CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patent application Ser. No. 17,696,922, filed Mar. 17, 2022, which claims the benefit of U.S. Provisional Patent Application No. 63/162,625, filed on Mar. 18, 2021, and U.S. Provisional Patent Application No. 63/162,627, filed on Mar. 18, 2021, each of which are incorporated by reference herein in their entireties.

FIELD OF THE INVENTION

The present invention is directed to imidazole substituted pyridine N-oxide derivatives, stereoisomers, isotopologues, isotopomers and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds, and the use of said compounds in the treatment and/or prophylaxis of thromboembolic disorders, inflammatory disorders and diseases or conditions in which plasma kallikrein activity is implicated.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developed countries despite the availability of anticoagulants such as warfarin (COUMADIN®), heparin, low molecular weight heparins (LMWH), and synthetic pentasaccharides and antiplatelet agents such as aspirin and clopidogrel (PLAVIX®). The oral anticoagulant warfarin inhibits the post-translational maturation of coagulation factors VII, IX, X and prothrombin, and has proven effective in both venous and arterial thrombosis. However, its usage is limited due to its narrow therapeutic index with respect to bleeding safety, slow onset of therapeutic effect, numerous dietary and drug-drug interactions, and a need for monitoring and dose adjustment. Novel oral anticoagulants directly targeting either thrombin or factor Xa, e.g., dabigatran, apixaban, betrixaban, edoxaban, rivaroxaban, have been approved for both venous and arterial indications. However, the risk of bleeding is not completely eliminated, and can be as high as 2-3% per year in patients with atrial fibrillation (Quan et al., J. Med. Chem. 2018, pp 7425-7447, Vol. 61). Thus discovering and developing safe and efficacious oral anticoagulants with minimal impacts on hemostasis for the prevention and treatment of a wide range of thromboembolic disorders has become increasingly important.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula (I)

[Image Omitted]

- R¹is selected from the group consisting of halogen, hydroxy, C_1-4alkyl, fluorinated C_1-4alkyl, C_1-4alkoxy, fluorinated C_1-4alkoxy, cyano, nitro, —NR^AR^B, —C(O)—C_1-4alkyl, C_3-6cycloalkyl, phenyl and 5 to 6 membered heterocyclyl;
- wherein the C_3-6cycloalkyl, phenyl or 5 to 6 membered heterocyclyl is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, cyano, C_1-4alkyl, fluorinated C_1-4alkyl, C_1-4alkoxy, fluorinated C_1-4alkoxy, —C(O)OH and —C(O)O—(C_1-4alkyl);
- and wherein R^Aand R^Bare each independently selected from the group consisting of hydrogen and C_1-4alkyl;
- a is an integer from 0 to 3;
- each R²is independently selected from the group consisting of chloro, fluoro, methyl and methoxy;
- Y is CH and Z is N, such that

[Image Omitted]

is

[Image Omitted]

- alternatively, Y is N and Z is N, such that

[Image Omitted]

is

[Image Omitted]

- R⁴is selected from the group consisting of
- (a) phenyl; wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated C_1-2alkoxy, —C(O)OH, —C(O)—O—(C_1-4alkyl), —NR^CR^D, —(C_1-2alkylene)-NR^CR^D, and —C(O)—NR^CR^D.
- wherein R^Cis selected from the group consisting of hydrogen, C_1-4alkyl, cyclopropyl, 3-hydroxy-cycloprop-1-yl, —C(O)—C_1-4alkyl, —C(O)-cyclopropyl, —C(O)—O—C_1-4alkyl; and R^Dis selected from the group consisting of hydrogen and C_1-4alkyl;
- and (b) 5 to 6 membered heterocyclyl; wherein the 5 membered heterocyclyl contains at least one heteroatom selected from the group consisting of O, N and S; optionally contains 1 to 3 additional heteroatoms independently selected from the group consisting of O, N and S; wherein the 5 membered heterocyclyl is saturated, partially unsaturated, or aromatic;
- and wherein the 5 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C_1-4alkyl, fluorinated C_1-4alkyl, C_1-4alkoxy, fluorinated C_1-4alkoxy, —C(O)OH, —C(O)—O—C_1-4alkyl, —NR^ER^F, and —C(O)—NR^ER^F;
- wherein R^Eis selected from the group consisting of hydrogen, C_1-4alkyl, cyclopropyl, 3-hydroxy-cycloprop-1-yl, —C(O)—C_1-4alkyl, —C(O)-cyclopropyl and —C(O)—O—C_1-4alkyl; and R^Fis selected from the group consisting of hydrogen and C_1-4alkyl;
- R⁵is selected from the group consisting of
- (a) C_1-4alkyl; wherein the C_1-4alkyl is optionally substituted with one or more halogen, and further optionally substituted with a substituent selected from the group consisting of hydroxy, C_1-4alkoxy, fluorinated C_1-4alkoxy, —C(O)OH, and —C(O)—O—(C_1-4alkyl);
- (b) —CH₂—C_3-8cycloalkyl; wherein the C_3-8cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen and C_1-4alkyl;
- (c) -L¹-(5 to 6 membered saturated heterocyclyl); wherein L¹is —CH₂—; and wherein the 5 to 6 membered saturated heterocyclyl is optionally substituted with one to two oxo group;
- and (d) —C_1-2alkylene-phenyl; wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C_1-4alkyl, fluorinated C_1-4alkyl, C_1-4alkoxy, and fluorinated C_1-4alkoxy;
- R⁶and R⁷are each independently selected from the group consisting of hydrogen, halogen, C_1-4alkyl and C_1-4alkoxy; provided that at least one of R⁶or R⁷is hydrogen;
- and stereoisomers, isotopomers, isotopologues and pharmaceutically acceptable salts thereof.

In some embodiments, the present invention is directed to compounds of formula (I) wherein the R⁵substituent group is present in a stereoisomeric excess of the corresponding R-stereoisomer. In some embodiments, the present invention is directed to compounds of formula (I) wherein the R⁵substituent group is present in a stereoisomeric excess of the corresponding S-stereoisomer.

The present invention is further directed to processes for the preparation of the compounds of formula (I). The present invention is further directed to a compound of formula (I) prepared according to any of the process(es) described herein.

Illustrative of the invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (I) as described herein. An illustration of the invention is a pharmaceutical composition made by mixing a compound of formula (I) as described herein and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing a compound of formula (I) as described herein and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods for the treatment and/or prophylaxis of 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.

Exemplifying the invention are methods or the treatment and/or prophylaxis of 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, an 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, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.

In an embodiment, the present invention is directed to a compound of formula (I) for use as a medicament. In another embodiment, the present invention is directed to a compound of formula (I) for use in the treatment and/or prophylaxis of thromboembolic disorders, inflammatory disorders or diseases or conditions in which plasma kallikrein activity is implicated.

In another embodiment, the present invention is directed to a compound of formula (I) for use in the treatment and/or prophylaxis of a thromboembolic disorder, 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 compound of formula (I) for use in the treatment and/or prophylaxis of a thromboembolic disorder selected from the group consisting of unstable angina, an 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, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. In another embodiment, the present invention is directed to a compound of formula (I) for use in the treatment and/or prophylaxis of a thromboembolic disorder selected from the group consisting of hereditary angioedema (HAE) and diabetic macular edema (DME).

In another embodiment, the present invention is directed to a composition comprising a compound of formula (I) for use in the treatment and/or prophylaxis of a disorder, disease or condition as described herein. In another embodiment, the present invention is directed to a composition comprising a compound of formula (I) for use in the treatment and/or prophylaxis of a thromboembolic disorder, and inflammatory disorder or a disease or condition in which plasma kallikrein activity is implicated.

In another embodiment, the present invention is directed to a composition comprising a compound of formula (I) for use in the treatment and/or prophylaxis of a thromboembolic disorder, 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) for use in the treatment and/or prophylaxis of a thromboembolic disorder selected from the group consisting of unstable angina, an 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, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. In another embodiment, the present invention is directed to a composition comprising a compound of formula (I) for use in the treatment and/or prophylaxis of a thromboembolic disorder such as hereditary angioedema (HAE) or diabetic macular edema (DME).

Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for the treatment and/or prophylaxis of a disorder, disease or condition as described herein. Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for the treatment and/or prophylaxis of a thromboembolic disorder, an inflammatory disorder or a disease or condition in which plasma kallikrein activity is implicated.

Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for the treatment and/or prophylaxis 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 example of the invention is the use of any of the compounds described herein in the preparation of a medicament for the treatment and/or prophylaxis of (a) unstable angina, (b) an acute coronary syndrome, (c) atrial fibrillation, (d) first myocardial infarction, (e) recurrent myocardial infarction, (f) ischemic sudden death, (g) transient ischemic attack, (h) stroke, (i) atherosclerosis, (j) peripheral occlusive arterial disease, (k) venous thrombosis, (l) deep vein thrombosis, (m) thrombophlebitis, (n) arterial embolism, (o) coronary arterial thrombosis, (p) cerebral arterial thrombosis, (q) cerebral embolism, (r) kidney embolism, (s) pulmonary embolism, or (t) thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for the treatment and/or prophylaxis of: (a) hereditary angioedema (HAE) or (b) diabetic macular edema (DME).

Another example of the invention is the use of any of the compounds described herein for use in a method for treating a thromboembolic, inflammatory or a disease or condition in which plasma kallikrein activity is implicated as described herein, in a subject in need thereof.

Another example of the invention is the use of any of the compounds described herein for use in a method for the treatment and/or prophylaxis of (a) arterial cardiovascular thromboembolic disorders, (b) venous cardiovascular thromboembolic disorders, (c) arterial cerebrovascular thromboembolic disorders, or (d) venous cerebrovascular thromboembolic disorders, in a subject in need thereof. Another example of the invention is the use of any of the compounds described herein for use in a method for the treatment and/or prophylaxis of (a) unstable angina, (b) an acute coronary syndrome, (c) atrial fibrillation, (d) first myocardial infarction, (e) recurrent myocardial infarction, (f) ischemic sudden death, (g) transient ischemic attack, (h) stroke, (i) atherosclerosis, (j) peripheral occlusive arterial disease, (k) venous thrombosis, (l) deep vein thrombosis, (m) thrombophlebitis, (n) arterial embolism, (o) coronary arterial thrombosis, (p) cerebral arterial thrombosis, (q) cerebral embolism, (r) kidney embolism, (s) pulmonary embolism, or (t) thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis, in a subject in need thereof. Another example of the invention is the use of any of the compounds described herein for use in a method for the treatment and/or prophylaxis of (a) hereditary angioedema (HAE) or (b) diabetic macular edema (DME), in a subject in need thereof.

In another example, the present invention is directed to a compound as described herein, for use in a method for the treatment and/or prophylaxis of disorders, diseases or conditions as described herein, in a subject in need thereof. In another example, the present invention is directed to a compound as described herein, for use in a method for the treatment and/or prophylaxis of a thromboembolic, inflammatory disorder, or a disease or condition in which plasma kallikrein activity is implicated, as described herein, in a subject in need thereof.

In another example, the present invention is directed to a compound as described herein, for use in methods for the treatment and/or prophylaxis of thromboembolic disorder, 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 is directed to a compound as described herein, for use in methods for the treatment and/or prophylaxis of unstable angina, an 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, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis, in a subject in need thereof. In another example, the present invention is directed to a compound as described herein, for use in a method for the treatment and/or prophylaxis of hereditary angioedema (HAE) or diabetic macular edema (DME), in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION
Pyridine N-Oxide Derivatives

Factor XIa is a plasma serine protease involved in the regulation of blood coagulation. While blood coagulation is a necessary and important part of the regulation of an organism's homeostasis, abnormal blood coagulation can also have deleterious effects. For instance, thrombosis is the formation or presence of a blood clot inside a blood vessel or cavity of the heart. Such a blood clot can lodge in a blood vessel blocking circulation and causing a heart attack or stroke. Thromboembolic disorders are the leading cause of mortality and disability in the industrialized world.

Blood clotting is a process of control of the bloodstream essential for the survival of mammals. The process of clotting, and the subsequent dissolution of the clot after wound healing has taken place, commences after vascular injury, and can be divided into four phases. The first phase, vasoconstriction or vasocontraction, can cause a decrease in blood loss in the injured area. In the next phase, platelet activation by thrombin, platelets attach to the site of the vessel wall damage and form a platelet aggregate. In the third phase, formation of clotting complexes leads to massive formation of thrombin, which converts soluble fibrinogen to fibrin by cleavage of two small peptides. In the fourth phase, after wound healing, the thrombus is dissolved by the action of the key enzyme of the endogenous fibrinolysis system, plasmin.

Two alternative pathways can lead to the formation of a fibrin clot, the intrinsic and the extrinsic pathway. These pathways are initiated by different mechanisms, but in the later phase they converge to give a common final path of the clotting cascade. In this final path of clotting, clotting Factor X is activated. The activated Factor X is responsible for the formation of thrombin from the inactive precursor prothrombin circulating in the blood. The formation of a thrombus on the bottom of a vessel wall abnormality without a wound is the result of the intrinsic pathway. Fibrin clot formation as a response to tissue injury or an injury is the result of the extrinsic pathway. Both pathways comprise a relatively large number of proteins, which are known as clotting factors. The intrinsic pathway requires the clotting Factors V, VIII, IX, X, XI and XII and also prekallikrein, high molecular weight kininogen, calcium ions and phospholipids from platelets.

Factor XIa, a plasma serine protease involved in the regulation of blood coagulation, is initiated in vivo by the binding of tissue Factor (TF) to factor VII (FVII) to generate Factor VIIa (FVIIa). The resulting TF:FVIIa complex activates Factor IX (FIX) and Factor X (FX) that leads to the production of Factor Xa (FXa). The generated FXa catalyzes the transformation of prothrombin into small amounts of thrombin before this pathway is shut down by tissue factor pathway inhibitor (TFPI). The process of coagulation is then further propagated via the feedback activation of Factors V, VIII and XI by catalytic amounts of thrombin. (Gailani, D. et al., Arterioscler Thromb. Vasc. Biol., 27:2507-2513 (2007)). The resulting burst of thrombin converts fibrinogen to fibrin that polymerizes to form the structural framework of a blood clot, and activates platelets, which are a key cellular component of coagulation (Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Factor XIa plays a key role in propagating this amplification loop. Epidemiological studies showed that increased circulating FXI levels in humans have been associated with increased risk for venous and arterial thrombosis, including stroke (se 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.

In addition to stimulation via tissue factor, the coagulation system can be activated particularly on negatively charged surfaces, which include not only surface structures of foreign cells (e.g. bacteria) but also artificial surfaces such as vascular prostheses, stents and extracorporeal circulation. On the surface, initially Factor XII (FXII) is activated to Factor XIIa which subsequently activates Factor XI, attached to cell surfaces, to Factor XIa. This leads to further activation of the coagulation cascade as described above. In addition, Factor XIIa also activates bound plasma prokallikrein to plasma kallikrein (PK) which, in a potentiation loop, leads to further Factor XII activation, overall resulting in amplification of the initiation of the coagulation cascade. In addition, PK is an important bradykinin-releasing protease which leads to increased endothelial permeability. Further substrates that have been described are prorenin and prourokinase, whose activation may influence the regulatory processes of the renin-angiotensin system and fibrinolysis. The activation of PK is therefore an important link between coagulative and inflammatory processes.

OGAWA et al., in PCT Publication WO2017095760 A1, published 8 Jun. 2017 describe compounds which are selective Factor XIa inhibitors or dual inhibitors of Factor XIa and plasma kallilkrein.

Xu, et al., in PCT Publication WO 2017074832 A1, published 4 May 2017, describe compounds which are selective Factor XIa inhibitors or dual inhibitors of Factor XIa and plasma kallilkrein.

JIMENEZ NUNES et al., in PCT Publication WO 2017005725 A1, published 12 Jan. 2017 describe substituted oxopyridine derivatives and their use in the preparation of medicaments for the treatment and/or prophylaxis of cardiovascular diseases, preferably thrombotic or thromboembolic disorders, and or edemas, and also ophthalmic disorders.

MERTZ et al., in PCT Publication WO2016168098 A1, published 20 Oct. 2016 describe compounds which are selective Factor XIa inhibitors or dual inhibitors of Factor XIa and plasma kallilkrein.

LIU et al., in PCT Publication WO2016015593 A1, published 4 Feb. 2016 describe compounds which are selective Factor XIa inhibitors or dual inhibitors of Factor XIa and plasma kallilkrein.

LIU et al., in PCT Publication WO2015183709 A1, published 3 Dec. 2015 describe compounds which are selective Factor XIa inhibitors or dual inhibitors of Factor XIa and plasma kallilkrein.

ROHRIG et al., in PCT Publication WO2015011087 A1, published 29 Jan. 2015 describe substituted oxopyridine derivatives and their use in the preparation of medicaments for the treatment and/or prophylaxis of cardiovascular diseases, preferably thrombotic or thromboembolic disorders, and or edemas, and also ophthalmic disorders.

The present invention is directed to compounds of formula (I)

[Image Omitted]

- wherein a, R¹, R², Y, Z, R⁴, R⁵, R⁶, R⁷, etc. are as herein described; and stereoisomers, isotopologues, isotopomers, and pharmaceutically acceptable salts thereof.

The compounds of the present invention are useful for the treatment and/or prophylaxis of thromboembolic disorders, inflammatory disorders and diseases or conditions in which plasma kallikrein activity is implicated.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R¹is selected from the group consisting of C_3-6cycloalkyl, phenyl and 5 to 6 membered heterocyclyl; wherein the C_3-6cycloalkyl, phenyl or 5 to 6 membered heterocyclyl is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, cyano, C_1-4alkyl, fluorinated C_1-4alkyl, C_1-4alkoxy, fluorinated C_1-4alkoxy, —C(O)OH and —C(O)O—(C_1-4alkyl). In certain embodiments, the present invention is directed to compounds of formula (I) wherein R¹is selected from the group consisting of C_3-6cycloalkyl, phenyl and 5 to 6 membered heterocyclyl; wherein the 5 to 6 membered heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C_1-4alkyl and fluorinated C_1-4alkyl.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R¹is 5 to 6 membered heterocyclyl; wherein the 5 to 6 membered heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C_1-4alkyl and fluorinated C_1-4alkyl.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R¹is selected from the group consisting of 1,2,3,4-tetrazol-1-yl, 4-chloro-1,2,3-triazol-1-yl and 4-(trifluoromethyl)-1,2,3-triazol-1-yl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R¹is selected from the group consisting of 1,2,3,4-tetrazol-1-yl and 4-(trifluoromethyl)-1,2,3-triazol-1-yl.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is an integer from 1 to 2. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 0. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 1. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 2. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 3.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R²is selected from the group consisting of fluoro and chloro. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R²is fluoro. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R²is chloro.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is an integer from 1 to 2; and wherein each R²is independently selected from the group consisting of 5-chloro and 6-fluoro. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 2; and wherein one R²is 5-chloro and one R²is 6-fluoro.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁴is carboxy. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁴is phenyl, wherein the phenyl is optionally substituted as described herein. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁴is a 5 membered heterocyclyl, wherein the 5 membered heterocyclyl is optionally substituted as described herein. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁴is a 6 membered heterocyclyl, wherein the 6 membered heterocyclyl is optionally substituted as described herein.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁴is selected from the group consisting of phenyl (wherein the phenyl is optionally substituted with one to two substituents independently selected from the group consisting of —C(O)OH, —NR^CR^Dand —C(O)—NR^CR^D; wherein R^Cis selected from the group consisting of hydrogen, cyclopropyl, 3-hydroxy-cycloprop-1-yl, —C(O)-cyclopropyl and —C(O)—O—C_1-4alkyl; and R^Dis hydrogen), 5 membered heterocyclyl (wherein the 5 membered heterocyclyl contains at least one N; optionally contains 1 to 3 additional N; wherein the 5 membered heterocyclyl is saturated, partially unsaturated, or aromatic; and wherein the 5 membered heterocyclyl is optionally substituted one to two substituents independently selected from the group consisting of C_1-4alkyl and fluorinated C_1-4alkyl), and 6 membered heterocyclyl.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁴is selected from the group consisting of phenyl (wherein the phenyl is optionally substituted with one to two substituents independently selected from the group consisting of —C(O)OH, —NR^CR^Dand —C(O)—NR^CR^D; wherein R^Cis selected from the group consisting of hydrogen, cyclopropyl, 3-hydroxy-cycloprop-1-yl and —C(O)—O—C_1-4alkyl; and R^Dis hydrogen), 5 membered heterocyclyl (wherein the 5 membered heterocyclyl contains at least one N; optionally contains 1 to 3 additional N; wherein the 5 membered heterocyclyl is saturated, partially unsaturated, or aromatic; and wherein the 5 membered heterocyclyl is optionally substituted one to two substituents independently selected from the group consisting of C_1-4alkyl and fluorinated C_1-4alkyl), and 6 membered heterocyclyl.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁴is selected from the group consisting of phenyl (wherein the phenyl is optionally substituted with one to two substituents independently selected from the group consisting of —C(O)OH, —NR^CR^Dand —C(O)—NR^CR^D; wherein R^Cis selected from the group consisting of hydrogen, cyclopropyl, —C(O)-cyclopropyl and —C(O)—O—C_1-4alkyl; and R^Dis hydrogen), and 5 membered heterocyclyl (wherein the 5 membered heterocyclyl contains at least one N; optionally contains 1 to 3 additional N; wherein the 5 membered heterocyclyl is saturated, partially unsaturated, or aromatic; and wherein the 5 membered heterocyclyl is optionally substituted one to two substituents independently selected from the group consisting of C_1-4alkyl and fluorinated C_1-4alkyl).

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is selected from the group consisting of C_1-4alkyl (wherein the C_1-4alkyl is optionally substituted with fluorinated C_1-4alkoxy), —CH₂—C_3-6cycloalkyl, and —C_1-2alkylene-phenyl (wherein the phenyl is optionally substituted with halogen). In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is selected from the group consisting of C_1-4alkyl (wherein the C_1-4alkyl is optionally substituted with fluorinated C_1-4alkoxy), and —CH₂—C_3-6cycloalkyl.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁴is selected from the group consisting of 4-carboxyphenyl, 4-(methoxy-carbonyl-amino)-phenyl, 4-(trans-3-hydroxy-cyclopropyl-amino-carbonyl)-phenyl, pyridin-4-yl, 1-(methyl-d₃)-pyrazol-5-yl, 1-methyl-1,2,3-triazol-5-yl and 1-(difluoro-methyl)-1,2,4-triazol-5-yl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁴is selected from the group consisting of 4-carboxy-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, pyridin-4-yl, 1-(methyl-d₃)-pyrazol-5-yl, 1-methyl-1,2,3-triazol-5-yl and 1-(difluoro-methyl)-1,2,4-triazol-5-yl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁴is selected from the group consisting of pyridin-4-yl, 1-(methyl-d₃)-pyrazol-5-yl, 1-methyl-1,2,3-triazol-5-yl and 1-(difluoro-methyl)-1,2,4-triazol-5-yl.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁴is selected from the group consisting of 4-carboxy-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 4-(cyclopropyl-carbonyl-amino)-phenyl, 1-methyl-1,2,3-triazol-5-yl and 1-(difluoro-methyl)-1,2,3-triazol-5-yl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁴is selected from the group consisting of 4-carboxy-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 1-methyl-1,2,3-triazol-5-yl and 1-(difluoro-methyl)-1,2,3-triazol-5-yl.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is (a) C_1-4alkyl, wherein the C_1-4alkyl is optionally substituted as described herein. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is (b) —CH₂—C_3-8cycloalkyl, wherein the —CH₂—C_3-8cycloalkyl is optionally substituted as described herein. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is —CH₂-cyclopropyl, wherein the —CH₂-cyclopropyl is optionally substituted as described herein. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is (c) -Li-(5 to 6 membered saturated heterocyclyl), wherein L¹is selected from the group consisting of —CH₂— and —C(O)—; and wherein the 5 to 6 membered saturated heterocyclyl is optionally substituted as described herein. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is (d) —C_1-2alkylene-phenyl, wherein the —C_1-2alkylene-phenyl is optionally substituted as described herein.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is selected from the group consisting of C_1-4alkyl (wherein the C_1-4alkyl is optionally substituted with fluorinated C_1-4alkoxy), —CH₂—C_3-6cycloalkyl, and —C_1-2alkylene-phenyl (wherein the phenyl is optionally substituted with halogen). In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is selected from the group consisting of C_1-4alkyl (wherein the C_1-4alkyl is optionally substituted with fluorinated C_1-4alkoxy); and —CH₂—C_3-6cycloalkyl.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is selected from the group consisting of ethyl, cyclopropyl-methyl-, 4-fluorophenyl-methyl-, 2-(difluoromethoxy)-ethyl-, S*-(2-(difluoromethoxy)-ethyl-), R*-(2-(difluoromethoxy)-ethyl-), S-(2-(difluoromethoxy)-ethyl-) and R-(2-(difluoromethoxy)-ethyl-). In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is selected from the group consisting of ethyl, cyclopropyl-methyl-, 4-fluorophenyl-methyl-, 2-(difluoromethoxy)-ethyl-, S*-(2-(difluoromethoxy)-ethyl-), and R-(2-(difluoromethoxy)-ethyl-). In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is selected from the group consisting of 4-fluorophenyl-methyl-, S*-(2-(difluoromethoxy)-ethyl-), and R-(2-(difluoromethoxy)-ethyl-).

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is selected from the group consisting of cyclopropyl-methyl-, R*-(cyclopropyl-methyl-), S*-(cyclopropyl-methyl-), R-(cyclopropyl-methyl-), S-(cyclopropyl-methyl-), 2-(difluoro-methoxy)-ethyl-, R-(2-(difluoro-methoxy)-ethyl-) and S-(2-(difluoro-methoxy)-ethyl-). In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is selected from the group consisting of cyclopropyl-methyl-, R*-(cyclopropyl-methyl-), S*-(cyclopropyl-methyl-), R-(cyclopropyl-methyl-), S-(cyclopropyl-methyl-), 2-(difluoromethoxy)-ethyl- and R-(2-(difluoromethoxy)-ethyl-). In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁵is selected from the group consisting of cyclopropyl-methyl-, S*-(cyclopropyl-methyl-), 2-(difluoromethoxy)-ethyl- and R-(2-(difluoromethoxy)-ethyl-).

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁶and R⁷are each independently selected from the group consisting of hydrogen, chloro, fluoro, methoxy, ethoxy, and iso-propyloxy; provided that at least one of R⁶or R⁷is hydrogen.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁶is selected from the group consisting of hydrogen and halogen. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁶is hydrogen. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁶is selected from the group consisting of fluoro and chloro. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁶is fluoro.

In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁷is selected from the group consisting of hydrogen, halogen, C_1-4alkyl and C_1-4alkoxy. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁷is selected from the group consisting of hydrogen, chloro, methyl, methoxy, ethoxy and isopropyloxy. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁷is hydrogen. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁷is chloro. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁷is methyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁷is selected from the group consisting of methoxy, ethoxy and isopropyloxy. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R⁷is methoxy.

In certain embodiments, the present invention is directed to compounds of formula (I-M)

[Image Omitted]

- wherein
- R¹is selected from the group consisting of halogen, hydroxy, C_1-4alkyl, fluorinated C_1-4alkyl, C_1-4alkoxy, fluorinated C_1-4alkoxy, cyano, nitro, —NR^AR^B—C(O)—C_1-4alkyl, C_3-6cycloalkyl, phenyl and 5 to 6 membered heterocyclyl;
- wherein the C_3-6cycloalkyl, phenyl or 5 to 6 membered heterocyclyl is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, cyano, C_1-4alkyl, fluorinated C_1-4alkyl, C_1-4alkoxy, fluorinated C_1-4alkoxy, —C(O)OH and —C(O)O—(C_1-4alkyl);
- and wherein R^Aand R^Bare each independently selected from the group consisting of hydrogen and C_1-4alkyl;
- a is an integer from 0 to 3;
- each R²is independently selected from the group consisting of chloro, fluoro, methyl and methoxy;
- R⁴is selected from the group consisting of
- (a) phenyl; wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated C_1-2alkoxy, —C(O)OH, —C(O)—O—(C_1-4alkyl), —NR^CR^D, —(C_1-2alkylene)-NR^CR^D, and —C(O)—NR^CR^D.
- wherein R^Cis selected from the group consisting of hydrogen, C_1-4alkyl, cyclopropyl, 3-hydroxy-cycloprop-1-yl, —C(O)—C_1-4alkyl, —C(O)-cyclopropyl, —C(O)—O—C_1-4alkyl; and R^Dis selected from the group consisting of hydrogen and C_1-4alkyl;
- and (b) 5 to 6 membered heterocyclyl; wherein the 5 membered heterocyclyl contains at least one heteroatom selected from the group consisting of O, N and S; optionally contains 1 to 3 additional heteroatoms independently selected from the group consisting of O, N and S; wherein the 5 membered heterocyclyl is saturated, partially unsaturated, or aromatic;
- and wherein the 5 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C_1-4alkyl, fluorinated C_1-4alkyl, C_1-4alkoxy, fluorinated C_1-4alkoxy, —C(O)OH, —C(O)—O—C_1-4alkyl, —NR^ER^F, and —C(O)—NR^ER^F; wherein R^Eis selected from the group consisting of hydrogen, C_1-4alkyl, cyclopropyl, 3-hydroxy-cycloprop-1-yl, —C(O)—C_1-4alkyl, —C(O)— cyclopropyl and —C(O)—O—C_1-4alkyl; and R^Fis selected from the group consisting of hydrogen and C_1-4alkyl;
- R⁵is selected from the group consisting of
- (a) C_1-4alkyl; wherein the C_1-4alkyl is optionally substituted with one or more halogen, and further optionally substituted with a substituent selected from the group consisting of hydroxy, C_1-4alkoxy, fluorinated C_1-4alkoxy, —C(O)OH, and —C(O)—O—(C_1-4alkyl);
- (b) —CH₂—C_3-8cycloalkyl; wherein the C_3-8cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen and C_1-4alkyl;
- (c) -L-(5 to 6 membered saturated heterocyclyl); wherein L¹is —CH₂—; and wherein the 5 to 6 membered saturated heterocyclyl is optionally substituted with one to two oxo groups;
- and (d) —C_1-2alkylene-phenyl; wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C_1-4alkyl, fluorinated C_1-4alkyl, C_1-4alkoxy, and fluorinated C_1-4alkoxy;
- R⁶and R⁷are each independently selected from the group consisting of hydrogen, halogen, C_1-4alkyl and C_1-4alkoxy; provided that at least one of R⁶or R⁷is hydrogen;
- or a stereoisomer, isotopologue, isotopomer, or pharmaceutically acceptable salt or solvate thereof.