF2OH, -CF2CH2OH, -CH(OH)CF3, and the like.

[0537] As used herein, unless otherwise indicated, the term "amino-substituted C 1-4 "Alkyl" shall mean any C alkyl group as defined above substituted by one or more amino groups, preferably one to two amino groups, more preferably one amino group. 1-4 Suitable examples include, but are not limited to, -CHF-NH2, -CF2-NH2, -CH2-CF2-NH2, -CF2-CH2-NH2, -CH2-CH(-NH2)-CH2F, -CH2-CH2-CH2-NH2, -CH(-NH2)-CH(CH3)2, and the like.

[0538] As used herein, unless otherwise indicated, the term "cyano-substituted C 1-4 "Alkyl" shall mean any C alkyl as defined above substituted by one or more cyano groups, preferably one to two cyano groups, more preferably one cyano group. 1-4 Suitable examples include, but are not limited to, -CHF-CN, -CF2-CN, -CH2-CF2-CN, -CF2-CH2-CN, -CH2-CH(-CN)-CH2F, -CH2-CH2-CH2-CN, -CH(-CN)-CH(CH3)2, and the like.

[0539] As used herein, unless otherwise indicated, "C X-Y "Alkoxy" (wherein X and Y are integers) shall mean a straight or branched chain C X-Y Alkyl oxygen ether radical. For example, C 1-4 Alkoxy shall include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

[0540] As used herein, unless otherwise indicated, the term "fluorinated C 1-4 "Alkoxy" shall mean any C 2 - 3 - substituted alkyl group as defined above which is substituted by one or more fluoro groups, preferably one to three fluoro groups. 1-4 Suitable examples include, but are not limited to, -OCH2F, -OCHF2, -OCF3, -OCH2-CF3, -OCF2-CH3, -OCH2-CH2-CH2F, -OCH2-CH2-CF3, -OC(CH3)2CF3, -OC(CF3)3, and the like.

[0541] As used herein, unless otherwise indicated, the term "hydroxy substituted C 1-4 "Alkoxy" shall mean any C 1 - ... 1-4 Suitable examples include, but are not limited to, -OCF2OH, -OCF2CH2OH, -OCH(OH)CF3, and the like.

[0542] As used herein, unless otherwise indicated, the term "C X - Y "Cycloalkyl" (wherein X and Y are integers) shall mean any stable X to Y membered monocyclic, bicyclic, polycyclic, bridged or spirocyclic saturated ring system, preferably a monocyclic, bicyclic, bridged or spirocyclic saturated ring system. For example, the term "C3-8 cycloalkyl" includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, cyclooctyl, bibicyclo[2.2.2]oct-2-yl, and the like.

[0543] As used herein, unless otherwise indicated, the term "heteroaryl" shall mean any five-membered or six-membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine-membered or ten-membered bicyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. The heteroaryl group may be attached through any ring atom that results in a stable structure. Suitable examples include, but are not limited to, furanyl, thienyl, furazanyl, Azolyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl, iso Azolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazole, pyrazinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, indolizinyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, purinyl, quinolizinyl, quinolyl, isoquinolyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyridin-7-yl, [1,2,4]triazolo[4,3-a]pyridin-7-yl, and the like.

[0544] As used herein, unless otherwise indicated, the term "5- to 6-membered heteroaryl" shall mean any five- or six-membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N, and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N, and S. Suitable examples include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, iso Azolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, diazolyl, English Foundation, Azine, iso Azine group, Thiazino, Diazine, etc.

[0545] The term "5- to 6-membered nitrogen-containing heteroaryl" shall mean any five- or six-membered monocyclic aromatic ring structure containing at least one N atom, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. Suitable examples include, but are not limited to, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, iso Azolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, Azine, iso Azine group, Thiazino, Diazine, etc.

[0546] Unless otherwise specified, any heteroaryl group (regardless of the number of ring atoms, the number and identity of ring heteroatoms, etc.) may be attached via any ring atom that results in a stable structure.

[0547] In some embodiments of the present invention, the 5- to 6-membered heteroaryl is a 5-membered heteroaryl. In some embodiments of the present invention, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl. In some embodiments of the present invention, the 5- to 6-membered heteroaryl is a 5- to 6-membered nitrogen-containing ...membered nitrogen-containing heteroaryl. In some embodiments of the present invention, the 5- to 6-membered heteroaryl is a 6-membered nitrogen-containing heteroaryl.

[0548] As used herein, unless otherwise indicated, the term "heterocyclyl" shall mean any monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or any saturated, partially unsaturated, partially aromatic or aromatic bicyclic, benzo-fused, bridged or spirocyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. Suitable examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolyl, furanyl, thienyl, Azolyl, imidazolyl, pyrazolyl, iso oxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, pyrrolinyl, pyrrolidinyl, dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxolane alkyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[b][1,4]diol Benzo[d][1,3]diol Ingki et al.

[0549] As used herein, unless otherwise specified, the term "5- to 6-membered heterocyclyl" shall mean 5 to 6 of any monocyclic, saturated, partially unsaturated or aromatic ring structures containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. Unless otherwise specified, the 5- to 6-membered heterocyclyl may be attached at any heteroatom or carbon atom of the ring so that the result is a stable structure. Suitable examples include, but are not limited to, furanyl, phenylthio, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, iso Azolyl, pyrazolyl, imidazolyl, triazolyl, isothiazolyl, diazolyl Pentyl, pyrazolidinyl, thiadiazolyl, pyranyl, pyridyl, di Alkyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, triazinyl, Azine, iso Azine group, Thiazinyl, etc.

[0550] As used herein, unless otherwise indicated, the term "5-membered heterocyclyl" shall mean a 5-membered monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. Unless otherwise indicated, the 5-membered heterocyclyl may be attached at any heteroatom or carbon atom of the ring so that the result is a stable structure. Suitable examples include, but are not limited to, furanyl, phenylthio, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, iso Azolyl, pyrazolyl, imidazolyl, triazolyl, isothiazolyl, diazolyl Pentyl, pyrazolidinyl, thiadiazolyl, etc.

[0551] As used herein, unless otherwise specified, the term "6-membered heterocyclyl" shall mean a 5-membered monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. Unless otherwise specified, the 6-membered heterocyclyl may be attached at any heteroatom or carbon atom of the ring so that the result is a stable structure. Suitable examples include, but are not limited to, pyranyl, pyridyl, dihydrogenyl, pyridin ... Alkyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, triazinyl, Azine, iso Azine group, Thiazinyl, etc.

[0552] As used herein, unless otherwise indicated, the term "9- to 10-membered heterocyclyl" shall mean a 9- to 10-membered monocyclic, bicyclic, bridged, spirocyclic, saturated, partially unsaturated, benzo-fused, or aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N, and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N, and S. Unless otherwise indicated, the 9- to 10-membered heterocyclyl may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Suitable examples include, but are not limited to, indolenyl, indolyl, isoindolyl, indolizinyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinolizinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, naphthyridinyl, pteridinyl, quinuclidineyl, benzothiophenyl, isobenzoxazolyl, pyrano[3,4-b]pyrrolyl, anthracenyl, benzopyranyl, chromenyl, coumarinyl, benzopyrone and the like.

[0553] As used herein, the term "4- to 6-membered heterocycloalkyl" shall mean any four- to six-membered saturated ring structure containing at least one heteroatom selected from the group consisting of O, N, and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N, and S. Unless otherwise specified, the 4- to 6-membered saturated heterocyclyl may be attached at any heteroatom or carbon atom of the ring so that the result is a stable structure. Suitable examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, dicyclopent ... Pentyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, and the like.

[0554] When a specific group (such as C X-YWhen an alkyl group (e.g., an alkyl group, a heteroaryl group) is "substituted", the group may have one or more substituents, preferably one to five substituents, more preferably one to three substituents, and most preferably one to two substituents, which are independently selected from the list of substituents. With respect to substituents, the term "independently" means that when there is more than one such substituent, such substituents may be the same or different from each other.

[0555] The abbreviations used in this specification, particularly in the schemes and examples, are listed in Table A below:

[0556] Table A: Abbreviations

[0557]

[0558]

[0559]

[0560]

[0561]

[0562] For use in medicine, salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts". However, other salts may also be used to prepare the compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts, which can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, if the compound of the invention has an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, such as sodium salts or potassium salts; alkaline earth metal salts (such as calcium salts or magnesium salts); and salts formed with suitable organic ligands (such as quaternary ammonium salts). Thus, representative pharmaceutically acceptable salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, edetate calcium, camphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolylaminophenylarsonic acid salt, hexylphenylamine salt, hydrazine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, iodide, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthenate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (enbolate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, toluenesulfonate, triethyl iodide, and valerate.

[0563] Representative acids that can be used to prepare pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (±)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid.

[0564] Representative bases that can be used to prepare pharmaceutically acceptable salts include, but are not limited to, the following: bases including ammonia, L-arginine, phenethylbenzylamine, benzathine, calcium hydroxide, choline, denanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrazine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amines, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide.

[0565] As used herein, the term "subject" refers to an animal, preferably a mammal, most preferably a human, that has been the object of treatment, observation or experiment. Preferably, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented.

[0566] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0567] As used herein, unless otherwise indicated, the terms "therapeutic", "treatment" and the like shall include the management and care of a subject or patient (preferably a mammal, more preferably a human) for the purpose of combating a disease, condition or disorder, and include the administration of a compound of the invention to prevent the onset of symptoms or complications, alleviate symptoms or complications, or eliminate the disease, condition or disorder. The terms "therapeutic" or "treatment" also include: (a) inhibiting the disease state, i.e., arresting its development; and / or (b) relieving the disease state, i.e., causing the disease state to regress.

[0568] As used herein, "prevention" encompasses preventative treatment of subclinical disease states in mammals, particularly humans, with the goal of reducing the likelihood of the clinical disease state occurring. Patients for preventative therapy are selected based on factors known to increase their risk of developing a clinical disease state compared to the general population.

[0569] As used herein, "prevention" is the protective treatment of a disease state by administering to a patient a therapeutically effective amount of a compound of the present invention, or at least one of its stereoisomers, isotopomers, or pharmaceutically acceptable salts, to reduce and / or minimize the risk of a clinical disease state and / or reduce the risk of recurrence of a disease state. Patients for preventive therapy may be selected based on factors known to increase the risk of developing a clinical disease state compared to the general population. For preventive treatment, symptoms of a clinical disease state may or may not have already occurred. "Prevention" treatment can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment that reduces or minimizes the risk of a disease state in a patient who has not yet developed a clinical disease state, while secondary prevention is defined as treatment that minimizes or reduces the risk of recurrence or a second occurrence of the same or similar clinical disease state.

[0570] As used herein, "risk reduction" encompasses therapies that reduce the incidence of developing a clinical disease state. Thus, primary prevention therapies and secondary prevention therapies are examples of risk reduction.

[0571] As used herein, the terms "combination" and "pharmaceutical combination" refer to: 1) a fixed dose combination in one unit dosage form; or 2) a non-fixed dose combination, optionally packaged together for combined administration.

[0572] As used herein, the term "therapeutically effective amount" means that amount of active compound or pharmaceutical agent that will elicit in a tissue system, animal or human the biological or medicinal response that is being sought by the researcher, veterinarian, medical doctor or other clinician, including alleviation of symptoms of the disease or disorder being treated.

[0573] Example

[0574] The following examples are presented to aid in understanding the present invention and are not intended to, and should not be construed to, limit in any way the invention set forth in the claims that follow the examples.

[0575] While the examples below only list analytical measurements such as LC / MS, 1 H NMR, 19 While reference is made to F NMR and the like (rather than reaction step details), it is to be understood that the title compounds can be prepared by selecting and substituting appropriate reagents and reactants according to the procedures as described in the synthetic schemes and examples herein, as will be readily recognized by one skilled in the art.

[0576] Unless otherwise stated in the examples, all temperatures are expressed in degrees Celsius (° C.). Unless otherwise stated, all reactions were carried out at ambient temperature and under an inert atmosphere. Unless otherwise stated, reaction solutions were kept at room temperature and N 2(g) or Ar (g) The mixture was stirred under a 4% tantalum atmosphere. The reagents used, for which no synthetic details are given, were either commercially available or prepared according to known methods, for example, according to literature procedures. When solutions are "concentrated to dryness," they are concentrated under reduced pressure using a rotary evaporator, and when solutions are dried, they are typically dried over a desiccant such as MgSO4 or Na2SO4. Where the synthetic products listed have been isolated as residues, those skilled in the art will understand that the term "residue" does not limit the physical state of the product when isolated and may include, for example, solids, oils, foams, gums, slurries, and the like.

[0577] In obtaining the compounds and corresponding analytical data described in the Examples below, the following experimental and analytical protocols were followed unless otherwise indicated.

[0578] LC-MSUnless otherwise stated, the analytical LC-MS system used consisted of a Shimadzu LCMS-2020 with electrospray ionization (ESI) in positive ion detection mode, equipped with a 20ADXR pump, a SIL-20ACXR autosampler, a CTO-20AC column oven, an M20APDA detector, and an LCMS 2020MS detector. The column was a HALO, i.e., C18, 30 mm × 5.0 mm, 2.7 μm. Mobile phase A was water containing 0.05% TFA, and mobile phase B was acetonitrile containing 0.05% TFA. The gradient was set as follows: from 5% mobile phase B to 100% (95%) in 2.0 minutes, held for 0.7 minutes, then returned to 5% mobile phase B in 0.05 minutes and held for 0.25 minutes. The column oven (CTO-20AC) was operated at 40.0°C. The flow rate was 1.5 mL / min, and the injection volume was 1 μL. The PDA (SPD-M20A) detection range was 190 nm to 400 nm. The MS detector was configured with electrospray ionization as the ionizable source; acquisition mode: scan; nebulizing gas flow rate: 1.5 L / min; drying gas flow rate: 15 L / min; detector voltage: tuning voltage ± 0.2 kV; DL temperature: 250°C; heating block temperature: 250°C; scan range: 90.00 m / z to 900.00 m / z. ELSD (Alltech 3300) detector parameters: drift tube temperature: 60 ± 5°C; N2 flow rate: 1.8 ± 0.2 L / min. The mobile phase gradient was optimized for each compound. The calculated masses correspond to the exact masses.

[0579] Preparative HPLC Unless otherwise noted, preparative HPLC purification was performed using a Waters Auto purification system (2545-2767) with a 2489 UV detector. Columns were selected from one of the following: Waters C18, 19 mm × 150 mm, 5 μm; XBridge Prep OBD C18 column, 30 mm × 150 mm, 5 μm; XSelect CSH Prep C18 OBD column, 5 μm, 19 mm × 150 mm; XBridge Shield RP18 OBD column, 30 mm × 150 mm, 5 μm; Xselect CSH Fluorophenyl, 30 mm × 150 mm, 5 μm; or YMC-Actus Triart C18, 30 mm × 150 mm, 5 μm. The mobile phase consisted of a mixture of acetonitrile (5%-95%) in an aqueous solution containing 0.1% FA or 10 mmol / L NH4HCO3. The flow rate was maintained at 25 mL / min, the injection volume was 1200 μL, and the UV detector used two channels, 254 nm and 220 nm.The mobile phase gradient was optimized for each compound.

[0580] Chiral chromatography Chiral analytical chromatography was performed on one of the following: Chiralpak AS, AD, Chiralcel OD, OJ, Chiralpak IA, IB, IC, ID, IE, IF, IG, IH columns (Daicel Chemical Industries, Ltd.), (R, R)-Whelk-O1, (S, S)-Whelk-O1 columns (Regis technologies, Inc.), CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.); different column dimensions (50 mm × 4.6 mm, 100 mm × 4.6 mm, 150 mm × 4.6 mm, 250 mm × 4.6 mm, 50 mm × 3.0 mm, 100 mm × 3.0 mm), percentage of ethanol in hexane (% Et / Hex) or percentage of isopropanol in hexane (% IPA / Hex) as an isocratic solvent system, or using supercritical fluid (SFC) conditions.

[0581] Normal phase flash chromatography Unless otherwise stated, normal phase flash column chromatography (FCC) was performed on silica gel using pre-packed silica gel columns such as ) using ethyl acetate (EtOAc) / hexane, ethyl acetate (EtOAc) / petroleum ether (bp 60° C. to 90° C.), CH 2 Cl 2 / MeOH or CH 2 Cl 2 / 10% 2N NH 3 in MeOH as eluent.

[0582] 1 H NMR : Unless otherwise stated, 1 H NMR spectra were obtained using a 400 MHz spectrometer (or a 300 MHz spectrometer) in DMSO-d6 solution. Nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (δ) expressed in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal standard in DMSO-d6 solution, and the residual CH3OH peak or TMS was used as an internal standard in CD3OD solution. Coupling constants (J) were reported in Hertz (Hz). The properties of the shifts with respect to multiplicity were reported as s (singlet), d (doublet), t (triplet), q (quartet), dd (double of doublets), dt (double of triplets), m (multiplet), br (broad peak).

[0583] Synthesis Example: Intermediates

[0584] Intermediate 1: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole- 3-Formic acid

[0585]

[0586] Step 1: 1-(tert-Butyl)2-methyl(2S)-5-methoxypyrrolidine-1,2-dicarboxylate

[0587] At -78 ° C and N2, to a solution of 1-(tert-butyl) 2-methyl (S) -5-oxopyrrolidine-1,2-dicarboxylate (2.1 g, 8.63 mmol, 1.0 equivalent) in THF (40 mL) was added dropwise lithium triethylborohydride (13 mL, 13 mmol, 1.5 equivalents, 1 M THF solution). The reaction mixture was stirred at -78 ° C for 40 minutes, then Na2CO3 (aqueous solution, 10 mL) was added at -78 ° C, and the mixture was warmed to 0 ° C. Hydrogen peroxide (1 mL, 30%) was added. The mixture was stirred at room temperature for 30 minutes. THF was removed in vacuo, and the resulting mixture was extracted with ether, washed with brine, dried and concentrated in vacuo to give a colorless oil. The oil was dissolved in methanol (40 mL) and p-toluenesulfonic acid (149 mg, 0.86 mmol, 0.1 equivalent) was added. The resulting solution was stirred at room temperature overnight. The reactants were quenched with water and the resulting mixture was extracted with ether. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give 1-(tert-butyl)2-methyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate as a colorless oil.

[0588] Step 2: 1-(tert-Butyl)2-methyl(2S)-5-allylpyrrolidine-1,2-dicarboxylate

[0589] At -40 ° C and N2 atmosphere, to 1-(tert-butyl) 2-methyl (2S) -5-methoxypyrrolidine-1,2-dicarboxylate (10.0 g, 38.60 mmol, 1.0 equivalent) in Et2O (200 mL) solution was added allyltrimethylsilane (27 mL, 169.70 mmol, 4.4 equivalents) and boron trifluoride etherate (6.6 g, 46.30 mmol, 1.2 equivalents). The reaction mixture was stirred at -40 ° C for 30 minutes, then warmed to room temperature and stirred for 40 minutes. The reaction was quenched with Na2CO3 (aqueous solution) and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (0-20% EtOAc / petroleum ether) to give 1-(tert-butyl) 2-methyl (2S)-5-allylpyrrolidine-1,2-dicarboxylate as a yellow oil. LC / MS: C 14 H 23 Calculated mass of NO4: 269.16, measured: 270.20 [M+H] + .

[0590] Step 3: 1-(tert-Butyl)2-methyl(2S)-5-(2-oxoethyl)pyrrolidine-1,2-dicarboxylate

[0591] To a solution of 1-(tert-butyl)2-methyl(2S)-5-allylpyrrolidine-1,2-dicarboxylate (7.3 g, 27.10 mmol, 1.0 equiv) in THF / H2O (120 mL) was added OsO4 (347 mg, 1.36 mmol, 0.05 equiv). The reaction mixture was stirred at room temperature in the dark for 5 minutes, and sodium periodate (14.5 g, 67.80 mmol, 2.5 equiv) was added. The reaction mixture was stirred at room temperature for 4 hours. The reactants were quenched with water, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EA / PE) to give 1-(tert-butyl)2-methyl(2S)-5-(2-oxoethyl)pyrrolidine-1,2-dicarboxylate as a yellow oil. LC / MS: C 13 H 21 Calculated mass of NO5: 271.14, found: 272.15 [M+H] + .

[0592] Step 4: 1-(tert-butyl)2-methyl(2S)-5-(4-ethoxy-2-hydroxy-4-oxobutyl)pyrrolidine-1,2- diformate

[0593] At -78 ° C and N2 atmosphere, to a solution of tert-butyl acetate (3.9 g, 44.23 mmol, 2.0 equivalents) in tetrahydrofuran (60 mL) was added bis(trimethylsilyl) lithium amide (44 mL, 44 mmol, 1.2 equivalents). The resulting solution was stirred at -78 ° C for 30 minutes, and then 1-(tert-butyl) 2-methyl (2S) -5-(2-oxoethyl) pyrrolidine-1,2-dicarboxylate (6 g, 22.1 mmol, 1.0 equivalents) was added. The reaction mixture was stirred at -78 ° C for 2 hours. The reactant was quenched with water, and the resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over Na2SO4. The solid was filtered off. The filtrate was concentrated in vacuo and concentrated. The residue was purified by silica gel chromatography (0-80% EA / PE) to give 1-(tert-butyl)2-methyl(2S)-5-(4-ethoxy-2-hydroxy-4-oxobutyl)pyrrolidine-1,2-dicarboxylate as a yellow oil. LC / MS: C 17 H 29 Calculated mass of NO7: 359.19, found: 360.10 [M+H] + .

[0594] Step 5: 1-(tert-Butyl)2-methyl(2S)-5-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1,2-dimethoxy acid esters

[0595] To a solution of 1-(tert-butyl)-2-methyl (2S)-5-(4-ethoxy-2-hydroxy-4-oxobutyl)pyrrolidine-1,2-dicarboxylate (3.3 g, 9.20 mmol, 1.0 equiv) in acetonitrile (30 mL) was added IBX (10.3 g, 36.80 mmol, 4.0 equiv). The reaction mixture was stirred at 50° C. overnight. The residue was purified by silica gel chromatography (0-80% EtOAc / petroleum ether) to give 1-(tert-butyl)-2-methyl (2S)-5-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1,2-dicarboxylate as a yellow oil. LC / MS: C 17 H 27 Calculated mass of NO7: 357.18, measured: 380.15 [M+Na] + .

[0596] Step 6: Methyl (3S)-5,7-dioxooctahydroindoleazine-3-carboxylate

[0597] To a solution of 1-(tert-butyl)2-methyl(2S)-5-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1,2-dicarboxylate (900 mg, 2.50 mmol, 1.0 equiv) was added HCl (in 1,4-dioxobutyl) pyrrolidine-1,2-dicarboxylate). The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give a yellow oil. The oil was dissolved in toluene (5 mL) and sodium bicarbonate (2.1 g, 25.20 mmol, 10.0 equivalents) was added. The reaction mixture was stirred at 110 ° C overnight. The reactants were quenched with water and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to give (3S)-5,7-dioxooctahydroindole-3-carboxylic acid methyl ester as a yellow solid. LC / MS: C 10 H 13 Calculated mass of NO4: 211.08, measured: 212.10 [M+H] + .

[0598] Step 7: (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindole- 3-Methyl formate

[0599] To a solution of (3S)-5,7-dioxooctahydroindole-3-carboxylic acid methyl ester (370 mg, 1.75 mmol, 1.0 equiv) in dichloromethane (5 mL) was added triethylamine (355 mg, 3.50 mmol, 2.0 equiv) and N,N-bis(trifluoromethylsulfonyl)aniline (751 mg, 2.10 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature overnight. The mixture was then concentrated. The residue was purified by silica gel chromatography (0-80% EA / PE) to give (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid methyl ester as a yellow solid. LC / MS: C 11 H 12 Calculated mass of F3NO6S: 343.03, found: 344.05 [M+H] + .

[0600] Step 8: (3S)-7-(6-amino-3-chloro-2-fluorophenyl-5-oxo-1,2,3,5,8,8a-hexahydroindole-3- Methyl formate

[0601] To a 1,4-dihydroindole-3-carboxylic acid solution of ethyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindole-3-carboxylate (350 mg, 1.02 mmol, 1.0 equiv), (6-amino-3-chloro-2-fluorophenyl)boronic acid (232 mg, 1.20 mmol, 1.2 equiv) and potassium carbonate (282 mg, 2.04 mmol, 2.0 equiv) was added 1,4-dihydroindole-3-carboxylate. To a solution of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (37 mg, 0.05 mmol, 0.1 equiv) in oxane / H₂O (5 mL, 10 / 1) was added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (37 mg, 0.05 mmol, 0.1 equiv). The reaction mixture was stirred at 80°C under N₂ for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na₂SO₄. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to give (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoleazine-3-carboxylic acid methyl ester as a yellow solid. LC / MS: C 16 H 16 Calculated mass of ClFN2O3: 338.08, found: 339.10 [M+H] + .

[0602] Step 9: (3S)-7-(6-amino-3-chloro-2-fluorophenyl-5-oxo-1,2,3,5,8,8a-hexahydroindole-3- Formic acid

[0603] To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid methyl ester (210 mg, 0.62 mmol, 1.0 equiv) in THF / H2O / MeOH (5 mL, 3 / 1 / 1) was added lithium hydroxide (124 mg, 3.10 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 1 hour. The residue was adjusted to pH 4 with HCl, then extracted with ethyl acetate and washed with brine, dried and concentrated in vacuo to give (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid as a yellow solid. LC / MS: C 15 H 14 Calculated mass of ClFN2O3: 324.07, found: 325.05 [M+H] + .

[0604] Intermediate 2: (3S)-5,7-dioxooctahydroindole-3-carboxylic acid methyl ester

[0605]

[0606] Step 1: Methyl (2S)-5-allylpyrrolidine-2-carboxylate

[0607] 1-(tert-Butyl) 2-methyl (2S)-5-allylpyrrolidine-1,2-dicarboxylate (10 g, 37.13 mmol, 1.0 eq) was dissolved in HCl solution (90 mL, 10.00 eq) (4 M 1,4-dicarboxylate) The resulting mixture was maintained at room temperature for 2 hours. The solvent was removed under reduced pressure to give (2S)-5-allylpyrrolidine-2-carboxylic acid methyl ester, which was used in the next step without further purification. LC / MS: C9H 15 Calculated mass of NO2: 169.11, measured: 170.20 [M+H] + .

[0608] Step 2: Methyl (2S)-1-acryloyl-5-allylpyrrolidine-2-carboxylate

[0609] To a solution of (2S)-5-allylpyrrolidine-2-carboxylic acid methyl ester (6.0 g, 35.46 mmol, 1.0 equiv) in THF (200 mL) was added TEA (23 mL, 177.28 mmol, 5.0 equiv) followed by acryloyl chloride (3.2 g, 35.46 mmol, 1.0 equiv) at -78°C. The resulting mixture was kept at room temperature for 40 minutes. The reaction was then quenched with NH4C1 (aq.). The aqueous phase was extracted with EA. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (EA / PE) to give (2S)-1-acryloyl-5-allylpyrrolidine-2-carboxylic acid methyl ester as a yellow oil. LC / MS: C 12 H 17 Calculated mass of NO3: 223.12, measured: 224.20 [M+H] + .

[0610] Step 3: (3S)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid methyl ester

[0611] To a solution of (2S)-1-acryloyl-5-allylpyrrolidine-2-carboxylic acid methyl ester (7.2 g, 32.25 mmol, 1.0 equiv) in DCM (100 mL) under N2 was added the second generation Grubbs catalyst (2.7 g, 3.23 mmol, 0.1 equiv). The resulting mixture was heated at 45°C for 10 hours, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE) to give (3S)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid methyl ester as a brown oil. LC / MS: C 10 H 13 Calculated mass of NO3: 195.09, measured: 196.10 [M+H] + .

[0612] Step 4: Methyl (3S)-7-hydroxy-5-oxooctahydroindole-3-carboxylate

[0613] To a solution of CuCl (0.102 g, 1.03 mmol, 0.2 equiv) in THF (100 mL) under N₂ was added BINAP (638 mg, 1.03 mmol, 0.2 equiv). The mixture was maintained at room temperature for 15 minutes. t-BuONa (98 mg, 1.03 mmol, 0.2 equiv) was then added. After 30 minutes, 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis(1,3,2-dioxaborolane) (1.6 g, 6.15 mmol, 1.2 equiv) was added, followed by (3S)-methyl 5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylate (1.0 g, 5.12 mmol, 1.0 equiv). MeOH (328 mg, 10.25 mmol, 2.0 equiv) was then added dropwise. The resulting mixture was stirred for 16 hours and then cooled to 0° C. H 2 O 2 (6 mL, 51.23 mmol, 10.0 equiv) was added and the reaction mixture was stirred for an additional hour. The solvent was removed under reduced pressure and the residue was purified by silica gel (DCM / MeOH) to give (3S)-7-hydroxy-5-oxoocthydroindoleazine-3-carboxylic acid methyl ester as a brown oil, which was used in the next step without further purification.

[0614] Step 5: Methyl (3S)-5,7-dioxooctahydroindoleazine-3-carboxylate

[0615] To a solution of (3S)-methyl 7-hydroxy-5-oxo-octahydroindole-3-carboxylate (1.0 g) in DCM (100 mL) was added pyridinium chlorochromate. The resulting mixture was stirred for 16 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel (EA / PE) to give (3S)-methyl 5,7-dioxo-octahydroindole-3-carboxylate as a yellow oil. LC / MS: C 10 H 13 Calculated mass of NO4: 211.08, measured: 212.10 [M+H] + .

[0616] Intermediate 3: (3S)-5,7-dioxooctahydroindole-3-carboxylic acid methyl ester

[0617]

[0618] Step 1: (S)-Diethyl 2-((tert-Butoxycarbonyl)amino-5-oxopimelic acid ester

[0619] Tetrahydrofuran (1.0 L) and LDA (253 mL, 2M THF solution, 1.00 equivalent) were placed in a 3L three-necked round-bottom flask purged and maintained with a nitrogen inert atmosphere. A solution of ethyl acetate (44.5 g, 505.2 mmol, 1.00 equivalent) in THF (100 mL) was then added dropwise at -78°C with stirring and stirred for 30 minutes. A solution of 1-tert-butyl 2-ethyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (130 g, 505.2 mmol, 1.00 equivalent) in THF (300 mL) was added to the resulting mixture at -78°C with stirring. The resulting solution was stirred at room temperature overnight. The reactants were then quenched by adding NH4Cl (aqueous solution, 50 mL). The resulting solution was extracted with DCM (3 × 1 L) and the organic layers were combined. The resulting mixture was washed with brine (2 × 500 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated.The residue was applied to a silica gel column with ethyl acetate to give (S)-diethyl 2-((tert-butoxycarbonyl)amino)-5-oxopimelic acid ester as a yellow oil. 1 HNMR: (300MHz, CDCl3, ppm) δ5.21-5.09 (m, 1H), 4.23-4.05 (m, 5H), 3.39 (s, 2H), 2.72 -2.56(m, 2H), 2.20-2.05(m, 1H), 1.94-1.80(m, 1H), 1.41(s, 9H), 1.31-1.20(m, 6H).

[0620] Step 2: Ethyl (S,Z)-5-(2-ethoxy-2-oxoethylidene)pyrrolidine-2-carboxylate

[0621] 1,7-Diethyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-oxopimelate (105.0 g, 304.0 mmol, 1.00 equiv) and trifluoroacetic acid (59.6 g, 608.0 mmol, 2.00 equiv) were placed in a 3 L three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred at 25° C. for 3 hours. The resulting mixture was concentrated. The resulting solution was diluted with DCM (100 mL). The pH value of the solution was adjusted to 7 with Na2CO3. The resulting solution was extracted with DCM (3×500 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1:4) to give (S,Z)-5-(2-ethoxy-2-oxoethylidene)pyrrolidine-2-carboxylic acid ethyl ester as a light yellow oil. LC / MS: C 11 Calculated mass of H17NO4: 227.12, found: 228.00 [M+H] + .

[0622] Step 3: Ethyl (2S,5R)-5-(2-ethoxy-2-oxoethyl)pyrrolidine-2-carboxylate

[0623] Acetic acid (280 mL), ethyl (2S,5Z)-5-(2-ethoxy-2-oxoethylidene)pyrrolidine-2-carboxylate (35.0 g, 154.0 mmol, 1.00 equiv), and PtO2 (4.2 g, 18.5 mmol, 0.12 equiv) were placed in a 500 ml round-bottom flask. The mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The mixture was concentrated and diluted with EA (3 L). Aqueous NaHCO3 was added to adjust the pH of the mixture to pH 7. The resulting solution was extracted with ethyl acetate (3 x 2 L), dried over anhydrous sodium sulfate, and concentrated to give ethyl (2S,5R)-5-(2-ethoxy-2-oxoethyl)pyrrolidine-2-carboxylate as a yellow oil. 1 HNMR (300MHz, CDCl3, ppm) δ4.19 (dq, J=11.5, 7.1Hz, 4H), 3.87 (dd, J=9.0, 5.5Hz, 1H), 3.71 (s, 1H), 3.63-3.48 (m , 1H), 2.69-2.49 (m, 2H), 2.23-2.08 (m, 1H), 2.05-1.91 (m, 2H), 1.55-1.36 (m, 1H), 1.29 (dt, J=11.5, 7.1Hz, 6H).

[0624] Step 4: (2S,5R)-5-(2-ethoxy-2-oxoethyl)-1-(3-ethoxy-3-oxopropanoyl)pyrrole Ethyl 2-oxanecarboxylate

[0625] DCM (700 mL), DIPEA (39.4 g, 305.3 mmol, 2.00 equiv), and ethyl (2S,5R)-5-(2-ethoxy-2-oxoethyl)pyrrolidine-2-carboxylate (35.0 g, 152.6 mmol, 1.00 equiv) were placed in a 2 L three-necked round-bottom flask purged and maintained with a nitrogen inert atmosphere. This was followed by the addition of a solution of ethyl 3-chloro-3-oxopropanoate (29.9 g, 198.4 mmol, 1.30 equiv) in DCM (50 mL) at 0° C. with stirring. The resulting solution was stirred at room temperature for 1 h. The resulting mixture was washed with water (2×200 mL). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1:20-1:2) to give (2S,5R)-5-(2-ethoxy-2-oxoethyl)-1-(3-ethoxy-3-oxopropanoyl)pyrrolidine-2-carboxylic acid ethyl ester as a yellow oil. LC / MS: C 16 H 25 Calculated mass of NO7: 343.16, found: 334.00 [M+H] + .

[0626] Step 5: Diethyl (3S,8aR)-5,7-dioxooctahydroindoleazine-3,6-dicarboxylate

[0627] Ethanol (500 mL), ethyl (2S,5R)-5-(2-ethoxy-2-oxoethyl)-1-(3-ethoxy-3-oxopropanoyl)pyrrolidine-2-carboxylate (38.6 g, 112.4 mmol, 1.00 equiv), and sodium ethoxide (8.0 g, 118.0 mmol, 1.05 equiv) were placed in a 1 L round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred at 60° C. for 50 minutes. The reaction mixture was cooled in a water / ice bath and concentrated. The mixture was poured into HCl (1N, 300 mL). The resulting solution was extracted with ethyl acetate (2×200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1:20-1:3) to give diethyl (3S,8aR)-5,7-dioxooctahydroindoleazine-3,6-dicarboxylate as a yellow oil. LC / MS: C 14 Calculated mass of H19NO6: 297.12, found: 298.00 [M+H] + .

[0628] Step 6: Ethyl (3S,8aR)-5,7-dioxooctahydroindoleazine-3-carboxylate

[0629] 3,6-Diethyl (3S,8aR)-5,7-dioxo-hexahydroindole-3,6-dicarboxylate (28.0 g, 94.1 mmol, 1.00 equiv) was placed in a 2 L three-necked round-bottom flask with acetic acid (196 mL) and H2O (20 mL). The resulting solution was stirred at 110°C for 2 hours. The reaction mixture was cooled with a water / ice bath. The resulting mixture was concentrated to give (3S,8aR)-5,7-dioxo-hexahydroindole-3-carboxylic acid ethyl ester as a yellow oil.

[0630] 1 HNMR (300MHz, CDCl3, ppm) δ4.63 (d, J=8.0Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 4.08-3.90 (m, 1H), 3.32 (s, 2H), 2. 88 (dd, J=16.6, 3.2Hz, 1H), 2.65-2.54 (m, 1H), 2.41-2.09 (m, 3H), 1.99-1.79 (m, 1H), 1.31 (t, J=7.1Hz, 3H).

[0631] Intermediate 4: (3S)-7-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-5-oxo-1, 2,3,5,8,8a-Hexahydroindole-3-carboxylic acid

[0632]

[0633] Step 1: 1-Azido-4-chloro-3-fluoro-2-iodobenzene

[0634] To a solution of 4-chloro-3-fluoro-2-iodoaniline (10 g, 36.83 mmol, 1.0 equiv) in CH3CN (100 mL) and trimethylsilyl azide (10 mL) was added tert-butyl nitrite (5.7 g, 55.25 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was applied to a silica gel column to give 1-azido-4-chloro-3-fluoro-2-iodobenzene as a yellow solid. LC / MS: Mass calculated for C6H2ClFIN3: 296.90, found: 297.00 [M+H] + .

[0635] Step 2: 1-(4-chloro-3-fluoro-2-iodophenyl)-4-(tri-tert-butylstannyl)-1H-1,2,3-triazole

[0636] To a solution of 1-azido-4-chloro-3-fluoro-2-iodobenzene (5 g, 16.81 mmol, 1.0 equiv) in toluene (50 mL) was added tributyl(ethynyl)stannane (5.3 g, 16.81 mmol, 1 equiv). The resulting mixture was stirred at 100° C. overnight. The mixture was concentrated. The residue was applied to a silica gel column to afford 1-(4-chloro-3-fluoro-2-iodophenyl)-4-(tributylstannyl)-1H-1,2,3-triazole as a yellow solid. LC / MS: C 20 H 30 Calculated mass of ClFIN3Sn: 613.02, found: 614.00 [M+H] + .

[0637] Step 3: 4-Chloro-1-(4-chloro-3-fluoro-2-iodophenyl)-1H-1,2,3-triazole

[0638] To a solution of 1-(4-chloro-3-fluoro-2-iodophenyl)-4-(tributylstannyl)-1H-1,2,3-triazole (10 g, 16.33 mmol, 1.0 equiv) in CH3CN (100 mL) was added NCS (2.2 g, 16.33 mmol, 1 equiv). The resulting mixture was stirred at 80°C for 4 hours and then concentrated. The residue was applied to a silica gel column to afford 4-chloro-1-(4-chloro-3-fluoro-2-iodophenyl)-1H-1,2,3-triazole. LC / MS: Mass calculated for CH3Cl2FIN3: 356.87, found: 358.10 [M+H] + .

[0639] Step 4: (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindole- 3-Methyl formate

[0640] To a solution of (3S)-7-hydroxy-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid methyl ester (1 g, 4.73 mmol, 1.0 equiv) in DCM (15 mL) was added 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.9 g, 5.32 mmol, 1.1 equiv) and TEA (958 mg, 9.47 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure to give a residue, which was purified by silica gel column chromatography using EA / PE (0-100%) to give (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid methyl ester as a yellow solid. LC / MS: C 11 H 12 Calculated mass of F3NO6: 343.03, found: 344.10 [M+H] + .

[0641] Step 5: (3S)-5-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3, 5,8,8a-Hexahydroindole-3-carboxylic acid methyl ester

[0642] Under an inert atmosphere of nitrogen, 1,4-difluoromethanesulfonyloxy-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid methyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindole-3-carboxylate (800 mg, 2.33 mmol, 1.0 equiv) was added to the mixture. To a solution of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis(1,3,2-dioxaborolane) (888 mg, 3.49 mmol, 1.5 equiv), Pd(dppf)Cl2 (171 mg, 0.23 mmol, 0.1 equiv) and KOAc (457 mg, 4.65 mmol, 2.0 equiv) was added 1,2-dioxaborolane (10 mL). The reaction mixture was stirred at 90° C. for 2 h. The solid was filtered off through celite. The filtrate was concentrated in vacuo to give (3S)-5-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid methyl ester as a yellow solid. LC / MS: C 16 H 24 Calculated mass of BNO5: 321.17, found: 322.10 [M+H] + .

[0643] Step 6: (3S)-7-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-5-oxo-1,2, 3,5,8,8a-Hexahydroindole-3-carboxylic acid methyl ester

[0644] Under an inert atmosphere of nitrogen, (3S)-5-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid methyl ester (500 mg, 1.56 mmol, 1.0 equivalent) was added to 1,4-dioxaborolan-2-yl. To a solution of 4-chloro-1-(4-chloro-3-fluoro-2-iodophenyl)-1H-1,2,3-triazole (613 mg, 1.71 mmol, 1.1 equiv), Pd(PPh3)4 (180 mg, 0.156 mmol, 0.1 equiv), and K2CO3 (430 mg, 3.11 mmol, 2.0 equiv) were added in 1,2-dextran (10 mL) and H2O (1.0 mL). The reaction mixture was stirred at 90°C for 2 hours and then concentrated to dryness under reduced pressure to give a residue, which was purified by silica gel column chromatography using MeOH / DCM (0-15%) to give (3S)-methyl 7-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylate as a yellow solid. LC / MS: C 18 H 15 Calculated mass of Cl2FN4O3: 424.05, found: 425.05 [M+H] + .

[0645] Step 7: (3S)-7-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-5-oxo-1,2, 3,5,8,8a-Hexahydroindole-3-carboxylic acid

[0646] To a solution of (3S)-7-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid methyl ester (300 mg, 0.70 mmol, 1.0 equiv) in THF (6 mL), MeOH (2 mL) and H O (2 mL) was added LiOH (84 mg, 3.51 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 3 hours. The pH was adjusted to 5-6 with HCl (2 M) at 0° C. and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give (3S)-7-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid as a yellow solid. LC / MS: C 17 H 13 Calculated mass of Cl2FN4O3: 410.03, found: 411.05 [M+H] + .

[0647] Intermediate 5: (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5- Oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid

[0648]

[0649] Step 1: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3- Methyl formate .

[0650] To a 1,4-dihydro-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid solution of methyl 5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindole-3-carboxylate (5.0 g, 14.57 mmol, 1.0 equiv) and (6-amino-3-chloro-2-fluorophenyl)boronic acid (5.5 g, 29.13 mmol, 2.0 equiv) was added 1,4-dihydroindole-3-carboxylic acid solution of methyl 5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindole-3-carboxylate (5.0 g, 14 To a mixture of oxane (50 mL) and water (10 mL) were added potassium phosphate (7.7 g, 36.41 mmol, 2.5 equiv) and Pd(dppf)Cl2 (1.1 g, 1.46 mmol, 0.1 equiv). The flask was evacuated and purged with nitrogen three times. The solution was stirred at 100°C under N2 for 1 hour. Water was added to the solution, and the resulting mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (0→80% EA / PE) to give methyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoleazine-3-carboxylate as a yellow solid. LC / MS: C 16 H 16 Calculated mass of ClFN2O3: 338.08, found (ES, m / z): 339.10 [M+H] + .

[0651] Step 2: (3S)-7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole- 3-Methyl formate .

[0652] To a mixture of 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid methyl ester (3.4 g, 10.04 mmol, 1.0 equivalent) and trimethylsilyl azide (2.6 mL, 20.07 mmol, 2.0 equivalent) in acetonitrile (35 mL) was added tert-butyl nitrite (2.4 mL, 20.07 mmol, 2.0 equivalent) at 0°C. The solution was stirred at room temperature for 1 hour. Water was added to the mixture and the resulting mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (0→80% EA / PE) to give methyl 7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylate as a yellow solid. LC / MS: C16 H 14 Calculated mass of ClFN4O3: 364.07, found (ES, m / z): 365.10 [M+H] + .

[0653] Step 3: (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo- Methyl 1,2,3,5,8,8a-hexahydroindole-3-carboxylate .

[0654] To a mixture of methyl 7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylate (2.9 g, 7.95 mmol, 1.0 equiv) and 4,4,4-trifluorobut-2-ynoic acid (5.5 g, 39.75 mmol, 5.0 equiv) in acetonitrile (30 mL) was added cuprous oxide (455 mg, 3.18 mmol, 0.4 equiv). The flask was evacuated and purged with nitrogen three times. The solution was stirred at 80° C. under N2 for 2 hours. The solution was concentrated in vacuo and purified by silica gel chromatography (0→60% EA / PE) to give methyl 7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylate as a white solid. LC / MS: C 19 H 15 Calculated mass of ClF4N4O3: 458.08, found (ES, m / z): 459.05 [M+H] + .

[0655] Step 4: (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo- Substituted-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid .

[0656] To a mixture of methyl 7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylate (2.8 g, 6.10 mmol, 1.0 equiv) in acetonitrile (30 mL) and water (0.2 mL) was added triethylamine (5.0 mL, 36.62 mmol, 6.0 equiv) and lithium bromide (1.6 g, 18.31 mmol, 3.0 equiv). The solution was stirred at 60° C. for 18 hours. The mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography on C18 (330 g, ACN / H2O (0.05% CF3COOH): 0→30%) to give 7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindole-3-carboxylic acid as a yellow solid. LC / MS: C 18 H 13Calculated mass of ClF4N4O3: 444.06, found (ES, m / z): 445.15 [M+H] + .

[0657] Intermediate 6: 7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2-methyl-5-oxo-1,2,3,5,8, 8a-Hexahydroindole-3-carboxylic acid

[0658]

[0659] Step 1: Ethyl (E)-2-((2,2-dimethylpropylidene)amino)acetate

[0660] To a solution of glycine ethyl hydrochloride (50.0 g, 358.22 mmol, 1.0 equiv) in dichloroethane (500 mL) was added pivalaldehyde (33.9 g, 394.04 mmol, 1.1 equiv), EtN (39.9 g, 394.04 mmol, 1.1 equiv), and MgSO (43.1 g, 358.22 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature overnight. The reaction was filtered and concentrated to afford ethyl (E)-2-((2,2-dimethylpropylidene)amino)acetate as a white solid.

[0661] Step 2: ...

Claims

1. A compound of formula (I) in R 1 Select from the group consisting of: C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy and 5- to 6-membered monocyclic heteroaryl containing at least one N; wherein the 5- to 6-membered monocyclic heteroaryl containing at least one N is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-4 Alkyl and fluorinated C 1-4 alkyl; a is an integer from 0 to 3; Each R 2 independently selected from the group consisting of chloro, fluoro, methyl and methoxy; R A and R B are each independently selected from the group consisting of: hydrogen and halogen; alternatively, R A and R B Together with the carbon atom to which they are attached, they form an oxo group; R C Selected from the group consisting of: hydrogen and C 1-4 alkyl; R D Selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 1-4 Alkoxy; R E Selected from the group consisting of: hydrogen and C 1-4 alkyl; Q is selected from the group consisting of: (a) and in R 4 Selected from the group consisting of: hydrogen and C 1-4 alkyl; R 5 Selected from the group consisting of hydrogen, halogen and C 1-4 alkyl; is selected from the group consisting of phenyl, 5-6 membered heteroaryl and 9 to 10 membered heterocyclyl containing at least one heteroatom selected from O, N and S; b is an integer from 0 to 1; R 6 Select from the group consisting of: C 3-8 Cycloalkyl, -O-(C 1-2 Alkylene)-C 3-8 Cycloalkyl, -C(O)-(C 3-8 Cycloalkyl), -NH-(C 3-8 Cycloalkyl), -NH-C(O)-(C 3-8 Cycloalkyl), -C(O)-NH-(C 3-8 Cycloalkyl), 4-6 membered heterocycloalkyl, -O-(C 1-2 alkylene)-(4-6 membered heterocycloalkyl), -C(O)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(O)-NH-(4-6 membered heterocycloalkyl), -NH-C(O)-(4-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -O-(C 1-2 alkylene)-(5-6 membered heteroaryl), -C(O)-(5-6 membered heteroaryl), -NH-(5-6 membered heteroaryl), -NH-C(O)-(5-6 membered heteroaryl), -C(O)-NH-(5-6 membered heteroaryl), 2-oxa-6-azaspiro[3.3]hept-6-yl, 6-oxa-2-azaspiro[3.4]oct-2-yl and 7-oxa-2-azaspiro[3.5]non-2-yl, wherein the 4-6 membered heterocycloalkyl contains at least one heteroatom selected from O, N and S, and the 5-6 membered heteroaryl is a 5 or 6 membered monocyclic aromatic ring structure containing at least one heteroatom selected from O, N and S; Wherein C 3-8 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, whether alone or as part of a substituent group, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-4 Alkyl, hydroxy, oxo, cyano and NR P R Q ; where R P and R Q are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl; c is an integer from 0 to 3; Each R 7 independently selected from the group consisting of halogen, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxy substituted C 1-6 Alkyl, hydroxy substituted fluorinated C 1-2 Alkyl, cyano substituted C 1-2 Alkyl, C 1-4 Alkoxy, fluorinated C 1-2 Alkoxy, hydroxy substituted C 1-4 Alkoxy, -(C 1-2 Alkylene)-O-(C 1-4 alkyl), oxo, -C(O)OH, -C(O)O-(C 1-2 Alkyl), -NR K R L 、-NR K -(Hydroxy-substituted C 1-4 Alkyl), -NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -C(O)-NR K R L 、-C(O)-NR K -O-(C 1-4 Alkyl), -C(O)-NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -(C 1-2 Alkylene)-C(O)-NR K R L 、-NR K -C(O)-(C 1-4 Alkyl), -NR K -C(O)-(fluorinated C 1-2 Alkyl), -NR K -C(O)O-(C 1-4 Alkyl), -NR K -C(O)-C 3-6 Cycloalkyl, -(C 1-2 Alkylene)-NR K -C(O)-(C 1-4 Alkyl), -(C 1-2 Alkylene)- NR K -C(O)O-(C 1-4 Alkyl), -(C 1-2 Alkylene)-OC(O)-(amino substituted C 1-4 Alkyl), -NR K -SO2-(C 1-4 Alkyl), -C(O)-NR K -SO2-(C 1-2 Alkyl), -(C 1-2 Alkylene)-OP(O)(OH)2 and -(C 1-2 Alkylene)-O-(C 1-2 Alkylene)-P(O)(OH)2; wherein R K and R L are each independently selected from hydrogen and C 1-4 alkyl; And as described When the heterocyclic, heteroaryl or heterocycloalkyl group present in any part of the group contains a nitrogen atom, the heterocyclic, heteroaryl or heterocycloalkyl group may be further substituted to form an N-oxide; The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and the two R 2 When the group is 2-fluoro and 3-chloro, Q is not (a) or (c) and Provided that the compound is not or a tautomer, stereoisomer, deuterated isotope or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R 1 Select from the group consisting of: C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy, fluorinated C 1-4 Alkoxy and a 5- to 6-membered monocyclic heteroaryl containing at least one N; wherein The 5- to 6-membered monocyclic heteroaryl containing at least one N is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-4 Alkyl and fluorinated C 1-4 alkyl; a is an integer from 0 to 2; Each R 2 independently selected from the group consisting of chloro, fluoro, and methyl; R A and R B are each independently selected from the group consisting of: hydrogen and halogen; alternatively, R A and R B Together with the carbon atom to which they are attached, they form an oxo group; R C Selected from the group consisting of: hydrogen and C 1-4 alkyl; R D Selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 1-4 Alkoxy; R E Selected from the group consisting of: hydrogen and C 1-4 alkyl; Q is selected from the group consisting of: (a) and (b) in R 4 Selected from the group consisting of: hydrogen and C 1-4 alkyl; R 5 Selected from the group consisting of hydrogen, halogen and C 1-4 alkyl; b is an integer from 0 to 1; R 6 Select from the group consisting of: C 3-6 Cycloalkyl, -O-(C 1-2 Alkylene)-C 3-6 Cycloalkyl, -NH-(C 3-8 Cycloalkyl), -NH-C(O)-(C 3-8 Cycloalkyl), 4-6 membered heterocycloalkyl, -O-(C 1-2 alkylene)-(4-6 membered heterocycloalkyl), -C(O)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(O)-NH-(4-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -O-(C 1-2 alkylene)-(5-6 membered heteroaryl), -NH-C(O)-(5-6 membered heteroaryl) and 2-oxa-6-azaspiro[3.3]hept-6-yl; Wherein C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, whether alone or as part of a substituent group, are optionally substituted with one to two substituents independently selected from the group consisting of halogen, C 1-2 Alkyl, hydroxy, oxo, cyano and NR P R Q ; where R P and R Q are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl; c is an integer from 0 to 2; Each R 7 independently selected from the group consisting of halogen, C 1-2 Alkyl, fluorinated C 1-2 Alkyl, hydroxy substituted C 1-6 Alkyl, hydroxy substituted fluorinated C 1-2 Alkyl, cyano substituted C 1-2 Alkyl, C 1-4 Alkoxy, fluorinated C 1-2 Alkoxy, hydroxy substituted C 1-4 Alkoxy, -(C 1-2 Alkylene)-O-(C 1-4 alkyl), oxo, -C(O)OH, -C(O)O-(C 1-2 Alkyl), -NR K R L 、-NR K -(Hydroxy-substituted C 1-4 Alkyl), -NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -C(O)-NR K R L 、-C(O)-NR K -O-(C 1-4 Alkyl), -C(O)-NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -(C 1-2 Alkylene)-C(O)-NR K R L 、-NR K -C(O)-(C 1-4 Alkyl), -NR K -C(O)-(fluorinated C 1-2 Alkyl), -NR K -C(O)O-(C 1-4 Alkyl), -NR K -C(O)-C 3-5 Cycloalkyl, -(C 1-2 Alkylene)-NR K -C(O)-(C 1-4 Alkyl), -(C 1-2 Alkylene)-NR K -C(O)O-(C 1-4 Alkyl), -(C 1-2 Alkylene)-OC(O)-(amino substituted C 1-4 Alkyl), -NR K -SO2-(C 1-2 Alkyl), -C(O)-NR K -SO2-(C 1-2 Alkyl), -(C 1-2 Alkylene)-OP(O)(OH)2 and -(C 1-2 Alkylene)-O-(C 1-2 Alkylene)-P(O)(OH)2; wherein R K and R L are each independently selected from hydrogen and C 1-4 alkyl; The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and the two R 2 When the group is 2-fluoro and 3-chloro, Q is not (a) (b) or (c) or a tautomer, stereoisomer, deuterated isotope or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein R 1 Selected from the group consisting of: fluorinated C 1-2 Alkyl, fluorinated C 1-2 alkoxy and a 5-membered monocyclic heteroaryl containing at least one N; wherein the 5-membered nitrogen-containing heteroaryl is optionally halogenated or fluorinated. 1-2 Alkyl substitution; a is an integer from 1 to 2; Each R 2 independently selected from the group consisting of chloro, fluoro, and methyl; R A and R B are each independently selected from the group consisting of: hydrogen and halogen; alternatively, R A and R B Together with the carbon atom to which they are attached, they form an oxo group; R C Selected from the group consisting of: hydrogen and C 1-2 alkyl; R D Selected from the group consisting of: hydrogen, C 1-2 Alkyl and C 1-2 Alkoxy; R E Selected from the group consisting of: hydrogen and C 1-2 alkyl; Q is selected from the group consisting of: (a) and (b) in R 4 Selected from the group consisting of: hydrogen and C 1-2 alkyl; R 5 Selected from the group consisting of hydrogen, halogen and C 1-2 alkyl; is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, and 9- to 10-membered heterocyclyl containing at least one heteroatom selected from O, N and S; b is an integer from 0 to 1; R 6 Select from the group consisting of: C 3-5 Cycloalkyl, -NH-C(O)-C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C 1-2 alkylene)-(4-6 membered heterocycloalkyl), -C(O)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(O)-NH-(5-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -O-(C 1-2 alkylene)-(5-6 membered heteroaryl), -NH-C(O)-(5-6 membered heteroaryl) and 2-oxa-6-azaspiro[3.3]hept-6-yl; Wherein C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, whether alone or as part of a substituent group, are optionally substituted with one to two substituents independently selected from the group consisting of halogen, C 1-2 Alkyl, hydroxy, oxo, cyano and NR P R Q ; where R P and R Q are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl; c is an integer from 0 to 2; Each R 7 independently selected from the group consisting of halogen, C 1-2 Alkyl, fluorinated C 1-2 Alkyl, hydroxy substituted C 1-6 Alkyl, hydroxy substituted fluorinated C 1-2 Alkyl, cyano substituted C 1-2 Alkyl, C 1-4 Alkoxy, fluorinated C 1-2 Alkoxy, hydroxy substituted C 1-4 Alkoxy, -(C 1-2 Alkylene)-O-(C 1-4 alkyl), oxo, -C(O)OH, -C(O)O-(C 1-2 Alkyl), -NR K R L 、-NR K -(Hydroxy-substituted C 1-4 Alkyl), -NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -C(O)-NR K R L 、-C(O)-NR K -O-(C 1-4 Alkyl), -C(O)-NR K -(C 1-2 Alkylene)-O-(C 1-2 Alkyl), -(C 1-2 Alkylene)-C(O)-NR K R L 、-NR K -C(O)-(C 1-4 Alkyl), -NR K -C(O)-(fluorinated C 1-2 Alkyl), -NR K -C(O)O-(C 1-4 Alkyl), -NR K -C(O)-C 3-5 Cycloalkyl, -(C 1-2 Alkylene)-NR K -C(O)-(C 1-4 Alkyl), -(C 1-2 Alkylene)-NR K -C(O)O-(C 1-4 Alkyl), -(C 1-2 Alkylene)-OC(O)-(amino substituted C 1-4 Alkyl), -NR K -SO2-(C 1-2 Alkyl), -C(O)-NR K -SO2-(C 1-2 Alkyl), -(C 1-2 Alkylene)-OP(O)(OH)2 and -(C 1-2 Alkylene)-O-(C 1-2 Alkylene)-P(O)(OH)2; wherein R K and R L are each independently selected from hydrogen and C 1-2 alkyl; And as described When the heterocyclic, heteroaryl or heterocycloalkyl group present in any part of the group contains a nitrogen atom, the heterocyclic, heteroaryl or heterocycloalkyl group may be further substituted to form an N-oxide; The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and the two R 2 When the group is 2-fluoro and 3-chloro, Q is not (a) (b) or (c) or a tautomer, stereoisomer, deuterated isotope or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein R 1 Selected from the group consisting of difluoromethyl, difluoro-methoxy, 2,2,2-trifluoro-ethoxy, pyrazol-5-yl, imidazol-5-yl, 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl; a is an integer from 1 to 2; Each R 2 independently selected from the group consisting of 2-fluoro, 3-chloro, 5-chloro, and 3-methyl; R A and R B are each independently selected from the group consisting of hydrogen, deuterium and fluorine; alternatively, R A and R B Together with the carbon atom to which they are attached, they form an oxo group; R C selected from the group consisting of: hydrogen, deuterium, and methyl; R D selected from the group consisting of hydrogen, deuterium, methyl, S*-methyl, R*-methyl, S-methoxy and R-methoxy; R E is selected from the group consisting of: hydrogen and methyl; Q is selected from the group consisting of: (a) and (b) in R 4 selected from the group consisting of: hydrogen, deuterium, and methyl; R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine and methyl; Select from the group consisting of: 2-methoxy-phenyl, 2-(isopropoxy)-phenyl, 3-fluoro-4-carboxy-phenyl, 2-amino-phenyl, 2-(dimethyl-amino)-phenyl, 2-(amino-carbonyl)-phenyl, 2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-3-(amino-carbonyl)-phenyl, 3-(amino-carbonyl)-4-fluoro-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 2-(methyl-amino-carbonyl)-phenyl, 2-(dimethyl-amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)-phenyl, 2-( methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 2-(methoxy-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 4-(1R-(methyl-carbonyl-amino)-ethyl)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl, 2-(methyl-sulfonyl-amino)-phenyl, 4-(1R-(methyl-carbonyl-amino)-ethyl)-phenyl, Oxazolidin-3-yl-2-one)-phenyl; 2-carboxy-thiophen-5-yl, 2-carboxy-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-4-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-5-yl, 3-(cyclopropyl-carbonyl-amino)-thiophen-2-yl, 2-(methyl-sulfonyl-amino-carbonyl)-3-fluoro-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 4-chloro-pyrazol-3-yl, 3-fluoro-pyrazol-4-yl, 3-chloro-pyrazol-4-yl, 3-methoxy-pyrazol-4-yl, 3-(trifluoromethyl)-pyrrol-4-yl )-pyrazol-4-yl, 5-chloro-pyrazol-4-yl, 1-methyl-3-(cyclopropyl-carbonyl-amino)-pyrazol-4-yl, 1-methyl-4-(cyclopropyl-carbonyl-amino)-pyrazol-5-yl, imidazol-2-yl, 2-(trifluoro-methyl)-imidazol-4-yl, 1-methyl-imidazol-2-yl, 4-(hydroxy-methyl)-thiazol-2-yl, 2-(hydroxy-methyl)-thiazol-4-yl, 2-(amino-carbonyl)-thiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-5-yl, 1-methyl-(1,2,4-triazol-3-yl), 1-methyl-1,2,3-triazol-5-yl; 3-Fluoro-pyridin-4-yl-2-one, 3-fluoro-pyridin-4-yl, 2-fluoro-5-chloro-pyridin-4-yl, 2-(difluoromethoxy)-pyridin-4-yl, 2-(trifluoro-methyl)-pyridin-4-yl, 2-(cyano-methyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-carboxy-3-fluoro-pyridin-4-yl, 2-(methoxy-carbonyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-d2-methyl)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-ethoxy)-pyridin-4-yl, 2-(2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin- 4-yl, 2-(2-hydroxy-2-methyl-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-chloro-6-(hydroxy-methyl)-pyridin-3-yl, 2-fluoro-6-(hydroxy-methyl)-pyridin-3-yl, 2-(hydroxy-d2-methyl)-3-chloro-pyridin-4-yl, 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-2,2-difluoro -ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 2-(3-hydroxy-3-methyl-n-butyl)-3-fluoro-pyridin-3-yl, 2-(1,1-difluoro-2-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(1S*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 4-amino-pyridin-3-yl, 2-chloro-6-amino-pyridin-3-yl, 3-chloro-6-amino-pyridin-4-yl, 2-amino-3-methyl-pyridin -4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-amino-6-(trifluoro-methyl)-pyridin-5-yl, 2-(methyl-amino)-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin-3-yl, 2-fluoro-6-(dimethyl-amino)-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-amino-3-methoxy-pyridin-4-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(1,1-dimethyl-2-hydroxy-ethyl-amino)-3-fluoro-pyridin-4-yl,2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2R*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deutero-6-amino-pyridin-3-yl, 2-fluoro-5-deutero-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(N-ethyl-N-2-hydroxy-ethyl-amino)-3-fluoro- pyridin-4-yl, 2-(amino-carbonyl)-pyridin-4-yl, 2-(amino-carbonyl)-pyridin-5-yl, 2-(amino-carbonyl)-3-fluoro-pyridin-3-yl, 2-chloro-6-(amino-carbonyl)-pyridin-3-yl, 2-(2-methoxy-ethyl-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(amino-carbonyl-methyl)-3-fluoro-pyridin-4-yl, 3-(trifluoromethyl-carbonyl-amino)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-pyridin-4-yl, 3-chloro-6-(methyl-carbonyl-amino)-pyridin-4-yl, 5-(methoxy-carbonyl-amino)-pyridin- 2-yl, 2-(methoxy-carbonyl-amino)-pyridin-5-yl, 2-(methoxy-carbonyl-amino)-pyridin-4-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 2-(ethoxy-carbonyl-amino)-pyridin-3-yl, 4-(ethoxy-carbonyl-amino)-pyridin-3-yl, 2-(ethoxy-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 3-(methyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(1S-amino-isopropyl-carbonyl-oxy 2-(1-Hydroxy-1-yl)-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-Hydroxy-1-yl)-3-fluoro-pyridin-4-yl,3-(Cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(Cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(oxetan-3-yl)-3-fluoro-pyridin-4-yl, 2-(3-cyano-oxetan-3-yl)-3-fluoro-pyridin-4-yl, 2-(azetidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(3-cyano-azetidin-1-yl)-3 -fluoro-pyridin-4-yl, 2-(pyrrolidin-1-yl-2-one)-3-fluoro-pyridin-4-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(3S-hydroxy-piperidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(pyrazol-1-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-2-yl, 2-(pyrazol-5-yl)-pyridin -4-yl, 2-(pyrazol-5-yl)-3-fluoro-pyridin-4-yl, 2-(5-amino-pyrazol-1-yl)-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(5-amino-pyrazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-pyridin-4-yl, 2-(imidazol-2-yl)-3-fluoro- Pyridin-4-yl, 2-(1,2,3-triazol-1-yl)-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 2-(1,2,3-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(1,3,4-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(1,2,4-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(, Oxazolidin-3-yl-2-one)-3-fluoro-pyridin-4-yl, 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3-fluoro-pyridin-4-yl, 2-(di Alkyl-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1R*- Oxazol-2-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S*- Oxazol-2-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S-(1,3,4- oxadiazole-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(3,3-difluoro-azetidin-1-yl-carbonyl)-3-fluoro-pyridin-4-yl, 2-fluoro-6-(bicyclo[ 1.1.1]pentyl-amino)-pyridin-3-yl, 2-(bicyclo[ 1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, 2-(bicyclo[ 1.1.1]pentyl-amino-carbonyl)-3-fluoro-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(3-methyl-isopropyl)- oxazol-5-yl-carbonyl-amino)-3-fluoro-pyridin-4-yl, pyridin-4-yl-2-one, pyridin-4-yl-N-oxide, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl-N-oxide; Indol-3-yl, indol-6-yl, indol-5-yl, indol-5-yl-2-one, 7-fluoro-indol-6-yl, indazol-5-yl, indazol-4-yl, 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, indolin-5-yl-2-one, 6-methyl-indololin-7-yl-2-one, benzimidazol-5-yl, 2-methyl-benzimidazol-6-yl, benzimidazol-5-yl-2-one, 1-methyl-benzimidazol-6-yl-2-one, 1-methyl-benzimidazol-5-yl-2-one, 3-amino-benzisodazole Azoles-5-yl, benzo oxazol-6-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 6-methyl-quinoxalin-5-yl-2(1H)-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 2,3-dihydrofuro[2,3-b]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3- c]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 5-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[3,2-c]pyridin-3-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl and 1H-pyrazolo[3,4-b]pyridin-5-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] oxazine-6-yl-2-one, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl and 7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl-7-ol; and wherein one or both of the following are optionally deuterated: (i) in R 1 a hydrogen atom bound to the phenyl ring at the meta-position of and (ii) a hydrogen atom bound to the 8a-position of 2,3,8,8a-tetrahydroindoleazine-5(1H)-one; The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and the two R 2 When the group is 2-fluoro and 3-chloro, Q is not (a) (b) or (c) or a tautomer, stereoisomer, deuterated isotope or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein R 1 Selected from the group consisting of 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl; a is an integer from 1 to 2; Each R 2 independently selected from the group consisting of: 2-fluoro and 3-chloro; R A and R B Each is hydrogen; R C is selected from the group consisting of: hydrogen and methyl; R D selected from the group consisting of hydrogen, methyl, S*-methyl, R*-methyl, S-methoxy and R-methoxy; R E is hydrogen; Q is selected from the group consisting of: (a) and (b) in R 4 is hydrogen; R 5 selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine and methyl; Select from the group consisting of: 2-methoxy-phenyl, 2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-3-(amino-carbonyl)-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)-phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 2-(methoxy-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl; 2-carboxy-thiophen-5-yl, 2-carboxy-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-4-yl, 3-(cyclopropyl-carbonyl-amino)-thiophen-2-yl, 2-(methyl-sulfonyl-amino-carbonyl)-3-fluoro-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3-fluoro-pyrazol-4-yl, 3-chloro-pyrazol-4-yl, 3-methoxy-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 5-chloro-pyrazol-4-yl, 2-(amino-carbonyl)-thiazol-5-yl; 3-Fluoro-pyridin-4-yl-2-one, 3-fluoro-pyridin-4-yl, 2-(difluoromethoxy)-pyridin-4-yl, 2-(trifluoro-methyl)-pyridin-4-yl, 2-(cyano-methyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-carboxy-3-fluoro-pyridin-4-yl, 2-(methoxy-carbonyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(hydroxy-d2-methyl)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-ethoxy)-pyridin-4-yl, 2-(2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-2-methyl- 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 1R*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 2-(3-hydroxy-3-methyl-n-butyl)-3-fluoro-pyridin-3-yl, 2-(1,1-difluoro-2-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(1S*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 3-chloro-6-amino-pyridin-4-yl, 2-amino-3-methyl-pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin- 4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-amino-3-methoxy-pyridin-4-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(1,1-dimethyl-2-hydroxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl,3-(3-trifluoro-2R*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated-6-amino-pyridin-3-yl,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(N-ethyl-N-2-hydroxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(amino-carbonyl)-pyridin-5-yl, 2-(amino-carbonyl)-3-fluoro-pyridin-3-yl, 2-(2-methoxy-ethyl-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-amino-carbonyl)-3-fluoro-pyridin-4-yl, 2-(amino-carbonyl-methyl)-3-fluoro-pyridin-4-yl, 3-(trifluoromethyl-carbonyl-amino)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-pyridin-4-yl, 5-(methoxy- 2-(Methyl-carbonyl-amino)-pyridin-2-yl, 2-(methoxy-carbonyl-amino)-pyridin-5-yl, 2-(methoxy-carbonyl-amino)-pyridin-4-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 2-(ethoxy-carbonyl-amino)-pyridin-3-yl, 2-(ethoxy-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl, 2-(1S-amino-isopropyl-carbonyl-oxo-methyl)-3-fluoro-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(phosphonyl- 2-(1-hydroxy-cyclopropyl-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-3-chloro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(oxetan-3-yl)-3-fluoro-pyridin-4-yl, 2-(azetidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-3-fluoro-pyridin-4-yl, (3-cyano-azetidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(3S-hydroxy-piperidin-1-yl)-3-fluoro-pyridin-4-yl, 2-(pyrazol-1-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-3-fluoro-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(3-amino-pyrazol-1-yl)-pyridin-4-yl, 2-(imidazol-2-yl)-3-fluoro-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 2-(1,2,5-triazol-1-yl)-pyridin-4-yl,4-triazol-1-yl)-3-fluoro-pyridin-4-yl, 2-(, Oxazolidin-3-yl-2-one)-3-fluoro-pyridin-4-yl, 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3-fluoro-pyridin-4-yl, 2-(di Alkyl-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S*- Oxazol-2-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S-(1,3,4- oxadiazole-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(bicyclo[ 1.1.1]pentyl-amino)-3-fluoro-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(3-methyl-isopropyl)- Oxazol-5-yl-carbonyl-amino)-3-fluoro-pyridin-4-yl, pyridin-4-yl-2-one; Indol-3-yl, indol-6-yl, indol-5-yl, indol-5-yl-2-one, 7-fluoro-indol-6-yl, indazol-5-yl, indazol-4-yl, 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, indolin-5-yl-2-one, 6-methyl-indololin-7-yl-2-one, benzimidazol-5-yl, 2-methyl-benzimidazol-6-yl, benzimidazol-5-yl-2-one, 1-methyl-benzimidazol-6-yl-2-one, 1-methyl-benzimidazol-5-yl-2-one, 3-amino-benzisodazole Azoles-5-yl, benzo oxazol-6-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 6-methyl-quinoxalin-5-yl-2(1H)-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 2,3-dihydrofuro[2,3-b]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2 ,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[3,2-c]pyridin-3-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] oxazine-6-yl-2-one, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl and 7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl-7-ol; and wherein one or both of the following are optionally deuterated: (i) in R 1 a hydrogen atom bound to the phenyl ring at the meta position of and (ii) a hydrogen atom bound to the 8a position of 2,3,8,8a-tetrahydroindoleazine-5(1H)-one; The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and the two R 2 When the group is 2-fluoro and 3-chloro, Q is not (a) or (b) or a tautomer, stereoisomer, deuterated isotope or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein R 1 Selected from the group consisting of 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl; a is an integer from 1 to 2; Each R 2 independently selected from the group consisting of: 2-fluoro and 3-chloro; R A and R B Each is hydrogen; R C is selected from the group consisting of: hydrogen and methyl; R D is selected from the group consisting of hydrogen, methyl, S*-methyl and R-methoxy; R E is hydrogen; Q is selected from the group consisting of: (a) and (b) in R 4 is hydrogen; R 5 selected from the group consisting of: hydrogen, deuterium, fluorine and chlorine; Select from the group consisting of: 2-Fluoro-4-(amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)-phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl; 2-carboxy-thiophen-5-yl, 2-carboxy-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 2-(amino-carbonyl)-3-fluoro-thiophen-4-yl, 3-(cyclopropyl-carbonyl-amino)-thiophen-2-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3-chloro-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 5-chloro-pyrazol-4-yl, 1-methyl-4-(cyclopropyl-carbonyl-amino)-pyrazol-5-yl, 2-(amino-carbonyl)-thiazol-5-yl; 2-carboxy-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-ethoxy)-pyridin-4-yl, 2-(2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(2-hydroxy-2-methyl-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-(hydroxy-d2-methyl)-3-chloro-pyridin-4-yl, 2 -(1R-(Hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1R*-hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 2-(3-hydroxy-3-methyl-n-butyl)-3-fluoro-pyridin-3-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 2-fluoro- 6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-amino-3-methoxy-pyridin-4-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-( 2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-(3,3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-amino-carbonyl)-3-fluoro-pyridin-4-yl, 3-(trifluoromethyl-carbonyl-amino)-pyridin-4-yl, 3-(d3-methyl-carbonyl-amino)-pyridin-4-yl, 5-(methoxy-carbonyl-amino)-pyridin-2-yl, 2-(methoxy-carbonyl- amino)-pyridin-5-yl, 2-(methoxy-carbonyl-amino)-pyridin-4-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(ethoxy-carbonyl-amino)-pyridin-3-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(phosphonyl-oxy-methyl)-3-fluoro-pyridin-4 -yl, 2-(phosphono-methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(3-cyano-azetidin-1-yl)-3- Fluoro-pyridin-4-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(pyrazol-1-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-4-yl, 2-(pyrazol-5-yl)-3-fluoro-pyridin-4-yl, 2-(imidazol-2-yl)-3-fluoro-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 2-(di, Alk-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, pyridin-4-yl-2-one; Indol-5-yl-2-one, 7-fluoro-indol-6-yl, indazol-5-yl, 3-(methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, benzimidazol-5-yl, 2-methyl-benzimidazol-6-yl, benzimidazol-5-yl-2-one, 1-methyl-benzimidazol-6-yl-2-one, 1-methyl-benzimidazol-5-yl-2-one, benzo oxazol-6-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 2,3-dihydrofuro[2,3-b]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 1H-pyrrolo[2, 3-b]pyridin-4-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one and 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl; and wherein one or both of the following are optionally deuterated: (i) in R 1 a hydrogen atom bound to the phenyl ring at the meta position of and (ii) a hydrogen atom bound to the 8a position of 2,3,8,8a-tetrahydroindoleazine-5(1H)-one; The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and the two R 2 When the group is 2-fluoro and 3-chloro, Q is not (a) or (b) or a tautomer, stereoisomer, deuterated isotope or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein R 1 Selected from the group consisting of 4-chloro-1,2,3-triazol-1-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl; a is an integer from 1 to 2; Each R 2 independently selected from the group consisting of: 2-fluoro and 3-chloro; R A and R B Each is hydrogen; R C is selected from the group consisting of: hydrogen and methyl; R D is selected from the group consisting of: hydrogen, methyl, and R-methoxy; R E is hydrogen; Q is selected from the group consisting of: (a) and (b) in R 4 is hydrogen; R 5 selected from the group consisting of: hydrogen, deuterium, fluorine and chlorine; Select from the group consisting of: 2-Fluoro-4-(amino-carbonyl)-phenyl, 2-(ethyl-carbonyl-amino)-phenyl, 2-(methyl-carbonyl-amino)-phenyl, 2-(isopropyl-carbonyl-amino)-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cyclopropyl-carbonyl-amino)-4-methoxy-phenyl; 2-Carboxy-thiophen-5-yl, 2-carboxy-3-fluoro-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3-chloro-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 1-methyl-4-(cyclopropyl-carbonyl-amino)-pyrazol-5-yl, 2-(amino-carbonyl)-thiazol-5-yl; 2-carboxy-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin- 3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloro-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(methoxy-ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-amino)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deuterated-6-amino-pyridin-3-yl, 2-fluoro-4,5-dideuterated-6-amino-pyridin- 3-yl, 2-fluoro-4,5-dideutero-6-(methyl-amino)-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 5-(methoxy-carbonyl-amino)-pyridin-2-yl, 2-(methoxy-carbonyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(phosphonyl-oxy-methyl)-3-fluoro-pyridin-4 -yl, 2-(1-hydroxy-cyclopropyl-1-yl)-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cyclopropyl-carbonyl-amino)-pyridin-3-yl, 2-(S-tetrahydrofuran-3-yl-amino)-3-fluoro-pyridin-4-yl, 2-(pyrazol-5-yl)-pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl; 3-(Methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, benzimidazol-5-yl-2-one, quinolin-5-yl-2-one, quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, quinazolin-6-yl-2-one, 7-methyl-5H-cyclopenta[b]pyridin-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one, 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one and 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl; and wherein one or both of the following are optionally deuterated: (i) in R 1 a hydrogen atom bound to the phenyl ring at the meta position of and (ii) a hydrogen atom bound to the 8a position of 2,3,8,8a-tetrahydroindoleazine-5(1H)-one; The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and the two R 2 When the group is 2-fluoro and 3-chloro, Q is not (a) or (b) or a tautomer, stereoisomer, deuterated isotope or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, wherein R 1 Selected from the group consisting of: 4-chloro-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl; a is an integer from 1 to 2; Each R 2 independently selected from the group consisting of: 2-fluoro and 3-chloro; R A and R B Each is hydrogen; R C is hydrogen; R D is hydrogen; R E is hydrogen; Q is selected from the group consisting of: (a) and (b) in R 4 is hydrogen; R 5 selected from the group consisting of: hydrogen, deuterium, fluorine and chlorine; Select from the group consisting of: 4-(Methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl; 2-Carboxy-thiophen-5-yl, 2-(amino-carbonyl)-thiophen-4-yl, 2-(amino-carbonyl)-thiophen-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 2-(amino-carbonyl)-thiazol-5-yl; 2-Carboxy-3-fluoro-pyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3-fluoro-pyridin-4-yl, 2-fluoro-5-deuterated-6-amino-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-chloro-6-amino-pyridin-3-yl, 2-(ethyl-amino)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n- propyl-amino)-3-fluoro-pyridin-4-yl, 2-fluoro-4,5-dideutero-6-amino-pyridin-3-yl, 2-(methyl-amino)-3-fluoro-pyridin-4-yl, 2-(methyl-sulfonyl-amino)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cyclopropyl-1-yl)-pyridin-4-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl; 3-(Methyl-amino)-indazol-6-yl, 3-amino-indazol-6-yl, benzimidazol-5-yl-2-one, 2H-quinolin-6-yl-2-one, 3,4-dihydro-2H-quinolin-6-yl-2-one, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one and 5-fluoro-1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one; and wherein one or both of the following are optionally deuterated: (i) in R 1 a hydrogen atom bound to the phenyl ring at the meta-position of and (ii) a hydrogen atom bound to the 8a-position of 2,3,8,8a-tetrahydroindoleazine-5(1H)-one; The prerequisite is that when R 1 is 1,2,3,4-tetrazolyl-1-yl, a is 2, and the two R 2 When the group is 2-fluoro and 3-chloro, Q is not (b) or a tautomer, stereoisomer, deuterated isotope or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, wherein R 1 is 1,2,3,4-tetrazol-1-yl; a is 2; The two R 2 are 2-fluoro and 3-chloro; R A and R B Each is hydrogen; R C is hydrogen; R D is hydrogen; R E is hydrogen; Q is selected from the group consisting of: (a) and (b) in R 4 is hydrogen; R 5 selected from the group consisting of: hydrogen and chlorine; Selected from the group consisting of: 4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2-(amino-carbonyl)-thiophen-5-yl, 2-(amino-carbonyl)-thiazol-5-yl, 2-chloro-6-amino-pyridin-3-yl, 3-(cyclopropyl-carbonyl-amino)-pyridin-4-yl, 3-amino-indazol-6-yl, 2H-quinolin-6-yl-2-one, 1H-pyrrolo[2,3-b]pyridin-4-yl and 1,4-dihydro-2H-benzo[d][1,3] Oxazine-6-yl-2-one; or a tautomer, stereoisomer, deuterated isotope or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, selected from the group consisting of: (3S,8aR)-3-[5-(6-amino-2-fluoro-3-pyridyl)-1H-imidazol-2-yl]-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizin-5-one; (3S,8aR)-3-[5-(6-amino-2-chloro-3-pyridinyl)-1H-imidazol-2-yl]-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizin-5-one; (3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[5-[3-fluoro-2-(2-hydroxy-2-methyl-propoxy)-4-pyridinyl]-1H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1H-indolizin-5-one; (3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[5-[3-fluoro-2-(1-hydroxycyclopropyl)-4-pyridinyl]-1H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1H-indolizin-5-one; (3S,8aR)-3-[5-(2-amino-3-fluoro-4-pyridyl)-1H-imidazol-2-yl]-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizin-5-one; (3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[4-fluoro-5-[3-fluoro-2-(hydroxymethyl)-4-pyridinyl]-1H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1H-indolizin-5-one; (3S,8aR)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-3-[4-fluoro-5-[3-fluoro-2-(hydroxymethyl)-4-pyridinyl]-1H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1H-indolizin-5-one; (3S*,8aR)-3-[5-(2-amino-3-fluoro-4-pyridinyl)-1H-imidazol-2-yl]-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indolizin-5-one; Methyl N-[4-[2-[(3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizin-3-yl]-1H-imidazol-5-yl]-3-fluoro-2-pyridinyl]carbamate; (3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)-1H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1H-indolizin-5-one; and tautomers, deuterated isotopes and pharmaceutically acceptable salts thereof.

11. The compound according to claim 1, selected from the group consisting of: (a) Compounds of formula (Ix) (b) Compounds of formula (Iy) (c) Compounds of formula (Iz) and tautomers, deuterated isotopes and pharmaceutically acceptable salts thereof.

12. A compound of formula (II) and their tautomers, stereoisomers, deuterated isotopes and pharmaceutically acceptable salts.

13. A compound selected from the group consisting of (a) Compounds of formula (III) and tautomers, stereoisomers, deuterated isotopomers and pharmaceutically acceptable salts thereof; (b) Compounds of formula (IV) and their tautomers, stereoisomers, deuterated isotopes and pharmaceutically acceptable salts.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to claim 1, 12 or 13.

15. A method for preparing a pharmaceutical composition, comprising: The compound described in 12 or 13 is mixed with a pharmaceutically acceptable carrier.

16. Use of a therapeutically effective amount of a compound according to claim 1, 12 or 13 in the preparation of a medicament for treating or preventing: (a) thromboembolic disorders; or (c) diseases or conditions involving plasma kallikrein activity.

17. The use according to claim 16, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorder, venous cardiovascular thromboembolic disorder, arterial cerebrovascular thromboembolic disorder and venous cerebrovascular thromboembolic disorder.

18. The use according to claim 16, wherein the thromboembolic disorder is selected from the group consisting of unstable angina, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism and thrombosis caused by artificial valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis or other procedures in which blood is exposed to artificial surfaces that promote thrombosis.

19. The use according to claim 16, wherein the thromboembolic disorder is deep vein thrombosis.

20. The use according to claim 16, wherein the thromboembolic disorder is selected from the group consisting of hereditary angioedema (HAE) and diabetic macular edema (DME).

21. The use according to claim 16, wherein the disease or condition involving plasma kallikrein activity is selected from the group consisting of: impaired vision, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, septic shock, hypotension, cancer, adult respiratory distress syndrome and disseminated intravascular coagulation.

22. The use according to claim 16, wherein the disease or condition involving plasma kallikrein activity is inflammation.

23. A composition comprising a compound according to claim 1, 12 or 13 for use in treating or preventing (a) a thromboembolic disorder or (c) a disease or condition involving plasma kallikrein activity.

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